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1
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Grizzi F, Hegazi MA. Functional foods and celiac disease prevalent in North America and globally. FUNCTIONAL FOODS AND CHRONIC DISEASE 2024:105-114. [DOI: 10.1016/b978-0-323-91747-6.00006-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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2
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Triantopoulou N, Vidaki M. Local mRNA translation and cytoskeletal reorganization: Mechanisms that tune neuronal responses. Front Mol Neurosci 2022; 15:949096. [PMID: 35979146 PMCID: PMC9376447 DOI: 10.3389/fnmol.2022.949096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/07/2022] [Indexed: 12/31/2022] Open
Abstract
Neurons are highly polarized cells with significantly long axonal and dendritic extensions that can reach distances up to hundreds of centimeters away from the cell bodies in higher vertebrates. Their successful formation, maintenance, and proper function highly depend on the coordination of intricate molecular networks that allow axons and dendrites to quickly process information, and respond to a continuous and diverse cascade of environmental stimuli, often without enough time for communication with the soma. Two seemingly unrelated processes, essential for these rapid responses, and thus neuronal homeostasis and plasticity, are local mRNA translation and cytoskeletal reorganization. The axonal cytoskeleton is characterized by high stability and great plasticity; two contradictory attributes that emerge from the powerful cytoskeletal rearrangement dynamics. Cytoskeletal reorganization is crucial during nervous system development and in adulthood, ensuring the establishment of proper neuronal shape and polarity, as well as regulating intracellular transport and synaptic functions. Local mRNA translation is another mechanism with a well-established role in the developing and adult nervous system. It is pivotal for axonal guidance and arborization, synaptic formation, and function and seems to be a key player in processes activated after neuronal damage. Perturbations in the regulatory pathways of local translation and cytoskeletal reorganization contribute to various pathologies with diverse clinical manifestations, ranging from intellectual disabilities (ID) to autism spectrum disorders (ASD) and schizophrenia (SCZ). Despite the fact that both processes are essential for the orchestration of pathways critical for proper axonal and dendritic function, the interplay between them remains elusive. Here we review our current knowledge on the molecular mechanisms and specific interaction networks that regulate and potentially coordinate these interconnected processes.
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Affiliation(s)
- Nikoletta Triantopoulou
- Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (IMBB-FORTH), Heraklion, Greece
| | - Marina Vidaki
- Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (IMBB-FORTH), Heraklion, Greece
- *Correspondence: Marina Vidaki,
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Abstract
This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review.
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Affiliation(s)
- Stuart Stokes
- Spinal Unit, Department of Neurosurgery, Hull Royal Infirmary, Hull, UK
| | - Martin Drozda
- Spinal Unit, Department of Neurosurgery, Hull Royal Infirmary, Hull, UK
| | - Christopher Lee
- Spinal Unit, Department of Neurosurgery, Hull Royal Infirmary, Hull, UK
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4
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Vinton J, Aninweze A, Birgbauer E. Ibuprofen does not inhibit RhoA-mediated growth cone collapse of embryonic chicken retinal axons by LPA. Exp Brain Res 2021; 239:2969-2977. [PMID: 34322723 DOI: 10.1007/s00221-021-06172-y] [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: 05/14/2020] [Accepted: 05/15/2021] [Indexed: 11/28/2022]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that causes neuronal growth cones to collapse and neurites to retract through a RhoA-ROCK mediated pathway. It has been reported that the NSAID ibuprofen improves regeneration after spinal cord injury through a mechanism of inhibiting RhoA. This leads to the hypothesis that ibuprofen should block LPA-mediated growth cone collapse. We tested this hypothesis by treating embryonic chick retinal neurons with ibuprofen followed by LPA. Retinal growth cones collapsed with LPA in the presence of ibuprofen similar to control; however, growth cone collapse was effectively blocked by a ROCK inhibitor. Thus, our results do not support the designation of ibuprofen as a direct RhoA inhibitor.
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Affiliation(s)
- James Vinton
- Department of Biology, Winthrop University, Rock Hill, SC, 29733, USA
| | - Adaeze Aninweze
- Department of Biology, Winthrop University, Rock Hill, SC, 29733, USA
| | - Eric Birgbauer
- Department of Biology, Winthrop University, Rock Hill, SC, 29733, USA.
