|
1
|
Falconi-Sobrinho LL, Fonseca-Rodrigues D, da Silva ML, Coimbra NC, Pinto-Ribeiro F. Neuroanatomical and neurochemical substrates mediating fear-induced antinociception: A systematic review of rodent preclinical studies. Neurosci Biobehav Rev 2025; 168:105959. [PMID: 39613200 DOI: 10.1016/j.neubiorev.2024.105959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 11/06/2024] [Accepted: 11/25/2024] [Indexed: 12/01/2024]
Abstract
Fear-induced antinociception (FIA), an instinctive defensive response producing pain suppression in stressful and/or dangerous situations, has been the subject of extensive research to elucidate the mechanisms involved in triggering and controlling pain during emotional disorders. In this systematic review, we synthesized pre-clinical studies that demonstrated the neural hodology and the neurochemical bases of FIA in laboratory animals. The literature search in PubMed, Web of Science, Science Direct, and Scopus, from inception up to July 2022, retrieved 797 articles from which 50 studies were included in this review. This review highlights key encephalic regions implicated in the modulation of FIA, such as the prefrontal cortex, the amygdaloid complex, the hippocampus, the hypothalamus, the corpora quadrigemina, the periaqueductal gray matter, and some reticular formation nuclei. FIA-related neural pathways, neurotransmitters and neuromodulators such as glutamatergic, serotonergic, norepinephrine, GABAergic, nitrergic, opioidergic and endocannabinoid connections across these encephalic regions were also addressed. Understanding these neural circuits and molecular neural mediation sheds light on the complex interplay between fear, anxiety, and pain modulation, offering potential avenues for therapeutic interventions targeting pain management in the context of heightened emotional states.
Collapse
Affiliation(s)
- Luiz Luciano Falconi-Sobrinho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Gualtar Campus, Braga 4710-057, Portugal; ICVS/3B's-PT Government Associate Laboratory, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Guimarães, Portugal; Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL), Alfenas, Minas Gerais, Brazil; Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL), Alfenas, Brazil
| | - Diana Fonseca-Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Gualtar Campus, Braga 4710-057, Portugal; ICVS/3B's-PT Government Associate Laboratory, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Guimarães, Portugal
| | - Marcelo Lourenço da Silva
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL), Alfenas, Minas Gerais, Brazil; Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL), Alfenas, Brazil
| | - Norberto Cysne Coimbra
- Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
| | - Filipa Pinto-Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Gualtar Campus, Braga 4710-057, Portugal; ICVS/3B's-PT Government Associate Laboratory, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Guimarães, Portugal.
| |
Collapse
|
|
2
|
Choudhary AG, Awathale SN, Dudhabhate BB, Pawar N, Jadhav G, Upadhya MA, Khedkar T, Gadhikar YA, Sakharkar AJ, Subhedar NK, Kokare DM. Response of nitrergic system in the brain of rat conditioned to intracranial self-stimulation. J Neurochem 2024; 168:1402-1419. [PMID: 38445395 DOI: 10.1111/jnc.16090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 02/15/2024] [Accepted: 02/21/2024] [Indexed: 03/07/2024]
Abstract
The role of nitrergic system in modulating the action of psychostimulants on reward processing is well established. However, the relevant anatomical underpinnings and scope of the involved interactions with mesolimbic dopaminergic system have not been clarified. Using immunohistochemistry, we track the changes in neuronal nitric oxide synthase (nNOS) containing cell groups in the animals conditioned to intracranial self-stimulation (ICSS) via an electrode implanted in the lateral hypothalamus-medial forebrain bundle (LH-MFB) area. An increase in the nNOS immunoreactivity was noticed in the cells and fibers in the ventral tegmental area (VTA) and nucleus accumbens shell (AcbSh), the primary loci of the reward system. In addition, nNOS was up-regulated in the nucleus accumbens core (AcbC), vertical limb of diagonal band (VDB), locus coeruleus (LC), lateral hypothalamus (LH), superficial gray layer (SuG) of the superior colliculus, and periaqueductal gray (PAG). The brain tissue fragments drawn from these areas showed a change in nNOS mRNA expression, but in opposite direction. Intracerebroventricular (icv) administration of nNOS inhibitor, 7-nitroindazole (7-NI) showed decreased lever press activity in a dose-dependent manner in ICSS task. While an increase in the dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysates collected from the AcbSh of ICSS rats, pre-administration of 7-NI (icv route) attenuated the response. The study identifies nitrergic centers that probably mediate sensory, cognitive, and motor components of the goal-directed behavior.
Collapse
Affiliation(s)
- Amit G Choudhary
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
| | - Sanjay N Awathale
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
| | - Biru B Dudhabhate
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
| | - Namrata Pawar
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
| | - Gouri Jadhav
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
| | - Manoj A Upadhya
- Indian Institute of Science Education and Research (IISER), Pune, India
| | - Trupti Khedkar
- Department of Zoology, Nabira Mahavidyalay, Katol, India
| | - Yashashree A Gadhikar
- Department of Zoology, Government Vidarbha Institute of Science and Humanities, Amravati, India
| | - Amul J Sakharkar
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
| | | | - Dadasaheb M Kokare
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
| |
Collapse
|
|
3
|
Amini‐Khoei H, Tahmasebi‐Dehkordi H, Bijad E. Resocialization mitigates depressive behaviors induced by social isolation stress in mice: Attenuation of hippocampal neuroinflammation and nitrite level. Brain Behav 2024; 14:e3604. [PMID: 38898740 PMCID: PMC11187168 DOI: 10.1002/brb3.3604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 04/30/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND AND AIM Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well-established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP). METHODS We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open-field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)-1β, tumor necrosis factor (TNF), and toll-like receptor 4 (TLR4) in the HIP, were measured. RESULTS The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL-1β, TLR4, and TNF, along with a reduction in nitrite levels following resocialization. CONCLUSION These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.
Collapse
Affiliation(s)
- Hossein Amini‐Khoei
- Medical Plants Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| | - Hossein Tahmasebi‐Dehkordi
- Medical Plants Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| | - Elham Bijad
- Medical Plants Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| |
Collapse
|
|
4
|
Sun L, Wang X, Chen R, Dong X, Sun J, Dong C, Xie H, Gu X, Zhao C. Engineering organelle-specific activatable molecules for ultra-fast and reliable in situ mapping of subcellular nitric oxide. J Mater Chem B 2024; 12:2304-2312. [PMID: 38348949 DOI: 10.1039/d3tb02920d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Nitric oxide (NO), a ubiquitous gaseous transmitter in living systems, is closely associated with physiopathological processes in the endoplasmic reticulum and lysosomes. This free radical gas is very widely but very heterogeneously distributed in the biological microenvironment, which poses a great challenge to specifically detect its localized levels in certain subcellular regions. In this study, we proposed six subcellular targeting probes by rational molecular engineering and selected two probes with optimal performance for the precise spatiotemporal identification of endoplasmic reticulum (ER) and lysosomal NO fluctuations. The probes could rapidly undergo a N-nitrosation reaction with NO at a riveted subcellular location, blocking the initial photoinduced electron transfer (PET) process and generating bright fluorescence for precise mapping of NO in the ER and lysosomes. The screened probes have ultra-sensitive reactivity and ultra-low detection limits for NO, realizing the precise depiction of exogenous and endogenous NO in the corresponding subcellular area. Fluctuations in the subcellular levels of NO during inflammation were also successfully mapped by the probes. Our work will contribute to the accurate study of the physiological and pathological consequences of subcellular NO in various biological events.
Collapse
Affiliation(s)
- Lixin Sun
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Xinyu Wang
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Rui Chen
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Xuemei Dong
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Jie Sun
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Chengjun Dong
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| | - Haijiao Xie
- Hangzhou Yanqu Information Technology Co., Ltd, Y2, 2nd Floor, Building 2, Xixi Legu Creative Pioneering Park, No. 712 Wen'er West Road, Xihu District, Hangzhou, Zhejiang, 310003, P. R. China
| | - Xianfeng Gu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, P. R. China.
| | - Chunchang Zhao
- Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
| |
Collapse
|
|
5
|
Ali R, Sen S, Hameed R, Nazir A, Verma S. Strategies for gaseous neuromodulator release in chemical neuroscience: Experimental approaches and translational validation. J Control Release 2024; 365:132-160. [PMID: 37972768 DOI: 10.1016/j.jconrel.2023.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
Gasotransmitters are a group of short-lived gaseous signaling molecules displaying diverse biological functions depending upon their localized concentration. Nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) are three important examples of endogenously produced gasotransmitters that play a crucial role in human neurophysiology and pathogenesis. Alterations in their optimal physiological concentrations can lead to various severe pathophysiological consequences, including neurological disorders. Exogenous administration of gasotransmitters has emerged as a prominent therapeutic approach for treating such neurological diseases. However, their gaseous nature and short half-life limit their therapeutic delivery. Therefore, developing synthetic gasotransmitter-releasing strategies having control over the release and duration of these gaseous molecules has become imperative. However, the complex chemistry of synthesis and the challenges of specific quantified delivery of these gases, make their therapeutic application a challenging task. This review article provides a focused overview of emerging strategies for delivering gasotransmitters in a controlled and sustained manner to re-establish neurophysiological homeostasis.
