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Sun Y, Zhou D, Liu A, Zhou Y, Zhao Y, Yuan Y, Guo W, Li J. Liangxue Tongyu Prescription exerts neuroprotection by regulating the microbiota-gut-brain axis of rats with acute intracerebral hemorrhage. Brain Res Bull 2025; 220:111186. [PMID: 39746523 DOI: 10.1016/j.brainresbull.2024.111186] [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: 11/07/2024] [Revised: 12/21/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Liangxue Tongyu Prescription (LTP) is a classic herbal formula for treating acute intracerebral hemorrhage (AICH) in China. Previous studies have shown that LTP significantly ameliorates neurological impairments and gastrointestinal dysfunction in patients with AICH. However, the underlying molecular mechanism remains unclear. The aim of this study is to investigate whether LTP exerts its neuroprotective effect on AICH rats through the microbiota-gut-brain axis and explore its potential underlying mechanism. In the current study, AICH models were established by injecting autologous whole blood into the right caudate nucleus of rats. Behavioural and pathological evaluations demonstrated that LTP ameliorated neuronal and intestinal damage in AICH rats. Analysis via western blot, quantitative real-time PCR, immunohistochemistry (IHC) and tunel staining indicated that LTP upregulated the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor(NGF) and reduced neuronal cell apoptosis. Additionally, 16S rDNA sequencing revealed that LTP mitigated dysbiosis of intestinal microbiota in AICH rats. LTP increased the levels of noradrenaline (NA), dopamine (DA), glutamate (GLU) and modulated brain-gut peptides such as gastrin (GAS), motilin (MTL), ghrelin in AICH rats. Furthermore, LTP enhanced vagus nerve discharge. In summary, this research provides evidence suggesting that LTP's influence on AICH may involve modulation of the microbiota-gut-brain axis, offering a potential scientific rationale for its therapeutic efficacy in improving outcomes of AICH.
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Affiliation(s)
- Yingying Sun
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Dandan Zhou
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Anlan Liu
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yu Zhou
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yang Zhao
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yuan Yuan
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
| | - Weifeng Guo
- First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
| | - Jianxiang Li
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, China.
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Sikiric P, Skrtic A, Gojkovic S, Krezic I, Zizek H, Lovric E, Sikiric S, Knezevic M, Strbe S, Milavic M, Kokot A, Blagaic AB, Seiwerth S. Cytoprotective gastric pentadecapeptide BPC 157 resolves major vessel occlusion disturbances, ischemia-reperfusion injury following Pringle maneuver, and Budd-Chiari syndrome. World J Gastroenterol 2022; 28:23-46. [PMID: 35125818 PMCID: PMC8793015 DOI: 10.3748/wjg.v28.i1.23] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/14/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
The stable gastric pentadecapeptide BPC 157 counteracts various venous occlusion-induced syndromes. Summarized are all these arguments, in the Robert's cytoprotection concept, to substantiate the resolution of different major vessel occlusion disturbances, in particular ischemia-reperfusion injury following the Pringle maneuver and Budd-Chiari syndrome, which was obtained by BPC 157 therapy. Conceptually, there is a new point, namely, endothelium maintenance to epithelium maintenance (the recruitment of collateral blood vessels to compensate for vessel occlusion and reestablish blood flow or bypass the occluded or ruptured vessel). In this paper, we summarize the evidence of the native cytoprotective gastric pentadecapeptide BPC 157, which is stable in the human gastric juice, is a membrane stabilizer and counteracts gut-leaky syndrome. As a particular target, it is distinctive from the standard peptide growth factors, involving particular molecular pathways and controlling VEGF and NO pathways. In the early 1990s, BPC 157 appeared as a late outbreak of the Robert's and Szabo's cytoprotection-organoprotection concept, like the previous theoretical/practical breakthrough in the 1980s and the brain-gut axis and gut-brain axis. As the time went on, with its reported effects, it is likely most useful theory practical implementation and justification. Meantime, several reviews suggest that BPC 157, which does not have a lethal dose, has profound cytoprotective activity, used to be demonstrated in ulcerative colitis and multiple sclerosis trials. Likely, it may bring the theory to practical application, starting with the initial argument, no degradation in human gastric juice for more than 24 h, and thereby, the therapeutic effectiveness (including via a therapeutic per-oral regimen) and pleiotropic beneficial effects.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine Osijek, J.J.Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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Zhang Q, Huang L, Leng B, Li Y, Jiao N, Jiang S, Yang W, Yuan X. Zearalenone Affect the Intestinal Villi Associated with the Distribution and the Expression of Ghrelin and Proliferating Cell Nuclear Antigen in Weaned Gilts. Toxins (Basel) 2021; 13:toxins13100736. [PMID: 34679029 PMCID: PMC8537219 DOI: 10.3390/toxins13100736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/10/2021] [Accepted: 10/15/2021] [Indexed: 01/17/2023] Open