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Guijarro-Belmar A, Domanski DM, Bo X, Shewan D, Huang W. The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3',5'-monophosphate (Epac) for central nervous system trauma. Neural Regen Res 2021; 16:460-469. [PMID: 32985466 PMCID: PMC7996029 DOI: 10.4103/1673-5374.293256] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Millions of people worldwide are affected by traumatic spinal cord injury, which usually results in permanent sensorimotor disability. Damage to the spinal cord leads to a series of detrimental events including ischaemia, haemorrhage and neuroinflammation, which over time result in further neural tissue loss. Eventually, at chronic stages of traumatic spinal cord injury, the formation of a glial scar, cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth. This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system. The intracellular signalling molecule, cyclic adenosine 3′,5′-monophosphate (cAMP), is known to play many important roles in the central nervous system, and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models. However, therapies directly targeting cAMP have not found their way into the clinic, as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects. A downstream effector of cAMP, exchange protein directly activated by cAMP 2 (Epac2), is mainly expressed in the adult central nervous system, and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration. Recently, using ex vivo modelling of traumatic spinal cord injury, Epac2 activation was found to profoundly modulate the post-lesion environment, such as decreasing the activation of astrocytes and microglia. Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury. Therefore, targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair, and future work is needed to fully establish its therapeutic potential.
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Affiliation(s)
- Alba Guijarro-Belmar
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen; Sainsbury Wellcome Centre, University College London, London, UK
| | - Dominik Mateusz Domanski
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, UK
| | - Xuenong Bo
- Center for Neuroscience, Surgery and Trauma, Queen Mary University of London, London, UK
| | - Derryck Shewan
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, UK
| | - Wenlong Huang
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, UK
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6
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In Vivo Assessment of Cell Death and Nigrostriatal Pathway Integrity Following Continuous Expression of C3 Transferase. Neuroscience 2020; 442:183-192. [PMID: 32652176 DOI: 10.1016/j.neuroscience.2020.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 11/23/2022]
Abstract
The bacterial exoenzyme C3 transferase (C3) irreversibly inhibits RhoA GTPase leading to stimulation of axonal outgrowth in injured neurons. C3 has been used successfully in models of neurotrauma and shows promise as an option to support cell survival and axonal growth of dopaminergic (DA) neurons in Parkinson's disease (PD) cell therapy. Whether the continuous expression of C3 in DA neurons is well-tolerated is unknown. To assess the potential neurotoxicity of sustained expression of C3 in DA neurons, we generated Cre recombinase-dependent adeno-associated viral vectors (AAV) for targeted C3 delivery to DA neurons of the mouse substantia nigra pars compacta (SNc). The effect of continuous expression of C3 on DA neurons was assessed by immunohistochemistry and compared to that of Enhanced Yellow Fluorescent Protein (EYFP) as negative controls. We did not find significant reduction of tyrosine hydroxylase (TH) expression levels nor the presence of cleaved activated caspase 3. Astrocytic activation as determined by GFAP expression was comparable to EYFP controls. To evaluate the impact of C3 expression on striatal terminals of the nigrostriatal pathway, we compared the rotational behavior of wildtype mice injected unilaterally with either C3 or 6-hydroxydopamine (6-OHDA). Mice injected with C3 exhibited similar ipsiversive rotations to the site of injection in comparison to control mice injected with EYFP and significantly fewer ipsiversive rotations compared to 6-OHDA lesioned mice. Non-significant difference between C3 and EYFP controls in behavioral and histological analyses demonstrate that transduced DA neurons express C3 continuously without apparent adverse effects, supporting the use of C3 in efficacy studies targeting DA neurons.
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7
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Sami A, Selzer ME, Li S. Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors. Front Cell Neurosci 2020; 14:174. [PMID: 32714150 PMCID: PMC7346763 DOI: 10.3389/fncel.2020.00174] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.
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Affiliation(s)
- Armin Sami
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Michael E Selzer
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Shuxin Li
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
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8
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Lindsay SL, McCanney GA, Willison AG, Barnett SC. Multi-target approaches to CNS repair: olfactory mucosa-derived cells and heparan sulfates. Nat Rev Neurol 2020; 16:229-240. [PMID: 32099190 DOI: 10.1038/s41582-020-0311-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Spinal cord injury (SCI) remains one of the biggest challenges in the development of neuroregenerative therapeutics. Cell transplantation is one of numerous experimental strategies that have been identified and tested for efficacy at both preclinical and clinical levels in recent years. In this Review, we briefly discuss the state of human olfactory cell transplantation as a therapy, considering both its current clinical status and its limitations. Furthermore, we introduce a mesenchymal stromal cell derived from human olfactory tissue, which has the potential to induce multifaceted reparative effects in the environment within and surrounding the lesion. We argue that no single therapy will be sufficient to treat SCI effectively and that a combination of cell-based, rehabilitation and pharmaceutical interventions is the most promising approach to aid repair. For this reason, we also introduce a novel pharmaceutical strategy based on modifying the activity of heparan sulfate, an important regulator of a wide range of biological cell functions. The multi-target approach that is exemplified by these types of strategies will probably be necessary to optimize SCI treatment.
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Affiliation(s)
- Susan L Lindsay
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - George A McCanney
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Alice G Willison
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Susan C Barnett
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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9
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Estrada V, Krebbers J, Voss C, Brazda N, Blazyca H, Illgen J, Seide K, Jürgens C, Müller J, Martini R, Trieu HK, Müller HW. Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury. Commun Biol 2018; 1:205. [PMID: 30511019 PMCID: PMC6255786 DOI: 10.1038/s42003-018-0210-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 10/31/2018] [Indexed: 12/16/2022] Open
Abstract
Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.