Collapse
Affiliation(s)
- Rafat Ali
- Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India
| | - Shantanu Sen
- Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India
| | - Rohil Hameed
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Aamir Nazir
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, UP, India.
| | - Sandeep Verma
- Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India; Center for Nanoscience, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India; Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India.
| |
Collapse
|
|
6
|
Mendez-Encinas MA, Valencia D, Ortega-García J, Carvajal-Millan E, Díaz-Ríos JC, Mendez-Pfeiffer P, Soto-Bracamontes CM, Garibay-Escobar A, Alday E, Velazquez C. Anti-Inflammatory Potential of Seasonal Sonoran Propolis Extracts and Some of Their Main Constituents. Molecules 2023; 28:molecules28114496. [PMID: 37298970 DOI: 10.3390/molecules28114496] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Biological properties of Sonoran propolis (SP) are influenced by harvest time. Caborca propolis showed cellular protective capacity against reactive oxygen species, which might be implicated in anti-inflammatory effects. However, the anti-inflammatory activity of SP has not been investigated so far. This study investigated the anti-inflammatory activity of previously characterized seasonal SP extracts (SPE) and some of their main constituents (SPC). The anti-inflammatory activity of SPE and SPC was evaluated by measuring nitric oxide (NO) production, protein denaturation inhibition, heat-induced hemolysis inhibition, and hypotonicity-induced hemolysis inhibition. SPE from spring, autumn, and winter showed a higher cytotoxic effect on RAW 264.7 cells (IC50: 26.6 to 30.2 µg/mL) compared with summer extract (IC50: 49.4 µg/mL). SPE from spring reduced the NO secretion to basal levels at the lowest concentration tested (5 µg/mL). SPE inhibited the protein denaturation by 79% to 100%, and autumn showed the highest inhibitory activity. SPE stabilized erythrocyte membrane against heat-induced and hypotonicity-induced hemolysis in a concentration-dependent manner. Results indicate that the flavonoids chrysin, galangin, and pinocembrin could contribute to the anti-inflammatory activity of SPE and that the harvest time influences such a property. This study presents evidence of SPE pharmacological potential and some of their constituents.
Collapse
Affiliation(s)
- Mayra A Mendez-Encinas
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Dora Valencia
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Jesús Ortega-García
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Elizabeth Carvajal-Millan
- Research Center for Food and Development, CIAD, A.C. Carretera Gustavo Enrique Astiazaran Rosas No. 46, Hermosillo 83304, Mexico
| | - José C Díaz-Ríos
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Pablo Mendez-Pfeiffer
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Cinthia M Soto-Bracamontes
- Department of Chemical Biological and Agropecuary Sciences, University of Sonora, Avenida Universidad e Irigoyen, Caborca 83621, Mexico
| | - Adriana Garibay-Escobar
- Department of Chemistry-Biology, University of Sonora, Blvd. Luis Encinas y Rosales S/N, Hermosillo 83000, Mexico
| | - Efrain Alday
- Department of Chemistry-Biology, University of Sonora, Blvd. Luis Encinas y Rosales S/N, Hermosillo 83000, Mexico
| | - Carlos Velazquez
- Department of Chemistry-Biology, University of Sonora, Blvd. Luis Encinas y Rosales S/N, Hermosillo 83000, Mexico
| |
Collapse
|
|
7
|
Usategui-Martín R, Jiménez-Arribas P, Sakas-Gandullo C, González-Sarmiento R, Rodríguez-Arias CA. Endothelial nitric oxide synthase rs1799983 gene polymorphism is associated with the risk of developing intracranial aneurysm. Acta Neurochir (Wien) 2023; 165:1261-1267. [PMID: 36932233 DOI: 10.1007/s00701-023-05552-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/20/2023] [Indexed: 03/19/2023]
Abstract
PURPOSE The intracranial aneurysm (IA) rupture is associated with a subarachnoid hemorrhage. One third of patients die, and one third remain depend for daily activities. Genetic factors are crucial in the formation and clinical evolution of IAs. Multiple loci have been associated with AIs, much of them implicating multiple pathways related to vascular endothelial maintenance and extracellular matrix integrity. Thus, the aim of our study was to characterize whether polymorphisms in genes implicated in the vascular endothelial maintenance could modify the risk of developing IAs. SUBJECTS AND METHODS We have studied 176 patients with IA recruited in the Service of Neurosurgery at the University Hospital of Valladolid (Spain) and a control group if 150 sex-matched healthy subjects. Clinical variables were collected from each patient. We have analyzed VEGFA rs833061, VEGFR2 rs2071559, endothelin rs5370, endoglin rs3739817, and eNOS rs1799983 polymorphisms. RESULTS Our results showed that allele T of the eNOS rs1799983 polymorphism is correlated with decreased risk of developing the disease; thus, allele G of the eNOS rs1799983 polymorphism increased the risk of developing IA. CONCLUSION The association of eNOS rs1799983 polymorphism with the risk to suffer IA reinforces the hypothesis that genetic variants in eNOS gene could be crucial in the pathogenesis of IA.
Collapse
Affiliation(s)
- Ricardo Usategui-Martín
- Department of Cell Biology, Genetics, Histology and Pharmacology, University of Valladolid, Valladolid, Spain.,Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain.,Salamanca Institute of Biomedical Research (IBSAL), University Hospital of Salamanca-University of Salamanca, Salamanca, Spain
| | | | - Carmen Sakas-Gandullo
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain.,Salamanca Institute of Biomedical Research (IBSAL), University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.,Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | | |
Collapse
|
|
8
|
Haider AA, Rex TS, Wareham LK. cGMP Signaling in the Neurovascular Unit-Implications for Retinal Ganglion Cell Survival in Glaucoma. Biomolecules 2022; 12:1671. [PMID: 36421684 PMCID: PMC9687235 DOI: 10.3390/biom12111671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often progresses. Hence, effective clinical targets for the treatment of glaucoma remain elusive. Glaucoma shares comorbidities with a multitude of vascular diseases, and evidence in humans and animal models demonstrates an association between vascular dysfunction of the retina and glaucoma pathology. Integral to the survival of retinal ganglion cells (RGCs) is functional neurovascular coupling (NVC), providing RGCs with metabolic support in response to neuronal activity. NVC is mediated by cells of the neurovascular unit (NVU), which include vascular cells, glial cells, and neurons. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling is a prime mediator of NVC between endothelial cells and neurons, but emerging evidence suggests that cGMP signaling is also important in the physiology of other cells of the NVU. NO-cGMP signaling has been implicated in glaucomatous neurodegeneration in humans and mice. In this review, we explore the role of cGMP signaling in the different cell types of the NVU and investigate the potential links between cGMP signaling, breakdown of neurovascular function, and glaucoma pathology.
Collapse
Affiliation(s)
| | | | - Lauren K. Wareham
- Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37212, USA
| |
Collapse
|
|
9
|
Zhou L, Liu C, Zheng Y, Huang Z, Zhang X, Xiao Y. Bio-orthogonal Toolbox for Monitoring Nitric Oxide in Targeted Organelles of Live Cells and Zebrafishes. Anal Chem 2022; 94:15678-15685. [DOI: 10.1021/acs.analchem.2c02768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Lin Zhou
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Chuanhao Liu
- School of Medicine, Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Huaqiao University, Quanzhou 362021, China
| | - Ying Zheng
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Zhenlong Huang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Xinfu Zhang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Yi Xiao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| |
Collapse
|
|
10
|
Atukuri D, M R, M C, T A, Mujavar PH. Recent Update on the Pharmacological Significance of Isatis tinctoria L. (Brassicaceae) Extracts. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2021.1886126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Dorababu Atukuri
- SRMPP Govt. First Grade College, Huvinahadagali, Karnataka, India
| | - Rashmi M
- SRMPP Govt. First Grade College, Huvinahadagali, Karnataka, India
| | - Chandrashekhar M
- SRMPP Govt. First Grade College, Huvinahadagali, Karnataka, India
| | - Afreen T
- SRMPP Govt. First Grade College, Huvinahadagali, Karnataka, India
| | | |
Collapse
|
|
11
|
Ranjana M, Sunil D. Naphthalimide derivatives as fluorescent probes for imaging endogenous gasotransmitters. Chem Biol Interact 2022; 363:110022. [PMID: 35753358 DOI: 10.1016/j.cbi.2022.110022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/07/2022] [Accepted: 06/17/2022] [Indexed: 11/03/2022]
Abstract
Gasotransmitters have gained significant recognition attributed to their evident biological impacts, and is accepted as a promising and less-explored area with immense research scope. The three-member family comprising of nitric oxide, carbon monoxide and hydrogen sulphide as endogenous gaseous signaling molecules have been found to elicit a plethora of crucial biological functions, spawning a new research area. The sensing of these small molecules is vital to gain deeper insights into their functions, as they can act both as a friend or a foe in mammalian systems. The initial sections of the review present the physiological and pathophysiological roles of these endogenous gas transmitters and their synergistic interactions. Further, various detection approaches, especially the usage of fascinating features of 1,8-naphthalimide as fluorescent probe in the detection and monitoring of these small signaling molecules are highlighted. The current limitations and the future scope of improving the sensing of the three gasotransmitters are also discussed.
Collapse
Affiliation(s)
- M Ranjana
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India
| | - Dhanya Sunil
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India.
| |
Collapse
|
|
12
|
Melis MR, Argiolas A. Erectile Function and Sexual Behavior: A Review of the Role of Nitric Oxide in the Central Nervous System. Biomolecules 2021; 11:biom11121866. [PMID: 34944510 PMCID: PMC8699072 DOI: 10.3390/biom11121866] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 12/21/2022] Open
Abstract
Nitric oxide (NO), the neuromodulator/neurotransmitter formed from l-arginine by neuronal, endothelial and inducible NO synthases, is involved in numerous functions across the body, from the control of arterial blood pressure to penile erection, and at central level from energy homeostasis regulation to memory, learning and sexual behavior. The aim of this work is to review earlier studies showing that NO plays a role in erectile function and sexual behavior in the hypothalamus and its paraventricular nucleus and the medial preoptic area, and integrate these findings with those of recent studies on this matter. This revisitation shows that NO influences erectile function and sexual behavior in males and females by acting not only in the paraventricular nucleus and medial preoptic area but also in extrahypothalamic brain areas, often with different mechanisms. Most importantly, since these areas are strictly interconnected with the paraventricular nucleus and medial preoptic area, send to and receive neural projections from the spinal cord, in which sexual communication between brain and genital apparatus takes place, this review reveals that central NO participates in concert with neurotransmitters/neuropeptides to a neural circuit controlling both the consummatory (penile erection, copulation, lordosis) and appetitive components (sexual motivation, arousal, reward) of sexual behavior.