Abstract
This study explored and investigated how zearalenone (ZEA) affects the morphology of small intestine and the distribution and expression of ghrelin and proliferating cell nuclear antigen (PCNA) in the small intestine of weaned gilts. A total of 20 weaned gilts (42-day-old, D × L × Y, weighing 12.84 ± 0.26 kg) were divided into the control and ZEA groups (ZEA at 1.04 mg/kg in diet) in a 35-d study. Histological observations of the small intestines revealed that villus injuries of the duodenum, jejunum and ileum, such as atrophy, retardation and branching dysfunction, were observed in the ZEA treatment. The villi branch of the ileum in the ZEA group was obviously decreased compared to that of the ileum, jejunum and duodenum, and the number of lymphoid nodules of the ileum was increased. Additionally, the effect of ZEA (1.04 mg/kg) was decreased by the immunoreactivity and distribution of ghrelin and PCNA in the duodenal and jejunal mucosal epithelial cells. Interestingly, ZEA increased the immunoreactivity of ghrelin in the ileal mucosal epithelial cells and decreased the immunoreactivity expression of PCNA in the gland epithelium of the small intestine. In conclusion, ZEA (1.04 mg/kg) had adverse effects on the development and the absorptive capacity of the villi of the intestines; yet, the small intestine could resist or ameliorate the adverse effects of ZEA by changing the autocrine of ghrelin in intestinal epithelial cells.
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Affiliation(s)
- Quanwei Zhang
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Libo Huang
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Bo Leng
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Yang Li
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Ning Jiao
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Shuzhen Jiang
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
| | - Weiren Yang
- College of Animal Sciences and Technology, Shandong Agricultural University, Tai’an City 271018, China; (Q.Z.); (L.H.); (B.L.); (Y.L.); (N.J.); (S.J.)
- Correspondence: (W.Y.); (X.Y.); Tel.: +86-186-0548-9796 (W.Y.); +86-134-7538-6175 (X.Y.)
| | - Xuejun Yuan
- College of Life Sciences, Shandong Agricultural University, Tai’an City 271018, China
- Correspondence: (W.Y.); (X.Y.); Tel.: +86-186-0548-9796 (W.Y.); +86-134-7538-6175 (X.Y.)
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Gut Hormones as Potential Therapeutic Targets or Biomarkers of Response in Depression: The Case of Motilin. Life (Basel) 2021; 11:life11090892. [PMID: 34575041 PMCID: PMC8465535 DOI: 10.3390/life11090892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/22/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Recent research has identified the gut–brain axis as a key mechanistic pathway and potential therapeutic target in depression. In this paper, the potential role of gut hormones as potential treatments or predictors of response in depression is examined, with specific reference to the peptide hormone motilin. This possibility is explored through two methods: (1) a conceptual review of the possible links between motilin and depression, including evidence from animal and human research as well as clinical trials, based on a literature search of three scientific databases, and (2) an analysis of the relationship between a functional polymorphism (rs2281820) of the motilin (MLN) gene and cross-national variations in the prevalence of depression based on allele frequency data after correction for potential confounders. It was observed that (1) there are several plausible mechanisms, including interactions with diet, monoamine, and neuroendocrine pathways, to suggest that motilin may be relevant to the pathophysiology and treatment of depression, and (2) there was a significant correlation between rs2281820 allele frequencies and the prevalence of depression after correcting for multiple confounding factors. These results suggest that further evaluation of the utility of motilin and related gut peptides as markers of antidepressant response is required and that these molecular pathways represent potential future mechanisms for antidepressant drug development.