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Affiliation(s)
- Veronica Estrada
- 1Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Julia Krebbers
- 1Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Christian Voss
- 2Institute of Microsystems Technology, Hamburg University of Technology, Eißendorfer Str. 42, 21073 Hamburg, Germany.,BG Trauma Centre Hamburg, Bergedorfer Str. 10, 21033 Hamburg, Germany
| | - Nicole Brazda
- 1Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Heinrich Blazyca
- 4Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany
| | - Jennifer Illgen
- 1Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Klaus Seide
- BG Trauma Centre Hamburg, Bergedorfer Str. 10, 21033 Hamburg, Germany
| | - Christian Jürgens
- BG Trauma Centre Hamburg, Bergedorfer Str. 10, 21033 Hamburg, Germany
| | - Jörg Müller
- 2Institute of Microsystems Technology, Hamburg University of Technology, Eißendorfer Str. 42, 21073 Hamburg, Germany
| | - Rudolf Martini
- 4Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany
| | - Hoc Khiem Trieu
- 2Institute of Microsystems Technology, Hamburg University of Technology, Eißendorfer Str. 42, 21073 Hamburg, Germany
| | - Hans Werner Müller
- 1Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.,CNR (Center for Neuronal Regeneration), Merowinger Platz 1a, 40225 Düsseldorf, Germany.,6Biomedical Research Center, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
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10
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Moreno PMD, Ferreira AR, Salvador D, Rodrigues MT, Torrado M, Carvalho ED, Tedebark U, Sousa MM, Amaral IF, Wengel J, Pêgo AP. Hydrogel-Assisted Antisense LNA Gapmer Delivery for In Situ Gene Silencing in Spinal Cord Injury. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 11:393-406. [PMID: 29858074 PMCID: PMC5992461 DOI: 10.1016/j.omtn.2018.03.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 03/04/2018] [Accepted: 03/15/2018] [Indexed: 12/16/2022]
Abstract
After spinal cord injury (SCI), nerve regeneration is severely hampered due to the establishment of a highly inhibitory microenvironment at the injury site, through the contribution of multiple factors. The potential of antisense oligonucleotides (AONs) to modify gene expression at different levels, allowing the regulation of cell survival and cell function, together with the availability of chemically modified nucleic acids with favorable biopharmaceutical properties, make AONs an attractive tool for novel SCI therapy developments. In this work, we explored the potential of locked nucleic acid (LNA)-modified AON gapmers in combination with a fibrin hydrogel bridging material to induce gene silencing in situ at a SCI lesion site. LNA gapmers were effectively developed against two promising gene targets aiming at enhancing axonal regeneration-RhoA and GSK3β. The fibrin-matrix-assisted AON delivery system mediated potent RNA knockdown in vitro in a dorsal root ganglion explant culture system and in vivo at a SCI lesion site, achieving around 75% downregulation 5 days after hydrogel injection. Our results show that local implantation of a AON-gapmer-loaded hydrogel matrix mediated efficient gene silencing in the lesioned spinal cord and is an innovative platform that can potentially combine gene regulation with regenerative permissive substrates aiming at SCI therapeutics and nerve regeneration.
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Affiliation(s)
- Pedro M D Moreno
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Ana R Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Daniela Salvador
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Maria T Rodrigues
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Marília Torrado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Eva D Carvalho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Ulf Tedebark
- GE Healthcare Bio-Sciences AB, 75184 Uppsala, Sweden; SynMer AB, 17568 Järfälla, Sweden
| | - Mónica M Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Nerve Regeneration Group, Universidade do Porto, 4200-135 Porto, Portugal
| | - Isabel F Amaral
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Jesper Wengel
- Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5230 Odense, Denmark
| | - Ana P Pêgo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal; Faculdade de Engenharia da Universidade do Porto, 4200-465 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal.