Collapse
|
|
13
|
Han B, Song M, Li L, Sun X, Lei Y. The Application of Nitric Oxide for Ocular Hypertension Treatment. Molecules 2021; 26:molecules26237306. [PMID: 34885889 PMCID: PMC8659272 DOI: 10.3390/molecules26237306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/18/2021] [Accepted: 11/25/2021] [Indexed: 12/21/2022] Open
Abstract
Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using ‘nitric oxide’ and ‘glaucoma’ as key words.
Collapse
|
|
14
|
Castro SA, Taylor ET, Tavares D, Filogonio R, Rodriges GJ, Leite CAC. Role of nitric oxide in the cardiovascular system of South American rattlesnakes (Crotalus durissus). Physiol Biochem Zool 2021; 95:168-182. [DOI: 10.1086/718292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
|
|
15
|
Prashar V, Arora T, Singh R, Sharma A, Parkash J. Interplay of KNDy and nNOS neurons: A new possible mechanism of GnRH secretion in the adult brain. Reprod Biol 2021; 21:100558. [PMID: 34509713 DOI: 10.1016/j.repbio.2021.100558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 08/25/2021] [Accepted: 08/28/2021] [Indexed: 02/07/2023]
Abstract
Reproduction in mammals is favoured when there is sufficient energy available to permit the survival of offspring. Neuronal nitric oxide synthase expressing neurons produce nitric oxide in the proximity of the gonadotropin-releasing hormone neurons in the preoptic region. nNOS neurons are an integral part of the neuronal network controlling ovarian cyclicity and ovulation. Nitric oxide can directly regulate the activity of the GnRH neurons and play a vital role neuroendocrine axis. Kisspeptin neurons are essential for the GnRH pulse and surge generation. The anteroventral periventricular nucleus (AVPV), kisspeptin neurons are essential for GnRH surge generation. KNDy neurons are present in the hypothalamus's arcuate nucleus (ARC), co-express NKB and dynorphin, essential for GnRH pulse generation. Kisspeptin-neurokinin B-dynorphin (KNDy) neuroendocrine molecules of the hypothalamus are key components in the central control of GnRH secretion. The hypothalamic neurons kisspeptin, KNDy, nitric oxide synthase (NOS), and other mediators such as leptin, adiponectin, and ghrelin, play an active role in attaining puberty. Kisspeptin signalling is mediated by NOS, which further results in the secretion of GnRH. Neuronal nitric oxide is critical for attaining puberty, but its direct role in adult GnRH secretion is poorly understood. This review mainly focuses on the role of nNOS and its interplay with KNDy neurons in the hormonal regulation of reproduction.
Collapse
Affiliation(s)
- Vikash Prashar
- Department of Zoology, School of Basic and Applied Sciences, Central University Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Tania Arora
- Department of Zoology, School of Basic and Applied Sciences, Central University Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Randeep Singh
- Department of Zoology, School of Basic and Applied Sciences, Central University Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Arti Sharma
- Department of Computational Biology, School of Basic and Applied Sciences, Central University Punjab, Ghudda, Bathinda, 151401, Punjab, India
| | - Jyoti Parkash
- Department of Zoology, School of Basic and Applied Sciences, Central University Punjab, Ghudda, Bathinda, 151401, Punjab, India.
| |
Collapse
|
|
16
|
Lim DW, Kim M, Yoon M, Lee J, Lee C, Um MY. 1,3-Dicaffeoylquinic Acid as an Active Compound of Arctium lappa Root Extract Ameliorates Depressive-Like Behavior by Regulating Hippocampal Nitric Oxide Synthesis in Ovariectomized Mice. Antioxidants (Basel) 2021; 10:antiox10081281. [PMID: 34439529 PMCID: PMC8389256 DOI: 10.3390/antiox10081281] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 01/31/2023] Open
Abstract
Menopause is a risk factor for depression. Although 1,3-dicaffeoylquinic acid (1,3-diCQA), a phenolic compound in Arctium lappa (A. lappa) root, has various health benefits, its effects on menopausal depression remain to be determined. Therefore, this study investigates the antidepressant-like effects of 1,3-diCQA from an A. lappa root extract (AE) and the associated molecular mechanisms. Ovariectomized (OVX) mice were orally administered AE for 20 weeks, following which depression-like behaviors were assessed. Although the mice exhibited depression-like behaviors, AE administration mitigated these symptoms by activating the ERK–CREB–BDNF pathway and increasing nNOS levels in the hippocampus. Similarly, a significant increase in nNOS-derived NO production and activation of the ERK–CREB–BDNF pathway was observed in the primary hippocampal neurons. Although this stimulatory effect of 1,3-diCQA was not significantly affected by treatment with estrogen receptor agonist or antagonist, it was inhibited by 7-NI, an nNOS inhibitor. Moreover, mice treated with 1,3-diCQA exhibited a marked improvement in their forced swimming test and tail suspension test immobility, while pretreatment with 7-NI reversed the antidepressant-like effects of 1,3-diCQA. Our results suggest that 1,3-diCQA regulates nNOS in an estrogen recepters-independent manner to increase NO production in OVX mice.
Collapse
Affiliation(s)
- Dong Wook Lim
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Korea; (D.W.L.); (M.Y.); (J.L.); (C.L.)
| | - Minji Kim
- Division of Food Biotechnology, University of Science and Technology, Daejeon 34113, Korea;
| | - Minseok Yoon
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Korea; (D.W.L.); (M.Y.); (J.L.); (C.L.)
| | - Jaekwang Lee
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Korea; (D.W.L.); (M.Y.); (J.L.); (C.L.)
| | - Changho Lee
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Korea; (D.W.L.); (M.Y.); (J.L.); (C.L.)
| | - Min Young Um
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Korea; (D.W.L.); (M.Y.); (J.L.); (C.L.)
- Division of Food Biotechnology, University of Science and Technology, Daejeon 34113, Korea;
- Correspondence: ; Tel.: +82-63-219-9409
| |
Collapse
|
|
17
|
Mohan S, Tiwari MN, Stanojević M, Biala Y, Yaari Y. Muscarinic regulation of the neuronal Na + /K + -ATPase in rat hippocampus. J Physiol 2021; 599:3735-3754. [PMID: 34148230 DOI: 10.1113/jp281460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/16/2021] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Stimulation of postsynaptic muscarinic receptors was shown to excite principal hippocampal neurons by modulating several membrane ion conductances. We show here that activation of postsynaptic muscarinic receptors also causes neuronal excitation by inhibiting Na+ /K+ -ATPase activity. Muscarinic Na+ /K+ -ATPase inhibition is mediated by two separate signalling pathways that lead downstream to enhanced Na+ /K+ -ATPase phosphorylation by activating protein kinase C and protein kinase G. Muscarinic excitation through Na+ /K+ -ATPase inhibition is probably involved in cholinergic modulation of hippocampal activity and may turn out to be a widespread mechanism of neuronal excitation in the brain. ABSTRACT Stimulation of muscarinic cholinergic receptors on principal hippocampal neurons enhances intrinsic neuronal excitability by modulating several membrane ion conductances. The electrogenic Na+ /K+ -ATPase (NKA; the 'Na+ pump') is a ubiquitous regulator of intrinsic neuronal excitability, generating a hyperpolarizing current to thwart excessive neuronal firing. Using electrophysiological and pharmacological methodologies in rat hippocampal slices, we show that neuronal NKA pumping activity is also subjected to cholinergic regulation. Stimulation of postsynaptic muscarinic, but not nicotinic, cholinergic receptors activates membrane-bound phospholipase C and hydrolysis of membrane-integral phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3 ). Along one signalling pathway, DAG activates protein kinase C (PKC). Along a second signalling pathway, IP3 causes Ca2+ release from the endoplasmic reticulum, facilitating nitric oxide (NO) production. The rise in NO levels stimulates cGMP synthesis by guanylate-cyclase, activating protein kinase G (PKG). The two pathways converge to cause partial NKA inhibition through enzyme phosphorylation by PKC and PKG, leading to a marked increase in intrinsic neuronal excitability. This novel mechanism of neuronal NKA regulation probably contributes to the cholinergic modulation of hippocampal activity in spatial navigation, learning and memory.
Collapse
Affiliation(s)
- Sandesh Mohan
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem, 91120, Israel
| | - Manindra Nath Tiwari
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem, 91120, Israel
| | - Marija Stanojević
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem, 91120, Israel
| | - Yoav Biala
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem, 91120, Israel
| | - Yoel Yaari
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem, 91120, Israel
| |
Collapse
|
|
18
|
Wei D, Wu D, Zeng W, Che L, Xu S, Fang Z, Feng B, Li J, Zhuo Y, Wu C, Zhang J, Lin Y. Arginine promotes testicular development in boars through nitric oxide and putrescine. J Anim Physiol Anim Nutr (Berl) 2021; 106:266-275. [PMID: 34212433 DOI: 10.1111/jpn.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 12/01/2022]
Abstract
The present work aimed to explore the influence and underlying mechanisms involving arginine in testicular development in boars. To this end, thirty 30-day-old male Duroc piglets (7.00 ± 0.30 kg) were randomly sorted into two groups, maintained on either a basal diet (CON, n = 15) or a diet supplemented with 0.8% arginine (ARG, n = 15). Blood and testicular samples were collected during the experimental period to analyse amino acid composition and arginine metabolite levels. The results showed that dietary supplementation with arginine increased number of spermatogonia and height of the seminiferous epithelium (p < 0.05). Sperm density, total number and effective number of sperm of the boars in the ARG group increased significantly compared with those in the CON group (p < 0.05). Although arginine supplementation did not affect plasma amino acid levels, testicular arginine levels in 150-day-old boars exhibited a significant increase (p < 0.05). The level of serum nitric oxide (NO) and activity of nitric oxide synthase (NOS) also increased in 150-day-old boars in the ARG group (p < 0.05). Interestingly, dietary supplementation with arginine increased testicular levels of putrescine in 150-day-old boars (p < 0.05). These results indicated that arginine supplementation increased serum NO levels and testicular arginine and putrescine abundance, thereby improving testicular development and semen quality in boars.