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Du GM, Luo BP, Hu ZH, Wu JG, Yan WM, Han ZQ, Zhang YH, Liu MJ. The effect of ghrelin O-acyltransferase inhibitor on gastric H +-K +-ATPase activity and GOAT/ghrelin system in gastric mucosal cells in vitro. Gen Comp Endocrinol 2018; 267:167-171. [PMID: 29966658 DOI: 10.1016/j.ygcen.2018.06.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/22/2018] [Accepted: 06/29/2018] [Indexed: 11/25/2022]
Abstract
Ghrelin is implicated in the regulation of gastric functional development. The octanoylation of ghrelin is critical for its physiological functions which dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. To investigate the effect of GOAT on gastric acid secretion and expression of ghrelin in vitro. Primary cultures of gastric mucosal cells were challenged with 1.5 × 10-5, 1.5 × 10-4 and 1.5 × 10-3 mol/mL GO-CoA-Tat (The GOAT inhibitor), respectively, for 24 h in order to further clarify the effect of GOAT on H+-K+-ATPase activity. In vitro, GO-CoA-Tat significantly increased ghrelin and GOAT mRNA expression at 1.5 × 10-5, 1.5 × 10-4 and 1.5 × 10-3 mol/mL, and augmented cell total ghrelin secretion at 1.5 × 10-3 mol/mL. But cell acylated ghrelin secretion was reduced at 1.5 × 10-3 mol/mL GO-CoA-Tat (P < 0.05). And cell acylated ghrelin synthesis was reduced at 1.5 × 10-4 and 1.5 × 10-3 mol/mL GO-CoA-Tat (P < 0.05). In accordance with acylated ghrelin level, H+-K+-ATPase activity were decreased with 1.5 × 10-4 and 1.5 × 10-3 mol/mL GO-CoA-Tat (P < 0.05). These results indicated that GOAT inhibitor decreases the acylated ghrelin level and H+-K+-ATPase activity in vitro.
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Affiliation(s)
- Gai Mei Du
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Bi Ping Luo
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Zhi Hua Hu
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Jie Ge Wu
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Wen Mei Yan
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Zheng Qiang Han
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Yu Hong Zhang
- Department of Animal Science and Technology, Jinling Technology Institution, Nanjing 210038, PR China
| | - Mao Jun Liu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, PR China; Key Lab of Food Quality and Safety of Jiangsu Province-State Key Laboratory Breeding Base, Nanjing, PR China.
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Romański KW. Importance of the enteric nervous system in the control of the migrating motility complex. Physiol Int 2017; 104:97-129. [PMID: 28665193 DOI: 10.1556/2060.104.2017.2.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The migrating motility complex (MMC), a cyclical phenomenon, represents rudimentary motility pattern in the gastrointestinal tract. The MMC is observed mostly in the stomach and gut of man and numerous animal species. It contains three or four phases, while its phase III is the most characteristic. The mechanisms controlling the pattern are unclear in part, although the neural control of the MMC seems crucial. The main goal of this article was to discuss the importance of intrinsic innervation of the gastrointestinal tract in MMC initiation, migration, and cessation to emphasize that various MMC-controlling mechanisms act through the enteric nervous system. Two main neural regions, central and peripheral, are able to initiate the MMC. However, central regulation of the MMC may require cooperation with the enteric nervous system. When central mechanisms are not active, the MMC can be initiated peripherally in any region of the small bowel. The enteric nervous system affects the MMC in response to the luminal stimuli which can contribute to the initiation and cessation of the cycle, and it may evoke irregular phasic contractions within the pattern. The hormonal regulators released from the endocrine cells may exert a modulatory effect upon the MMC mostly through the enteric nervous system. Their central action could also be considered. It can be concluded that the enteric nervous system is involved in the great majority of the MMC-controlling mechanisms.
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Affiliation(s)
- K W Romański
- 1 Department of Animal Physiology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences , Wrocław, Poland
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Zan J, Song L, Wang J, Zou R, Hong F, Zhao J, Cheng Y, Xu M. Role of ghrelin in small intestinal motility following pediatric intracerebral hemorrhage in mice. Mol Med Rep 2017; 16:6958-6966. [DOI: 10.3892/mmr.2017.7468] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 04/25/2017] [Indexed: 11/06/2022] Open
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Cheng Y, Wei Y, Yang W, Cai Y, Chen B, Yang G, Shang H, Zhao W. Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice. Int J Mol Sci 2016; 17:ijms17122032. [PMID: 27929421 PMCID: PMC5187832 DOI: 10.3390/ijms17122032] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/10/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy.
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Affiliation(s)
- Yijun Cheng
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yongxu Wei
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Wenlei Yang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yu Cai
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Bin Chen
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Guoyuan Yang
- Department of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Hanbing Shang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Weiguo Zhao
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Sim YB, Park SH, Kim SS, Kim CH, Kim SJ, Lim SM, Jung JS, Suh HW. Ghrelin administered spinally increases the blood glucose level in mice. Peptides 2014; 54:162-5. [PMID: 24472858 DOI: 10.1016/j.peptides.2014.01.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 01/17/2014] [Accepted: 01/17/2014] [Indexed: 02/07/2023]
Abstract
Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 μg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 μg) markedly attenuated ghrelin-induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 μg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level.
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Affiliation(s)
- Yun-Beom Sim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Soo-Hyun Park
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Sung-Su Kim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Chea-Ha Kim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Su-Jin Kim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Su-Min Lim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Jun-Sub Jung
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
| | - Hong-Won Suh
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 39 Hallymdaehak-gil, Chuncheon, Gangwon-do 200-702, Republic of Korea.
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