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11
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Gómez RM, Sánchez MY, Portela-Lomba M, Ghotme K, Barreto GE, Sierra J, Moreno-Flores MT. Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs). Glia 2018; 66:1267-1301. [PMID: 29330870 DOI: 10.1002/glia.23282] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 11/20/2017] [Accepted: 11/28/2017] [Indexed: 01/18/2023]
Abstract
The prospects of achieving regeneration in the central nervous system (CNS) have changed, as most recent findings indicate that several species, including humans, can produce neurons in adulthood. Studies targeting this property may be considered as potential therapeutic strategies to respond to injury or the effects of demyelinating diseases in the CNS. While CNS trauma may interrupt the axonal tracts that connect neurons with their targets, some neurons remain alive, as seen in optic nerve and spinal cord (SC) injuries (SCIs). The devastating consequences of SCIs are due to the immediate and significant disruption of the ascending and descending spinal pathways, which result in varying degrees of motor and sensory impairment. Recent therapeutic studies for SCI have focused on cell transplantation in animal models, using cells capable of inducing axon regeneration like Schwann cells (SchCs), astrocytes, genetically modified fibroblasts and olfactory ensheathing glia cells (OECs). Nevertheless, and despite the improvements in such cell-based therapeutic strategies, there is still little information regarding the mechanisms underlying the success of transplantation and regarding any secondary effects. Therefore, further studies are needed to clarify these issues. In this review, we highlight the properties of OECs that make them suitable to achieve neuroplasticity/neuroregeneration in SCI. OECs can interact with the glial scar, stimulate angiogenesis, axon outgrowth and remyelination, improving functional outcomes following lesion. Furthermore, we present evidence of the utility of cell therapy with OECs to treat SCI, both from animal models and clinical studies performed on SCI patients, providing promising results for future treatments.
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Affiliation(s)
- Rosa M Gómez
- Fundación de Neuroregeneración en Colombia, Grupo de investigación NeuroRec, Bogota D.C, Colombia
| | - Magdy Y Sánchez
- Fundación de Neuroregeneración en Colombia, Grupo de investigación NeuroRec, Bogota D.C, Colombia.,Maestría en Neurociencias, Universidad Nacional de Colombia, Bogota D.C, Colombia
| | - Maria Portela-Lomba
- Facultad de CC Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain
| | - Kemel Ghotme
- Facultad de Medicina, Universidad de la Sabana, Chía, Colombia
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota D.C, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Javier Sierra
- Facultad de CC Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain
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12
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Pires LR, Lopes CDF, Salvador D, Rocha DN, Pêgo AP. Ibuprofen-loaded fibrous patches-taming inhibition at the spinal cord injury site. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2017; 28:157. [PMID: 28894995 DOI: 10.1007/s10856-017-5967-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 08/19/2017] [Indexed: 06/07/2023]
Abstract
It is now widely accepted that a therapeutic strategy for spinal cord injury (SCI) demands a multi-target approach. Here we propose the use of an easily implantable bilayer polymeric patch based on poly(trimethylene carbonate-co-ε-caprolactone) (P(TMC-CL)) that combines physical guidance cues provided by electrospun aligned fibres and the delivery of ibuprofen, as a mean to reduce the inhibitory environment at the lesion site by taming RhoA activation. Bilayer patches comprised a solvent cast film onto which electrospun aligned fibres have been deposited. Both layers were loaded with ibuprofen. In vitro release (37°C, in phosphate buffered saline) of the drug from the loaded scaffolds under sink condition was found to occur in the first 24 h. The released ibuprofen was shown to retain its bioactivity, as indicated by the reduction of RhoA activation when the neuronal-like cell line ND7/23 was challenged with lysophosphatidic acid. Ibuprofen-loaded P(TMC-CL) bilayer scaffolds were successfully implanted in vivo in a dorsal hemisection rat SCI model mediating the reduction of RhoA activation after 5 days of implantation in comparison to plain P(TMC-CL) scaffolds. Immunohistochemical analysis of the tissue shows βIII tubulin positive cells close to the ibuprofen-loaded patches further supporting the use of this strategy in the context of regeneration after a lesion in the spinal cord.
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Affiliation(s)
- Liliana R Pires
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INL- International Iberian Nanotechnology Laboratory, Braga, Portugal
| | - Cátia D F Lopes
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Daniela Salvador
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
| | - Daniela N Rocha
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
| | - Ana Paula Pêgo
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal.
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto (ICBAS), Porto, Portugal.
- Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, Portugal.
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Parzanese I, Qehajaj D, Patrinicola F, Aralica M, Chiriva-Internati M, Stifter S, Elli L, Grizzi F. Celiac disease: From pathophysiology to treatment. World J Gastrointest Pathophysiol 2017; 8:27-38. [PMID: 28573065 PMCID: PMC5437500 DOI: 10.4291/wjgp.v8.i2.27] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 03/08/2017] [Accepted: 03/23/2017] [Indexed: 02/06/2023] Open
Abstract
Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.
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Cornel Iridoid Glycoside Improves Locomotor Impairment and Decreases Spinal Cord Damage in Rats. BIOMED RESEARCH INTERNATIONAL 2016; 2016:6725381. [PMID: 27990434 PMCID: PMC5136393 DOI: 10.1155/2016/6725381] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/06/2016] [Accepted: 10/04/2016] [Indexed: 01/21/2023]
Abstract
Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy.