Collapse
Affiliation(s)
- Dongqin Wei
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - De Wu
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Wenxian Zeng
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Lianqiang Che
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Shengyu Xu
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Zhengfeng Fang
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Bin Feng
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Jian Li
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Yong Zhuo
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Caimei Wu
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Junjie Zhang
- School of Life Sciences, Sichuan Agricultural University, Ya'an, China
| | - Yan Lin
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed Science, Ministry of Agriculture, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Sichuan Agricultural University, Chengdu, China
| |
Collapse
|
|
19
|
Villar-Martínez MD, Moreno-Ajona D, Chan C, Goadsby PJ. Indomethacin-responsive headaches-A narrative review. Headache 2021; 61:700-714. [PMID: 34105154 DOI: 10.1111/head.14111] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Indomethacin is a nonsteroidal anti-inflammatory drug whose mechanism of action in certain types of headache disorders remains unknown. The so-called indomethacin-responsive headache disorders consist of a group of conditions with a very different presentation that have a particularly good response to indomethacin. The response is so distinct as to be used in the definition of two: hemicrania continua and paroxysmal hemicrania. METHODS This is a narrative literature review. PubMed and the Cochrane databases were used for the literature search. RESULTS We review the main pharmacokinetic and pharmacodynamics properties of indomethacin useful for daily practice. The proposed mechanisms of action of indomethacin in the responsive headache disorders, including its effect on cerebral blood flow and intracranial pressure, with special attention to nitrergic mechanisms, are covered. The current evidence for its use in primary headache disorders, such as some trigeminal autonomic cephalalgias, cough, hypnic, exertional or sexual headache, and migraine will be covered, as well as its indication for secondary headaches, such as those of posttraumatic origin. CONCLUSION Increasing understanding of the mechanism(s) of action of indomethacin will enhance our understanding of the complex pathophysiology that might be shared by indomethacin-sensitive headache disorders.
Collapse
Affiliation(s)
- Maria Dolores Villar-Martínez
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,Neurology, University of California, Los Angeles, Los Angeles, CA, USA
| | - David Moreno-Ajona
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,Neurology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Calvin Chan
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Peter J Goadsby
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,Neurology, University of California, Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
20
|
Mao YJ, Wu JB, Yang ZQ, Zhang YH, Huang ZJ. Nitric oxide donating anti-glaucoma drugs: advances and prospects. Chin J Nat Med 2021; 18:275-283. [PMID: 32402405 DOI: 10.1016/s1875-5364(20)30035-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Indexed: 12/11/2022]
Abstract
Glaucoma is a disease that causes irreversible blindness. Reducing intraocular pressure (IOP) is the main treatment at present. Nitric oxide (NO), an endogenous gas signaling molecule, can increase aqueous humor outflow facility, inhibit aqueous humor production thereby reducing IOP, as well as regulate eye blood flow and protect the optic nerve. Therefore, NO donating anti-glaucoma drugs have broad research prospects. In this review, we summarize NO-mediated therapy for glaucoma, and the state of the art of some NO donating molecules, including latanoprostene bunod in market and some other candidate compounds, for the intervention of glaucoma, as well as prospects and challenges ahead in this field.
Collapse
Affiliation(s)
- Yu-Jie Mao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Jian-Bing Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Ze-Qiu Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Yi-Hua Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Zhang-Jian Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
| |
Collapse
|
|
21
|
3-Nitrotyrosine and related derivatives in proteins: precursors, radical intermediates and impact in function. Essays Biochem 2020; 64:111-133. [PMID: 32016371 DOI: 10.1042/ebc20190052] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/22/2022]
Abstract
Oxidative post-translational modification of proteins by molecular oxygen (O2)- and nitric oxide (•NO)-derived reactive species is a usual process that occurs in mammalian tissues under both physiological and pathological conditions and can exert either regulatory or cytotoxic effects. Although the side chain of several amino acids is prone to experience oxidative modifications, tyrosine residues are one of the preferred targets of one-electron oxidants, given the ability of their phenolic side chain to undergo reversible one-electron oxidation to the relatively stable tyrosyl radical. Naturally occurring as reversible catalytic intermediates at the active site of a variety of enzymes, tyrosyl radicals can also lead to the formation of several stable oxidative products through radical-radical reactions, as is the case of 3-nitrotyrosine (NO2Tyr). The formation of NO2Tyr mainly occurs through the fast reaction between the tyrosyl radical and nitrogen dioxide (•NO2). One of the key endogenous nitrating agents is peroxynitrite (ONOO-), the product of the reaction of superoxide radical (O2•-) with •NO, but ONOO--independent mechanisms of nitration have been also disclosed. This chemical modification notably affects the physicochemical properties of tyrosine residues and because of this, it can have a remarkable impact on protein structure and function, both in vitro and in vivo. Although low amounts of NO2Tyr are detected under basal conditions, significantly increased levels are found at pathological states related with an overproduction of reactive species, such as cardiovascular and neurodegenerative diseases, inflammation and aging. While NO2Tyr is a well-established stable oxidative stress biomarker and a good predictor of disease progression, its role as a pathogenic mediator has been laboriously defined for just a small number of nitrated proteins and awaits further studies.
Collapse
|
|
22
|
Gladulich LFH, Peixoto-Rodrigues MC, Campello-Costa P, Paes-de-Carvalho R, Cossenza M. NMDA-induced nitric oxide generation and CREB activation in central nervous system is dependent on eukaryotic elongation factor 2 kinase. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118783. [DOI: 10.1016/j.bbamcr.2020.118783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/11/2020] [Accepted: 06/17/2020] [Indexed: 01/28/2023]
|
|
23
|
Gartside SE, Yurttaser AE, Burns AL, Jovanović N, Smith KJ, Amegashiti NS, Olthof BMJ. A role for nitric oxide in serotonin neurons of the midbrain raphe nuclei. Eur J Neurosci 2020; 51:1881-1899. [DOI: 10.1111/ejn.14713] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/03/2020] [Accepted: 02/25/2020] [Indexed: 01/24/2023]
Affiliation(s)
- Sarah E. Gartside
- Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
| | | | - Amy L. Burns
- Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
| | - Nebojša Jovanović
- Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
| | - Katie J. Smith
- Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
| | | | - Bas M. J. Olthof
- Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
| |
Collapse
|
|
24
|
Kumawat VS, Kaur G. Insulinotropic and antidiabetic effects of β-caryophyllene with l-arginine in type 2 diabetic rats. J Food Biochem 2020; 44:e13156. [PMID: 31997410 DOI: 10.1111/jfbc.13156] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/28/2019] [Accepted: 01/08/2020] [Indexed: 12/16/2022]
Abstract
Beta-caryophyllene (BCP) is a flavoring agent, whereas l-arginine (LA) is used as a food supplement. They possess insulinotropic and β cell regeneration activities, respectively. We assessed the antidiabetic potential of BCP, LA, and its combination in RIN-5F cell lines and diabetic rats. Ex vivo studies were carried out for glucose uptake and absorption of the combination of BCP with LA. The results indicated that the combination of BCP with LA showed a significant decrease in glucose absorption and an increase in its uptake in tissues and also an increase in insulin secretion in RIN-5F cells. The combination treatment of BCP with LA showed a significant reduction in glucose, lipid levels, and oxidative stress in pancreatic tissue when compared with the diabetic group. Furthermore, the combination of BCP with LA normalized glucose tolerance and pancreatic cell damage in diabetic rats. In conclusion, the combinational treatment showed significant potentials in the treatment of type 2 diabetes mellitus. PRACTICAL APPLICATIONS: Type 2 diabetes mellitus is the most prevalent chronic metabolic disorder affecting a large population. Beta-caryophyllene is a CB2 receptor agonist shown to have insulinotropic activity. l-Arginine is a food supplement that possesses beta-cell regeneration property. The combination of BCP with LA could work as a potential therapeutic intervention, considering the individual pharmacological activities of each. We evaluated the antidiabetic activity of the combination of BCP with LA in diabetic rats using ex vivo and in vitro experimentations. Results from the study revealed that the combination of BCP with LA showed a significant (p < .001) reduction in glucose and lipid levels as compared to individual treatment. In vitro study also supports the diabetic potential of the combination of BCP with LA in the glucose-induced insulin secretion in RIN-5F cell lines. The study indicates a therapeutic approach to treat T2DM by BCP and LA combination as food and dietary supplement.