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Gutekunst CA, Tung JK, McDougal ME, Gross RE. C3 transferase gene therapy for continuous conditional RhoA inhibition. Neuroscience 2016; 339:308-318. [PMID: 27746349 DOI: 10.1016/j.neuroscience.2016.10.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/03/2016] [Accepted: 10/05/2016] [Indexed: 01/21/2023]
Abstract
Regrowth inhibitory molecules prevent axon regeneration in the adult mammalian central nervous system (CNS). RhoA, a small GTPase in the Rho family, is a key intracellular switch that mediates the effects of these extracellular regrowth inhibitors. The bacterial enzyme C3-ADP ribosyltransferase (C3) selectively and irreversibly inhibits the activation of RhoA and stimulates axon outgrowth and regeneration. However, effective intracellular delivery of the C3 protein in vivo is limited by poor cell permeability and a short duration of action. To address this, we have developed a gene therapy approach using viral vectors to introduce the C3 gene into neurons or neuronal progenitors. Our vectors deliver C3 in a cell-autonomous (endogenous) or a cell-nonautonomous (secretable/permeable) fashion and promote in vitro process outgrowth on inhibitory chondroitin sulfate proteoglycan substrate. Further conditional control of our vectors was achieved via the addition of a Tet-On system, which allows for transcriptional control with doxycycline administration. These vectors will be crucial tools for promoting continued axonal regeneration after CNS injuries or neurodegenerative diseases.
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Affiliation(s)
- Claire-Anne Gutekunst
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States.
| | - Jack K Tung
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States; Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology College of Engineering, Atlanta, GA, United States.
| | - Margaret E McDougal
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States.
| | - Robert E Gross
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States; Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States; Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology College of Engineering, Atlanta, GA, United States.
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Colón JM, Torrado AI, Cajigas Á, Santiago JM, Salgado IK, Arroyo Y, Miranda JD. Tamoxifen Administration Immediately or 24 Hours after Spinal Cord Injury Improves Locomotor Recovery and Reduces Secondary Damage in Female Rats. J Neurotrauma 2016; 33:1696-708. [PMID: 26896212 PMCID: PMC5035917 DOI: 10.1089/neu.2015.4111] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Spinal cord injury (SCI) is a condition with no available cure. The initial physical impact triggers a cascade of molecular and cellular events that generate a nonpermissive environment for cell survival and axonal regeneration. Spinal cord injured patients often arrive at the clinic hours after the initial insult. This indicates the need to study and develop treatments with a long therapeutic window of action and multiactive properties, which target the complex set of events that arise after the initial trauma. We provide evidence that tamoxifen (TAM), a drug approved by the Food and Drug Administration, exerts neuroprotective effects in an animal model when applied up-to 24 h after SCI. We hypothesized that continuous TAM administration will improve functional locomotor recovery by favoring myelin preservation and reducing secondary damage after SCI. Adult female Sprague-Dawley rats (∼230 g) received a moderate contusion to the thoracic (T9-T10) spinal cord, using the MASCIS impactor device. To determine the therapeutic window available for TAM treatment, rats were implanted with TAM pellets (15 mg) immediately or 24 h after SCI. Locomotor function (Basso, Beattie, Bresnahan open field test, grid walk, and beam crossing tests) was assessed weekly for 35 days post-injury. TAM-treated rats showed significant functional locomotor recovery and improved fine movements when treated immediately or 24 h after SCI. Further, TAM increased white matter preservation and reduced secondary damage caused by astrogliosis, axonal degeneration, and cell death after trauma. These results provide evidence for TAM as a potential therapeutic agent to treat SCI up to 24 h after the trauma.
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Affiliation(s)
- Jennifer M. Colón
- Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Aranza I. Torrado
- Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Ámbar Cajigas
- Department of Biology, University of Puerto Rico Rio Piedras Campus, San Juan, Puerto Rico
| | - José M. Santiago
- Department of Natural Sciences, University of Puerto Rico Carolina Campus, Carolina, Puerto Rico
| | - Iris K. Salgado
- Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Yaría Arroyo
- Department of Natural Sciences, University of Puerto Rico Carolina Campus, Carolina, Puerto Rico
| | - Jorge D. Miranda
- Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
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Kopp MA, Liebscher T, Watzlawick R, Martus P, Laufer S, Blex C, Schindler R, Jungehulsing GJ, Knüppel S, Kreutzträger M, Ekkernkamp A, Dirnagl U, Strittmatter SM, Niedeggen A, Schwab JM. SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. BMJ Open 2016; 6:e010651. [PMID: 27466236 PMCID: PMC4964175 DOI: 10.1136/bmjopen-2015-010651] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 02/25/2016] [Accepted: 05/19/2016] [Indexed: 11/30/2022] Open
Abstract
INTRODUCTION The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation. METHODS AND ANALYSIS Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. ETHICS AND DISSEMINATION The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT02096913; Pre-results.