Collapse
Affiliation(s)
- Vivek S Kumawat
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| | - Ginpreet Kaur
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| |
Collapse
|
|
25
|
Silver nanoparticles (Ag-NPs) in the central amygdala protect the rat conditioned by morphine from withdrawal attack due to naloxone via high-level nitric oxide. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:857-866. [PMID: 31897505 DOI: 10.1007/s00210-019-01784-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 11/28/2019] [Indexed: 10/25/2022]
Abstract
Repeated injection of morphine during conditioned place preference (CPP) leads to spatial craving due to high-level nitric oxide (NO) in the central nucleus of amygdala (CeA). Silver nanoparticles (Ag-NPs) can produce oxygen-free radicals that lead to NO formation. We aimed to show the Ag-NPs protective effect on naloxone (NLX)-induced morphine withdrawal in the conditioned rats. Wistar rats (300-350 g) were implanted with cannulae in the CeA. After recovery, they were randomly divided into experimental and saline groups. CPP was conducted by three-phase unbiased program. Morphine (0.5-7.5 mg/kg) was injected subcutaneously (s.c.) once/per day during the conditioning phase. Naloxone (NLX) (0.05-0.4 μg/rat) was given, intra-CeA, 10 min before the CPP test. Ag-NPs (0.0001-0.01 μg/rat) were administered alone or prior to the NLX effective dose (0.4 μg/rat), intra-CeA. Conditioning score and withdrawal signs (wet dog shaking and scratching) were obtained and compared with saline group data. All rats' brains were collected in formalin 10% and after 48-72 h stained with NADPH-diaphorase, the NO marker. All data were analyzed by one-way or two-way ANOVA. Morphine (2.5-7.5 mg/kg, s.c.) induced a significant CPP vs. saline (1 mL/kg, s.c.). The single Ag-NPs had no significant effect, whereas the NLX caused meaningful WDS and scratching. However, the NLX pre-treatment in combination with Ag-NPs eliminated these signs. Furthermore, the NO level increased in the CeA. The Ag-NPs may protect the morphine-conditioned rats against the NLX-induced withdrawal symptoms due to high-level NO in the CeA.
Collapse
|
|
26
|
Adebayo SA, Ondua M, Shai LJ, Lebelo SL. Inhibition of nitric oxide production and free radical scavenging activities of four South African medicinal plants. J Inflamm Res 2019; 12:195-203. [PMID: 31496781 PMCID: PMC6691489 DOI: 10.2147/jir.s199377] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 02/20/2019] [Indexed: 01/11/2023] Open
Abstract
Introduction Traditional healing is often the preferred form of therapy especially in rural and resource-limited communities. The extracts of plants are used to treat many diseases such as arthritis and chronic pain. Four medicinal plant species, namely, Acokanthera oppositifolia, Plantago lanceolata, Conyza canadensis and Artemisia vulgaris used in Southern Africa to treat pain and inflammation-related diseases were selected for evaluation in laboratory-based experiments. Methods The selected plant species were evaluated for phytochemical content, antioxidant and anti-inflammatory activities, as well as cytotoxicity effects against mammalian cells in culture. Results The results indicated that the n-hexane and chloroform extracts of P. lanceolata had the best antioxidant activities with an IC50=0.41 μg/mL. Also, the acetone extracts of P. lanceolata had 93.76% nitric oxide (NO) inhibition. However, the chloroform and n-hexane extracts of C. canadensis produced NO inhibition of 98.53% and 99.2%, respectively, at 100 μg/mL with IC50=17.69 μg/mL. Furthermore, the ethyl acetate extracts also had promising NO inhibitory activity (96.33%), but the cytotoxicity results with cell viabilities of 5.31%, 5.7% and 5.89%, respectively, suggested that the observed activity was due to a cytotoxic effect. Acetone extracts of C. canadensis were also cytotoxic at 30 µg/mL with 6.07–6.67% cell viabilities compared with the acetone extracts of P. lanceolata (99.57%). Conclusion The results partially validate the ethnomedicinal uses of the selected plant species used for inflammation-related conditions. However, because some of the extracts had potential cytotoxic effects, caution is advised in their use, especially those consumed orally.
Collapse
Affiliation(s)
- S A Adebayo
- Phytomedicine and Phytopharmacology Research Group, Department of Plant Sciences, University of the Free State, Phuthaditjhaba 9866, South Africa.,Department of Biomedical Sciences, Faculty of Science, Tshwane University of Technology, Pretoria 0001, South Africa
| | - M Ondua
- Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Onderstepoort 0110, South Africa
| | - L J Shai
- Department of Biomedical Sciences, Faculty of Science, Tshwane University of Technology, Pretoria 0001, South Africa
| | - S L Lebelo
- Department of Life and Consumer Sciences, University of South Africa, Florida 1710, South Africa
| |
Collapse
|
|
27
|
Picciano AL, Crane BR. A nitric oxide synthase-like protein from Synechococcus produces NO/NO 3- from l-arginine and NADPH in a tetrahydrobiopterin- and Ca 2+-dependent manner. J Biol Chem 2019; 294:10708-10719. [PMID: 31113865 PMCID: PMC6615690 DOI: 10.1074/jbc.ra119.008399] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/17/2019] [Indexed: 01/01/2023] Open
Abstract
Nitric oxide synthases (NOSs) are heme-based monooxygenases that convert l-Arg to l-citrulline and nitric oxide (NO), a key signaling molecule and cytotoxic agent in mammals. Bacteria also contain NOS proteins, but the role of NO production within these organisms, where understood, differs considerably from that of mammals. For example, a NOS protein in the marine cyanobacterium Synechococcus sp. PCC 7335 (syNOS) has recently been proposed to function in nitrogen assimilation from l-Arg. syNOS retains the oxygenase (NOSox) and reductase (NOSred) domains present in mammalian NOS enzymes (mNOSs), but also contains an N-terminal globin domain (NOSg) homologous to bacterial flavohemoglobin proteins. Herein, we show that syNOS functions as a dimer and produces NO from l-Arg and NADPH in a tetrahydrobiopterin (H4B)-dependent manner at levels similar to those produced by other NOSs but does not require Ca2+-calmodulin, which regulates NOSred-mediated NOSox reduction in mNOSs. Unlike other bacterial NOSs, syNOS cannot function with tetrahydrofolate and requires high Ca2+ levels (>200 μm) for its activation. NOSg converts NO to NO3- in the presence of O2 and NADPH; however, NOSg did not protect Escherichia coli strains against nitrosative stress, even in a mutant devoid of NO-protective flavohemoglobin. We also found that syNOS does not have NOS activity in E. coli (which lacks H4B) and that the recombinant protein does not confer growth advantages on l-Arg as a nitrogen source. Our findings indicate that syNOS has both NOS and NO oxygenase activities, requires H4B, and may play a role in Ca2+-mediated signaling.
Collapse
Affiliation(s)
- Angela L Picciano
- From the Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
| | - Brian R Crane
- From the Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
| |
Collapse
|
|
28
|
Chan JYH, Chan SHH. Differential impacts of brain stem oxidative stress and nitrosative stress on sympathetic vasomotor tone. Pharmacol Ther 2019; 201:120-136. [PMID: 31153955 DOI: 10.1016/j.pharmthera.2019.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
Abstract
Based on work-done in the rostral ventrolateral medulla (RVLM), this review presents four lessons learnt from studying the differential impacts of oxidative stress and nitrosative stress on sympathetic vasomotor tone and their clinical and therapeutic implications. The first lesson is that an increase in sympathetic vasomotor tone because of augmented oxidative stress in the RVLM is responsible for the generation of neurogenic hypertension. On the other hand, a shift from oxidative stress to nitrosative stress in the RVLM underpins the succession of increase to decrease in sympathetic vasomotor tone during the progression towards brain stem death. The second lesson is that, by having different cellular sources, regulatory mechanisms on synthesis and degradation, kinetics of chemical reactions, and downstream signaling pathways, reactive oxygen species and reactive nitrogen species should not be regarded as a singular moiety. The third lesson is that well-defined differential roles of oxidative stress and nitrosative stress with distinct regulatory mechanisms in the RVLM during neurogenic hypertension and brain stem death clearly denote that they are not interchangeable phenomena with unified cellular actions. Special attention must be paid to their beneficial or detrimental roles under a specific disease or a particular time-window of that disease. The fourth lesson is that, to be successful, future antioxidant therapies against neurogenic hypertension must take into consideration the much more complicated picture than that presented in this review on the generation, maintenance, regulation or modulation of the sympathetic vasomotor tone. The identification that the progression towards brain stem death entails a shift from oxidative stress to nitrosative stress in the RVLM may open a new vista for therapeutic intervention to slow down this transition.
Collapse
Affiliation(s)
- Julie Y H Chan
- Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
| | - Samuel H H Chan
- Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
| |
Collapse
|
|
29
|
Regulation of Neuronal Na +/K +-ATPase by Specific Protein Kinases and Protein Phosphatases. J Neurosci 2019; 39:5440-5451. [PMID: 31085608 DOI: 10.1523/jneurosci.0265-19.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/27/2019] [Accepted: 04/16/2019] [Indexed: 01/13/2023] Open
Abstract
The Na+/K+-ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na+ and K+ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic α subunit and/or associated proteins. In neurons, Na+/K+ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated.SIGNIFICANCE STATEMENT The Na+/K+-ATPase (NKA), known as the "Na+ pump," is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na+ and K+ electrochemical gradients across the plasma membrane of living cells. In neurons, as in most types of cells, the NKA generates the negative resting membrane potential, which is the basis for almost all aspects of cellular function. Here we used an electrophysiological approach to monitor physiological NKA transport activity in single hippocampal pyramidal cells in situ We have found that neuronal NKA activity is oppositely regulated by phosphorylation and dephosphorylation, and we have identified the main protein kinases and phosphatases mediating this regulation. This fundamental form of NKA regulation likely plays a role in multiple brain functions.
Collapse
|
|
30
|
Spiers JG, Chen HJC, Bourgognon JM, Steinert JR. Dysregulation of stress systems and nitric oxide signaling underlies neuronal dysfunction in Alzheimer's disease. Free Radic Biol Med 2019; 134:468-483. [PMID: 30716433 DOI: 10.1016/j.freeradbiomed.2019.01.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/19/2018] [Accepted: 01/21/2019] [Indexed: 12/12/2022]
Abstract
Stress is a multimodal response involving the coordination of numerous body systems in order to maximize the chance of survival. However, long term activation of the stress response results in neuronal oxidative stress via reactive oxygen and nitrogen species generation, contributing to the development of depression. Stress-induced depression shares a high comorbidity with other neurological conditions including Alzheimer's disease (AD) and dementia, often appearing as one of the earliest observable symptoms in these diseases. Furthermore, stress and/or depression appear to exacerbate cognitive impairment in the context of AD associated with dysfunctional catecholaminergic signaling. Given there are a number of homologous pathways involved in the pathophysiology of depression and AD, this article will highlight the mechanisms by which stress-induced perturbations in oxidative stress, and particularly NO signaling, contribute to neurodegeneration.
Collapse
Affiliation(s)
- Jereme G Spiers
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, 3083, Australia.
| | - Hsiao-Jou Cortina Chen
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia
| | | | - Joern R Steinert
- Department of Neuroscience, Psychology and Behavior, University of Leicester, Leicester, LE1 9HN, United Kingdom.
| |
Collapse
|
|
31
|
Nethi SK, Barui AK, Mukherjee S, Patra CR. Engineered Nanoparticles for Effective Redox Signaling During Angiogenic and Antiangiogenic Therapy. Antioxid Redox Signal 2019; 30:786-809. [PMID: 29943661 DOI: 10.1089/ars.2017.7383] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Redox signaling plays a vital role in regulating various cellular signaling pathways and disease biology. Recently, nanomedicine (application of nanotechnology in biology and medicine) has been demonstrated to regulate angiogenesis through redox signaling. A complete understanding of redox signaling pathways influenced angiogenesis/antiangiogenesis triggered by therapeutic nanoparticles is extensively reviewed in this article. Recent Advances: In recent times, nanomedicines are regarded as the Trojan horses that could be employed for successful drug delivery, gene delivery, peptide delivery, disease diagnosis, and others, conquering barriers associated with conventional theranostic approaches. CRITICAL ISSUES Physiological angiogenesis is a tightly regulated process maintaining a balance between proangiogenic and antiangiogenic factors. The redox signaling is one of the main factors that contribute to this physiological balance. An aberrant redox signaling cascade can be caused by several exogenous and endogenous factors and leads to reduced or augmented angiogenesis that ultimately results in several disease conditions. FUTURE DIRECTIONS Redox signaling-based nanomedicine approach has emerged as a new platform for angiogenesis-related disease therapy, where nanoparticles promote angiogenesis via controlled reactive oxygen species (ROS) production and antiangiogenesis by triggering excessive ROS formation. Recently, investigators have identified different efficient nano-candidates, which modulate angiogenesis by controlling intracellular redox molecules. Considering the importance of angiogenesis in health care a thorough understanding of nanomedicine-regulated redox signaling would inspire researchers to design and develop more novel nanomaterials that could be used as an alternative strategy for the treatment of various diseases, where angiogenesis plays a vital role.
Collapse
Affiliation(s)
- Susheel Kumar Nethi
- 1 Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,2 Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| | - Ayan Kumar Barui
- 1 Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,2 Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| | - Sudip Mukherjee
- 1 Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,2 Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| | - Chitta Ranjan Patra
- 1 Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,2 Academy of Scientific and Innovative Research (AcSIR), Chennai, India
| |
Collapse
|
|
32
|
Paul EJ, Kalk E, Tossell K, Irvine EE, Franks NP, Wisden W, Withers DJ, Leiper J, Ungless MA. nNOS-Expressing Neurons in the Ventral Tegmental Area and Substantia Nigra Pars Compacta. eNeuro 2018; 5:ENEURO.0381-18.2018. [PMID: 30456293 PMCID: PMC6240015 DOI: 10.1523/eneuro.0381-18.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/02/2018] [Indexed: 12/22/2022] Open
Abstract
GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.
Collapse
Affiliation(s)
- Eleanor J Paul
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Eliza Kalk
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Kyoko Tossell
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
| | - Elaine E Irvine
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Nicholas P Franks
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
| | - William Wisden
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
| | - Dominic J Withers
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - James Leiper
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Mark A Ungless
- MRC London Institute of Medical Sciences (LMS), London W12 0NN, United Kingdom
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
| |
Collapse
|
|
33
|
Abstract
INTRODUCTION Neuropathic pain (NP) is a particularly severe and intractable chronic condition that is not well treated by commonly recommended systemic pharmacological therapies, partly due to dose-limiting side effects or adverse events. The use of topical therapeutics for NP is growing and benefits from the reduced potential for adverse effects, as well as the ability to directly target peripheral pathological processes. AREAS COVERED The current review defines and describes the limitations of various commonly prescribed systemic pharmacological therapies for NP. It also provides a justification for increased research aimed at developing topical therapeutics for NP, particularly localized and peripheral NP. The review discusses the various classes of topical treatments used for NP, including agents that: block sensory inputs; activate inhibitory systems; provide mechanism-based therapeutics; are used in mucosal tissues; and include combinations that produce multimodal therapeutic effects. EXPERT OPINION There are arguments that the current topical therapeutics for NP rely too heavily on the use of local anesthetics and capsaicinoids, and more research is certainly needed on topical therapies that are multimodal and/or are targeted at the peripheral sources of pathology. The potential for novel topical therapeutics may be enhanced by further research on topical co-drugs, drug-drug salts, co-crystals and hydrates, and ionic liquids.
Collapse
Affiliation(s)
- Terence J Coderre
- a Depts. of Anesthesia, Neurology & Neurosurgery, and Psychology, and Division of Experimental Medicine , McGill University , Montreal , QC , Canada.,b McGill University Health Centre Research Institute , Montreal , QC , Canada
| |
Collapse
|
|
34
|
Horst BG, Marletta MA. Physiological activation and deactivation of soluble guanylate cyclase. Nitric Oxide 2018; 77:65-74. [PMID: 29704567 PMCID: PMC6919197 DOI: 10.1016/j.niox.2018.04.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 04/23/2018] [Accepted: 04/23/2018] [Indexed: 01/24/2023]
Abstract
Soluble guanylate cyclase (sGC) is responsible for transducing the gaseous signaling molecule nitric oxide (NO) into the ubiquitous secondary signaling messenger cyclic guanosine monophosphate in eukaryotic organisms. sGC is exquisitely tuned to respond to low levels of NO, allowing cells to respond to non-toxic levels of NO. In this review, the structure of sGC is discussed in the context of sGC activation and deactivation. The sequence of events in the activation pathway are described into a comprehensive model of in vivo sGC activation as elucidated both from studies with purified enzyme and those done in cells. This model is then used to discuss the deactivation of sGC, as well as the molecular mechanisms of pathophysiological deactivation.
Collapse
Affiliation(s)
- Benjamin G Horst
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
| | - Michael A Marletta
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
| |
Collapse
|
|
35
|
Falconi-Sobrinho LL, Coimbra NC. The Nitric Oxide Donor SIN-1-Produced Panic-Like Behaviour And Fear-Induced Antinociception Are Modulated By NMDA Receptors In The Anterior Hypothalamus. J Psychopharmacol 2018; 32:711-722. [PMID: 29737230 DOI: 10.1177/0269881118769061] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND An excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation elicits fear-related defensive reactions such as escape and freezing. In addition, these panic attack-like defensive reactions induced by hypothalamic neurons may cause antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic nucleus in these adaptive defensive mechanisms. Nitric oxide (NO) donors have been shown to evoke fear-related defensive responses when microinjected into paralimbic and limbic structures, and this excitatory neuromodulation can recruit the glutamatergic system. AIMS The aim of this work was to investigate the influence of the glutamatergic system in the nitrergic effects on fear-related defensive responses organised by anterior hypothalamic neurons. METHODS The present study evaluates the effects of the molsidomine active metabolite SIN-1 NO donor administered into the anterior hypothalamus (AH) of mice at different concentrations (75, 150 and 300 nmol/0.1 μL). Then, we investigated the effects of pre-treatment of the AH with AP-7 (an N-methyl-d-aspartate (NMDA) receptor-selective antagonist; 0.02, 0.2 and 2 nmol/0.1 μL) on the behavioural and antinociceptive effects provoked by AH chemical stimulation with SIN-1 microinjections. RESULTS The 300 nmol dose of SIN-1 was the most effective at causing panic-like defensive behaviours followed by a significant antinociceptive response. In addition, both of these effects were attenuated or inhibited by AH pre-treatment with AP-7. CONCLUSIONS These findings suggest that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on NMDA receptor activation.
Collapse
Affiliation(s)
- Luiz Luciano Falconi-Sobrinho
- 1 Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo, Brazil.,2 NAP-USP-Neurobiology of Emotions Research Centre, Ribeirão Preto Medical School of the University of São Paulo, Brazil.,3 Behavioural Neurosciences Institute, Ribeirão Preto, SP, Brazil
| | - Norberto Cysne Coimbra
- 1 Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo, Brazil.,2 NAP-USP-Neurobiology of Emotions Research Centre, Ribeirão Preto Medical School of the University of São Paulo, Brazil.,3 Behavioural Neurosciences Institute, Ribeirão Preto, SP, Brazil
| |
Collapse
|
|
36
|
Hacıoğlu C, KAR F, Kanbak G. Rat brain synaptosomes: In vitro neuroprotective effects of betaine against fluoride toxicity. ACTA ACUST UNITED AC 2018. [DOI: 10.17546/msd.421851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
37
|
Luo W, Tweedie D, Beedie SL, Vargesson N, Figg WD, Greig NH, Scerba MT. Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities. Bioorg Med Chem 2018; 26:1547-1559. [PMID: 29472124 PMCID: PMC5891396 DOI: 10.1016/j.bmc.2018.01.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/22/2018] [Accepted: 01/31/2018] [Indexed: 02/07/2023]
Abstract
A library of 15 novel and heretofore uncharacterized adamantyl and noradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF-α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.