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Affiliation(s)
- Marcel A Kopp
- Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Liebscher
- Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany
| | - Ralf Watzlawick
- Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Peter Martus
- Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Stefan Laufer
- Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Christian Blex
- Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ralf Schindler
- Division of Nephrology and Intensive Care, Department of Internal Medicine, Campus Virchow-Klinikum, Charité-University Medicine Berlin, Berlin, Germany
| | - Gerhard J Jungehulsing
- Department of Neurology, Jüdisches Krankenhaus Berlin, Berlin, Germany Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sven Knüppel
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Germany
| | - Martin Kreutzträger
- Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany
| | - Axel Ekkernkamp
- Trauma Surgery and Orthopedics Clinic, Trauma Hospital Berlin, Berlin, Germany
| | - Ulrich Dirnagl
- Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stephen M Strittmatter
- Department of Neurology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, USA
| | - Andreas Niedeggen
- Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany
| | - Jan M Schwab
- Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany Department of Neurology, Spinal Cord Injury Division, The Ohio State University, Wexner Medical Center, Columbus, USA Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, USA
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Zhang W, Liu Y, Zhu X, Cao Y, Liu Y, Mao X, Yang H, Zhou Z, Wang Y, Shen A. SCY1-Like 1-Binding Protein 1 (SCYL1BP1) Suppressed Sciatic Nerve Regeneration by Enhancing the RhoA Pathway. Mol Neurobiol 2015; 53:6342-6354. [PMID: 26572638 DOI: 10.1007/s12035-015-9531-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 11/08/2015] [Indexed: 12/13/2022]
Abstract
SCY1-like 1-binding protein 1 (SCYL1BP1) is first identified as an interacting protein with SCYL1. Since SCYL1BP1 is a soluble protein with coiled-coil domains known to be relevant with transcriptional regulation, it has been found to activate the transcription of murine double minute 2 (MDM2) and participate in neurite outgrowth and regeneration. However, the role and mechanism of SCYL1BP1 in peripheral nerve system lesion and repair are still unknown. Here in vitro, our work demonstrated that SCYL1BP1 inhibited cAMP-induced primary Schwann cell differentiation and suppressed nerve growth factor-mediated neurite outgrowth in PC12 cells by enhancing the RhoA pathway. Furthermore, we found that pretreatment with a Rho kinase inhibitor Y-27632 resulted in partial rescue of Schwann cell differentiation and neurite outgrowth. In vivo experiments showed that SCYL1BP1 could also suppress nerve fiber regeneration. In conclusion, we speculated that SCYL1BP1 participated in Schwann cell (SC) differentiation and neurite outgrowth in the sciatic nerve after crush by regulating the RhoA pathway.
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Affiliation(s)
- Weidong Zhang
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yonghua Liu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Xudong Zhu
- Medical College, Nantong University, 19 Qi-Xiu Road, Nantong, 226001, Jiangsu Province, People's Republic of China
| | - Yi Cao
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yang Liu
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.,Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xingxing Mao
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Huiguang Yang
- Department of Orthopaedics, Affiliated Jiangyin Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Zhengming Zhou
- Department of Orthopaedics, Affiliated Jiangyin Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Youhua Wang
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Aiguo Shen
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
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Cromm PM, Spiegel J, Grossmann TN, Waldmann H. Direkte Modulation von Aktivität und Funktion kleiner GTPasen. Angew Chem Int Ed Engl 2015. [DOI: 10.1002/ange.201504357] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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20
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Cromm PM, Spiegel J, Grossmann TN, Waldmann H. Direct Modulation of Small GTPase Activity and Function. Angew Chem Int Ed Engl 2015; 54:13516-37. [DOI: 10.1002/anie.201504357] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Indexed: 12/19/2022]
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21
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Pires LR, Pêgo AP. Bridging the lesion-engineering a permissive substrate for nerve regeneration. Regen Biomater 2015; 2:203-14. [PMID: 26816642 PMCID: PMC4669012 DOI: 10.1093/rb/rbv012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 07/21/2015] [Accepted: 06/30/2015] [Indexed: 01/30/2023] Open
Abstract
Biomaterial-based strategies to restore connectivity after lesion at the spinal cord are focused on bridging the lesion and providing an favourable substrate and a path for axonal re-growth. Following spinal cord injury (SCI) a hostile environment for neuronal cell growth is established by the activation of multiple inhibitory mechanisms that hamper regeneration to occur. Implantable scaffolds can provide mechanical support and physical guidance for axon re-growth and, at the same time, contribute to alleviate the hostile environment by the in situ delivery of therapeutic molecules and/or relevant cells. Basic research on SCI has been contributing with the description of inhibitory mechanisms for regeneration as well as identifying drugs/molecules that can target inhibition. This knowledge is the background for the development of combined strategies with biomaterials. Additionally, scaffold design is significantly evolving. From the early simple hollow conduits, scaffolds with complex architectures that can modulate cell fate are currently being tested. A number of promising pre-clinical studies combining scaffolds, cells, drugs and/or nucleic acids are reported in the open literature. Overall, it is considered that to address the multi-factorial inhibitory environment of a SCI, a multifaceted therapeutic approach is imperative. The progress in the identification of molecules that target inhibition after SCI and its combination with scaffolds and/or cells are described and discussed in this review.