Collapse
Affiliation(s)
- Weiming Luo
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - David Tweedie
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Shaunna L Beedie
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Neil Vargesson
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
| | - William D Figg
- Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nigel H Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
| | - Michael T Scerba
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| |
Collapse
|
|
38
|
Wareham LK, Buys ES, Sappington RM. The nitric oxide-guanylate cyclase pathway and glaucoma. Nitric Oxide 2018; 77:75-87. [PMID: 29723581 DOI: 10.1016/j.niox.2018.04.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/18/2018] [Accepted: 04/23/2018] [Indexed: 01/12/2023]
Abstract
Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca2+ channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions.
Collapse
Affiliation(s)
- Lauren K Wareham
- Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | | | - Rebecca M Sappington
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
| |
Collapse
|
|
39
|
Panthi S, Manandhar S, Gautam K. Hydrogen sulfide, nitric oxide, and neurodegenerative disorders. Transl Neurodegener 2018; 7:3. [PMID: 29456842 PMCID: PMC5810063 DOI: 10.1186/s40035-018-0108-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 01/31/2018] [Indexed: 12/12/2022] Open
Abstract
Hydrogen Sulfide (H2S) and Nitric Oxide (NO) have become recognized as important gaseous signaling molecules with enormous pharmacological effects, therapeutic value, and central physiological roles. NO is one of the most important regulators of the pathophysiological condition in central nervous system (CNS). It is critical in the various functioning of the brain; however, beyond certain concentration/level, it is toxic. H2S was regarded as toxic gas with the smell like rotten egg. But, it is now regarded as emerging neuroprotectant and neuromodulator. Recently, the use of donors and inhibitors of these signaling molecules have helped us to identify their accurate and precise biological effects. The most abundant neurotransmitter of CNS (glutamate) is the initiator of the reaction that forms NO, and H2S is highly expressed in brain. These molecules are shedding light on the pathogenesis of various neurological disorders. This review is mainly focused on the importance of H2S and NO for normal functioning of CNS.
Collapse
Affiliation(s)
- Sandesh Panthi
- Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | | | - Kripa Gautam
- China Medical University, Shenyang, People’s Republic of China
| |
Collapse
|
|
40
|
|
|
41
|
da Cunha Martins A, Carneiro MFH, Grotto D, Adeyemi JA, Barbosa F. Arsenic, cadmium, and mercury-induced hypertension: mechanisms and epidemiological findings. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2018; 21:61-82. [PMID: 29446707 DOI: 10.1080/10937404.2018.1432025] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Arsenic (As), cadmium (Cd), and mercury (Hg) are toxic elements widely distributed in the environment. Exposure to these elements was attributed to produce several acute and chronic illnesses including hypertension. The aim of this review is to provide a summary of the most frequently proposed mechanisms underlying hypertension associated with As, Cd, and Hg exposure including: oxidative stress, impaired nitric oxide (NO) signaling, modified vascular response to neurotransmitters and disturbed vascular muscle Ca2+ signaling, renal damage, and interference with the renin-angiotensin system. Due to the complexity of the vascular system, a combination rather than a singular mechanism needs to be considered. In addition, epidemiological findings showing the relationship between various biomarkers of metal exposure and hypertension are described. Given the complex etiology of hypertension, further epidemiological studies evaluating the roles of confounding factors such as age, gender, and life style are still necessary.
Collapse
Affiliation(s)
- Airton da Cunha Martins
- a Laboratório de Toxicologia e Essencialidade de Metais, Depto. de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto-SP , Brazil
| | - Maria Fernanda Hornos Carneiro
- a Laboratório de Toxicologia e Essencialidade de Metais, Depto. de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto-SP , Brazil
| | - Denise Grotto
- b Laboratório de Pesquisa em Toxicologia , Universidade de Sorocaba , Sorocaba-SP , Brazil
| | - Joseph A Adeyemi
- a Laboratório de Toxicologia e Essencialidade de Metais, Depto. de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto-SP , Brazil
| | - Fernando Barbosa
- a Laboratório de Toxicologia e Essencialidade de Metais, Depto. de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto-SP , Brazil
| |
Collapse
|
|
42
|
Dawson TM, Dawson VL. Nitric Oxide Signaling in Neurodegeneration and Cell Death. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 82:57-83. [PMID: 29413528 DOI: 10.1016/bs.apha.2017.09.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative diseases. NADPH diaphorase/nNOS neurons are resistant to neurotoxicity and neurodegeneration through the overexpression of manganese superoxide dismutase. The review also delves into the mechanisms by which NO kills neurons including NO's activation of the glyceraldehyde-3-phosphate dehydrogenase-dependent cell pathway. In addition, there is a review of parthanatos in which NO combines with the superoxide anion ( [Formula: see text] ) to form peroxynitrite (ONOO-) that damages DNA and activates poly (ADP-ribose) (PAR) polymerase (PARP). This ultimately leads to activation of the PARP-dependent apoptosis-inducing factor-associated nuclease, the final executioner in NO-dependent cell death. Finally, there is a discussion of potential targets that are under development that target the mechanisms by which NO kills neurons.
Collapse
Affiliation(s)
- Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Johns Hopkins University School of Medicine, Baltimore, MD, United States; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, United States; Diana Helis Henry Medical Research Foundation, New Orleans, LA, United States.
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Johns Hopkins University School of Medicine, Baltimore, MD, United States; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, United States; Diana Helis Henry Medical Research Foundation, New Orleans, LA, United States.
| |
Collapse
|
|
43
|
Gehring C, Turek IS. Cyclic Nucleotide Monophosphates and Their Cyclases in Plant Signaling. FRONTIERS IN PLANT SCIENCE 2017; 8:1704. [PMID: 29046682 PMCID: PMC5632652 DOI: 10.3389/fpls.2017.01704] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 09/19/2017] [Indexed: 05/19/2023]
Abstract
The cyclic nucleotide monophosphates (cNMPs), and notably 3',5'-cyclic guanosine monophosphate (cGMP) and 3',5'-cyclic adenosine monophosphate (cAMP) are now accepted as key signaling molecules in many processes in plants including growth and differentiation, photosynthesis, and biotic and abiotic defense. At the single molecule level, we are now beginning to understand how cNMPs modify specific target molecules such as cyclic nucleotide-gated channels, while at the systems level, a recent study of the Arabidopsis cNMP interactome has identified novel target molecules with specific cNMP-binding domains. A major advance came with the discovery and characterization of a steadily increasing number of guanylate cyclases (GCs) and adenylate cyclases (ACs). Several of the GCs are receptor kinases and include the brassinosteroid receptor, the phytosulfokine receptor, the Pep receptor, the plant natriuretic peptide receptor as well as a nitric oxide sensor. We foresee that in the near future many more molecular mechanisms and biological roles of GCs and ACs and their catalytic products will be discovered and further establish cNMPs as a key component of plant responses to the environment.
Collapse
Affiliation(s)
- Chris Gehring
- Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Ilona S. Turek
- Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
- Leibniz Institute of Plant Biochemistry, Halle, Germany
| |
Collapse
|
|
44
|
Lipina C, Hundal HS. The endocannabinoid system: 'NO' longer anonymous in the control of nitrergic signalling? J Mol Cell Biol 2017; 9:91-103. [PMID: 28130308 PMCID: PMC5439392 DOI: 10.1093/jmcb/mjx008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/18/2017] [Indexed: 12/18/2022] Open
Abstract
The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS–nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.
Collapse
Affiliation(s)
- Christopher Lipina
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, DundeeDD1 5EH, UK
| | - Harinder S Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, DundeeDD1 5EH, UK
| |
Collapse
|
|
45
|
Bath PMW, Krishnan K, Appleton JP. Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev 2017; 4:CD000398. [PMID: 28429459 PMCID: PMC6478181 DOI: 10.1002/14651858.cd000398.pub2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Nitric oxide (NO) has multiple effects that may be beneficial in acute stroke, including lowering blood pressure, and promoting reperfusion and cytoprotection. Some forms of nitric oxide synthase inhibition (NOS-I) may also be beneficial. However, high concentrations of NO are likely to be toxic to brain tissue. This is an update of a Cochrane review first published in 1998, and last updated in 2002. OBJECTIVES To assess the safety and efficacy of NO donors, L-arginine, and NOS-I in people with acute stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (last searched 6 February 2017), MEDLINE (1966 to June 2016), Embase (1980 to June 2016), ISI Science Citation Indexes (1981 to June 2016), Stroke Trials Registry (searched June 2016), International Standard Randomised Controlled Trial Number (ISRCTN) (searched June 2016), Clinical Trials registry (searched June 2016), and International Clinical Trials Registry Platform (ICTRP) (searched June 2016). Previously, we had contacted drug companies and researchers in the field. SELECTION CRITERIA Randomised controlled trials comparing nitric oxide donors, L-arginine, or NOS-I versus placebo or open control in people within one week of onset of confirmed stroke. DATA COLLECTION AND ANALYSIS Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. The review authors cross-checked data and resolved issues through discussion. We obtained published and unpublished data, as available. Data were reported as mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CI). MAIN RESULTS We included five completed trials, involving 4197 participants; all tested transdermal glyceryl trinitrate (GTN), an NO donor. The assessed risk of bias was low across the included studies; one study was double-blind, one open-label and three were single-blind. All included studies had blinded outcome assessment. Overall, GTN did not improve the primary outcome of death or dependency at the end of trial (modified Rankin Scale (mRS) > 2, OR 0.97, 95% CI 0.86 to 1.10, 4195 participants, high-quality evidence). GTN did not improve secondary outcomes, including death (OR 0.78, 95% CI 0.40 to 1.50) and quality of life (MD -0.01, 95% CI -0.17 to 0.15) at the end of trial overall (high-quality evidence). Systolic/diastolic blood pressure (BP) was lower in people treated with GTN (MD -7.2 mmHg (95% CI -8.6 to -5.9) and MD -3.3 (95% CI -4.2 to -2.5) respectively) and heart rate was higher (MD 2.0 beats per minute (95% CI 1.1 to 2.9)). Headache was more common in those randomised to GTN (OR 2.37, 95% CI 1.55 to 3.62). We did not find any trials assessing other nitrates, L-arginine, or NOS-I. AUTHORS' CONCLUSIONS There is currently insufficient evidence to recommend the use of NO donors, L-arginine or NOS-I in acute stroke, and only one drug (GTN) has been assessed. In people with acute stroke, GTN reduces blood pressure, increases heart rate and headache, but does not alter clinical outcome (all based on high-quality evidence).
Collapse
Affiliation(s)
- Philip MW Bath
- University of NottinghamStroke, Division of Clinical NeuroscienceCity Hospital CampusNottinghamUKNG5 1PB
| | - Kailash Krishnan
- University of NottinghamStroke, Division of Clinical NeuroscienceCity Hospital CampusNottinghamUKNG5 1PB
| | - Jason P Appleton
- University of NottinghamStroke, Division of Clinical NeuroscienceCity Hospital CampusNottinghamUKNG5 1PB
| | | |
Collapse
|
|
46
|
Restini CBA, Gonçalves L. Nitric Oxide and Related Aspects Underlying Angina. Open Cardiovasc Med J 2017; 11:33-46. [PMID: 28567132 PMCID: PMC5418930 DOI: 10.2174/1874192401711010033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/10/2017] [Accepted: 02/27/2017] [Indexed: 01/08/2023] Open
Abstract
Increased number of patients affected by metabolic syndrome (MS) has prompted the necessity of better understanding what is involved in such syndrome. Nevertheless, the establishment of promising therapies depends on the knowledge about the interaction of molecules within MS. In such context, Nitric Oxide (NO) emerges from a bulk of works relating its roles on aspects of MS, including cardiovascular diseases, their symptoms and comorbidities, which are thought to be triggered by similar sources. NO, nitric oxide synthase and enzymatic chains are keys for those disease and symptoms processes. NO has been separately described as part of hypertensive, ischemic and pain signaling. Although there are similar pathways likely shared for generating cardiovascular symptoms such angina, they are barely associated to NO in literature. The present review aims to clarify the patterns of NO alteration in metabolic syndrome directly concerned to cardiovascular symptoms, especially angina.
Collapse
Affiliation(s)
- Carolina Baraldi Araujo Restini
- Biotechnology Dept. (Lab: Cardiorenal Pharmacology)/Medical School, University of Ribeirao Preto (UNAERP), Ribeirão Preto-SP, Brazil
| | - Leticia Gonçalves
- Biotechnology Dept. (Lab: Cardiorenal Pharmacology)/Medical School, University of Ribeirao Preto (UNAERP), Ribeirão Preto-SP, Brazil
| |
Collapse
|
|
47
|
Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2017; 29:92-97. [DOI: 10.1016/j.arteri.2016.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 03/30/2016] [Accepted: 04/05/2016] [Indexed: 12/26/2022]
|
|
48
|
Freitas ACN, Silva GC, Pacheco DF, Pimenta AMC, Lemos VS, Duarte IDG, de Lima ME. The synthetic peptide PnPP-19 induces peripheral antinociception via activation of NO/cGMP/K ATP pathway: Role of eNOS and nNOS. Nitric Oxide 2017; 64:31-38. [PMID: 28087360 DOI: 10.1016/j.niox.2017.01.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 01/06/2017] [Accepted: 01/09/2017] [Indexed: 01/19/2023]
Abstract
BACKGROUND and purpose: The peptide PnPP-19, derived from the spider toxin PnTx2-6 (renamed as δ-CNTX-Pn1c), potentiates erectile function by activating the nitrergic system. Since NO has been studied as an antinociceptive molecule and PnPP-19 is known to induce peripheral antinociception, we intended to evaluate whether PnPP-19 could induce peripheral antinociception through activation of this pathway. EXPERIMENTAL APPROACH Nociceptive thresholds were measured by paw pressure test. PGE2 (2 μg/paw) was administered intraplantarly together with PnPP-19 and inhibitors/blockers of NOS, guanylyl cyclase and KATP channels. The nitrite concentration was accessed by Griess test. The expression and phosphorylation of eNOS and nNOS were determined by western blot. KEY RESULTS PnPP-19 (5, 10 and 20 μg/paw) induced peripheral antinociception in rats. Administration of NOS inhibitor (L-NOarg), selective nNOS inhibitor (L-NPA), guanylyl cyclase inhibitor (ODQ) and the blocker of KATP (glibenclamide) partially inhibited the antinociceptive effect of PnPP-19 (10 μg/paw). Tissue nitrite concentration increased after PnPP-19 (10 μg/paw) administration. Expression of eNOS and nNOS remained the same in all tested groups, however the phosphorylation of nNOS Ser852 (inactivation site) increased and phosphorylation of eNOS Ser1177 (activation site) decreased after PGE2 injection. Administration of PnPP-19 reverted this PGE2-induced effect. CONCLUSIONS AND IMPLICATIONS The peripheral antinociceptive effect induced by PnPP-19 is resulting from activation of NO-cGMP-KATP pathway. Activation of eNOS and nNOS might be required for such effect. Our results suggest PnPP-19 as a new drug candidate to treat pain and reinforce the importance of nNOS and eNOS activation, as well as endogenous NO release, for induction of peripheral antinociception.
Collapse
Affiliation(s)
- A C N Freitas
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - G C Silva
- Departamento Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - D F Pacheco
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil; Departamento Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - A M C Pimenta
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - V S Lemos
- Departamento Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - I D G Duarte
- Departamento Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil
| | - M E de Lima
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, M.G., Brazil.
| |
Collapse
|
|
49
|
Chen HS, Qi SH, Shen JG. One-Compound-Multi-Target: Combination Prospect of Natural Compounds with Thrombolytic Therapy in Acute Ischemic Stroke. Curr Neuropharmacol 2017; 15:134-156. [PMID: 27334020 PMCID: PMC5327453 DOI: 10.2174/1570159x14666160620102055] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 04/21/2016] [Accepted: 06/15/2016] [Indexed: 12/11/2022] Open
Abstract
Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seem not to be satisfied, and a multitarget strategy is warranted to resolve such complex disease. Recently, large amount of efforts have been made to explore the active compounds from herbal supplements to treat ischemic stroke. Some natural compounds revealed both neuro- and bloodbrain- barrier (BBB)-protective effects by concurrently targeting multiple cellular signaling pathways in cerebral ischemia-reperfusion injury. Thus, those compounds are potential to be one-drug-multi-target agents as combined therapy with t-PA for ischemic stroke. In this review article, we summarize current progress about molecular targets involving in t-PA-mediated HT and neurotoxicity in ischemic brain injury. Based on these targets, we select 23 promising compounds from currently available literature with the bioactivities simultaneously targeting several important molecular targets. We propose that those compounds merit further investigation as combined therapy with t-PA. Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important issues to be addressed in the future for the development of natural compound as an adjunct therapy.
Collapse
Affiliation(s)
- Han-Sen Chen
- School of Chinese Medicine, The University of Hong Kong, Hong Kong S.A.R, P. R China
- The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China
| | - Su-Hua Qi
- Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, China
| | - Jian-Gang Shen
- School of Chinese Medicine, The University of Hong Kong, Hong Kong S.A.R, P. R China
- The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China
| |
Collapse
|
|
50
|
Karanth S, Yu WH, Mastronardi CA, McCann SM. Inhibition of Stimulated Ascorbic Acid and Luteinizing Hormone-Releasing Hormone Release by Nitric Oxide Synthase or Guanyl Cyclase Inhibitors. Exp Biol Med (Maywood) 2016; 229:72-9. [PMID: 14709779 DOI: 10.1177/153537020422900109] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Ascorbic acid (AA), an antioxidant, is present in high concentrations in the hypothalamus. Previously, we have shown that AA inhibited stimulated release of luteinizing hormone-releasing hormone (LHRH) from medial basal hypothalami in vitro. We have also demonstrated that cell membrane depolarization by high [K+] media-induced AA release that is blocked by NG-monomethyl-l-arginine, a competitive inhibitor of nitric oxide synthase (NOS), indicating that the release process is mediated by NO. The release of LHRH is also mediated by NO. We hypothesized that AA is a co-transmitter released with classical transmitters from synaptic vesicles that acts to reduce chemically the NO formed, thereby providing feed-forward inhibitory control over LHRH release. Because NO acts by activating guanylyl cyclase (GC) resulting in production of cGMP, in the present investigation we studied the effects of an NOS inhibitor LY 83583 and GC inhibitor, O.D.Q. to further characterize the role of NO in high [K+]-induced AA and LHRH release. Medial basal hypothalami were incubated in 0.5 ml of Krebs-Ringer Bicarbonate buffer or medium containing increased potassium [K+ = 56 mM] for 1 hr or combinations of high [K+] + LY 83583 or O.D.Q. for 1 hr. AA and LHRH released into the incubation medium were measured by high-pressure liquid chromatography and radioimmunoassay, respectively. Cell membrane depolarization with high [K+] produced a significant increase in both AA and LHRH release. A combination of high [K+] + LY 83583 or high [K+] + O.D.Q. decreased basal AA and completely blocked high [K+]-induced AA and LHRH release. As in the case of high [K+], LHRH release induced by the excitatory amino acid N-methyl-d-aspartic acid (NMDA) was blocked by both the inhibitors. NMDA alone failed to alter AA release, but the combined presence of NMDA and the inhibitors totally blocked AA release. Because LY 83583 and O.D.Q. were shown to inhibit NOS and soluble GC, respectively, the data demonstrate that basal and high [K+]-induced AA and high [K+] and NMDA-stimulated LHRH release were mediated by NO by its activation of GC and consequent generation of cGMP.
Collapse
Affiliation(s)
- Sharada Karanth
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808-4124, USA
| | | | | | | |
Collapse
|