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Affiliation(s)
- Liliana R. Pires
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- Faculdade de Engenharia—Universidade do Porto (FEUP), Porto, Portugal and
| | - Ana P. Pêgo
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- Faculdade de Engenharia—Universidade do Porto (FEUP), Porto, Portugal and
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
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Kaplan A, Ong Tone S, Fournier AE. Extrinsic and intrinsic regulation of axon regeneration at a crossroads. Front Mol Neurosci 2015; 8:27. [PMID: 26136657 PMCID: PMC4470051 DOI: 10.3389/fnmol.2015.00027] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 06/03/2015] [Indexed: 11/16/2022] Open
Abstract
Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.
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Affiliation(s)
- Andrew Kaplan
- Department of Neurology/Neurosurgery, Montréal Neurological Institute, McGill University Montréal, QC, Canada
| | - Stephan Ong Tone
- Department of Neurology/Neurosurgery, Montréal Neurological Institute, McGill University Montréal, QC, Canada
| | - Alyson E Fournier
- Department of Neurology/Neurosurgery, Montréal Neurological Institute, McGill University Montréal, QC, Canada
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Papastefanaki F, Matsas R. From demyelination to remyelination: the road toward therapies for spinal cord injury. Glia 2015; 63:1101-25. [PMID: 25731941 DOI: 10.1002/glia.22809] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 12/14/2022]
Abstract
Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation.
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Affiliation(s)
- Florentia Papastefanaki
- Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, 11521, Greece
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Xu B, Park D, Ohtake Y, Li H, Hayat U, Liu J, Selzer ME, Longo FM, Li S. Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury. Neurobiol Dis 2015; 73:36-48. [PMID: 25220840 PMCID: PMC4427014 DOI: 10.1016/j.nbd.2014.08.030] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 08/05/2014] [Accepted: 08/29/2014] [Indexed: 12/11/2022] Open
Abstract
Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). Pharmacological LAR inhibition enhanced serotonergic axon growth in SCI mice. However, transgenic LAR deletion on axon growth in vivo and the role of LAR in regulating regrowth of other fiber tracts have not been studied. Here, we studied the role of LAR in restricting regrowth of injured descending CNS axons in deficient mice. LAR deletion increased regrowth of serotonergic axons into scar tissues and caudal spinal cord after dorsal over-hemitransection. LAR deletion also stimulated regrowth of CST fibers into the caudal spinal cord. LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates the crucial role of LAR in restricting regrowth of injured CNS axons.
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Affiliation(s)
- Bin Xu
- Department of Neurosurgery, Affiliated Shanxi Dayi Hospital, Shanxi Academy of Medical Sciences, China; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Dongsun Park
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Yosuke Ohtake
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Hui Li
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Umar Hayat
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Junjun Liu
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Michael E Selzer
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Frank M Longo
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
| | - Shuxin Li
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
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Estrada V, Müller HW. Spinal cord injury - there is not just one way of treating it. F1000PRIME REPORTS 2014; 6:84. [PMID: 25343041 PMCID: PMC4166939 DOI: 10.12703/p6-84] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In the last century, research in the field of spinal cord trauma has brought insightful knowledge which has led to a detailed understanding of mechanisms that are involved in injury- and recovery-related processes. The quest for a cure for the yet generally incurable condition as well as the exponential rise in gained information has brought about the development of numerous treatment approaches while at the same time the abundance of data has become quite unmanageable. Owing to an enormous amount of preclinical therapeutic approaches, this report highlights important trends rather than specific treatment strategies. We focus on current advances in the treatment of spinal cord injury and want to further draw attention to arising problems in spinal cord injury (SCI) research and discuss possible solutions.
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Affiliation(s)
- Veronica Estrada
- Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Center Düsseldorf Moorenstr. 5, 40225 Düsseldorf Germany
| | - Hans Werner Müller
- Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Center Düsseldorf Moorenstr. 5, 40225 Düsseldorf Germany
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Ohtake Y, Park D, Muneer PMA, Li H, Xu B, Sharma K, Smith GM, Selzer ME, Li S. The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury. Biomaterials 2014; 35:4610-26. [PMID: 24630093 PMCID: PMC4195449 DOI: 10.1016/j.biomaterials.2014.02.037] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 02/20/2014] [Indexed: 10/25/2022]
Abstract
Knockout studies suggest that PTEN limits the regenerative capacities of CNS axons as a dominant antagonist of PI3 kinase, but the transgenic approach is not feasible for treating patients. Although application of bisperoxovanadium may block PTEN function, it is a general inhibitor of phosphotyrosine phosphatases and may target enzymes other than PTEN, causing side effects and preventing firm conclusions about PTEN inhibition on regulating neuronal growth. A pharmacological method to selectively suppress PTEN post-injury could be a valuable strategy for promoting CNS axon regeneration. We identified PTEN antagonist peptides (PAPs) by targeting PTEN critical functional domains and evaluated their efficacy for promoting axon growth. Four PAPs (PAP 1-4) bound to PTEN protein expressed in COS7 cells and blocked PTEN signaling in vivo. Subcutaneous administration of PAPs initiated two days after dorsal over-hemisection injury significantly stimulated growth of descending serotonergic fibers in the caudal spinal cord of adult mice. Systemic PAPs induce significant sprouting of corticospinal fibers in the rostral spinal cord and limited growth of corticospinal axons in the caudal spinal cord. More importantly, PAP treatment enhanced recovery of locomotor function in adult rodents with spinal cord injury. This study may facilitate development of effective therapeutic agents for CNS injuries.
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Affiliation(s)
- Yosuke Ohtake
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Dongsun Park
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - P M Abdul Muneer
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Hui Li
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Bin Xu
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Kartavya Sharma
- Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390-8813, USA
| | - George M Smith
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Michael E Selzer
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Shuxin Li
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
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Regeneration of Aplysia bag cell neurons is synergistically enhanced by substrate-bound hemolymph proteins and laminin. Sci Rep 2014; 4:4617. [PMID: 24722588 PMCID: PMC3983596 DOI: 10.1038/srep04617] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 03/12/2014] [Indexed: 11/08/2022] Open
Abstract
We have investigated Aplysia hemolymph as a source of endogenous factors to promote regeneration of bag cell neurons. We describe a novel synergistic effect between substrate-bound hemolymph proteins and laminin. This combination increased outgrowth and branching relative to either laminin or hemolymph alone. Notably, the addition of hemolymph to laminin substrates accelerated growth cone migration rate over ten-fold. Our results indicate that the active factor is either a high molecular weight protein or protein complex and is not the respiratory protein hemocyanin. Substrate-bound factor(s) from central nervous system-conditioned media also had a synergistic effect with laminin, suggesting a possible cooperation between humoral proteins and nervous system extracellular matrix. Further molecular characterization of active factors and their cellular targets is warranted on account of the magnitude of the effects reported here and their potential relevance for nervous system repair.
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Tsygankov D, Bilancia CG, Vitriol EA, Hahn KM, Peifer M, Elston TC. CellGeo: a computational platform for the analysis of shape changes in cells with complex geometries. ACTA ACUST UNITED AC 2014; 204:443-60. [PMID: 24493591 PMCID: PMC3912527 DOI: 10.1083/jcb.201306067] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The open source MATLAB application CellGeo is a user-friendly computational platform that allows simultaneous, automated tracking and analysis of dynamic changes in cell shape, including protrusions ranging from filopodia to lamellipodia to growth cones. Cell biologists increasingly rely on computer-aided image analysis, allowing them to collect precise, unbiased quantitative results. However, despite great progress in image processing and computer vision, current computational approaches fail to address many key aspects of cell behavior, including the cell protrusions that guide cell migration and drive morphogenesis. We developed the open source MATLAB application CellGeo, a user-friendly computational platform to allow simultaneous, automated tracking and analysis of dynamic changes in cell shape, including protrusions ranging from filopodia to lamellipodia. Our method maps an arbitrary cell shape onto a tree graph that, unlike traditional skeletonization algorithms, preserves complex boundary features. CellGeo allows rigorous but flexible definition and accurate automated detection and tracking of geometric features of interest. We demonstrate CellGeo’s utility by deriving new insights into (a) the roles of Diaphanous, Enabled, and Capping protein in regulating filopodia and lamellipodia dynamics in Drosophila melanogaster cells and (b) the dynamic properties of growth cones in catecholaminergic a–differentiated neuroblastoma cells.
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Affiliation(s)
- Denis Tsygankov
- Department of Pharmacology, 2 Department of Biology, and 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
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Makharia GK. Current and emerging therapy for celiac disease. Front Med (Lausanne) 2014; 1:6. [PMID: 25705619 PMCID: PMC4335393 DOI: 10.3389/fmed.2014.00006] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 03/13/2014] [Indexed: 12/12/2022] Open
Abstract
At present, strict and lifelong gluten-free diet is the only effective treatment for celiac disease. Even small amounts of gluten (50 mg/day) can be immunogenic; therefore all food and food items and drugs that contain gluten and its derivatives must be eliminated completely from the diet. While prescribing gluten-free diet is easy; the key to the success is the dietary counseling by a nutrition specialist and maintenance of adherence to GFD by the patient. In recent times, a number of targets to halt the process of immunological injury have been explored to find out alternative treatment for celiac disease. These targets include exploration of ancient wheat if they are less immunogenic, intra-luminal digestion of gluten using prolylendopeptidases, pretreatment of whole gluten with bacterial-derived peptidase before ingestion; prevention of passage of immunogenic peptides through the tight junctions such as zonulin antagonists, Blocking of HLA-DQ2 to prevent binding of immunogenic peptides, inhibition of transglutaminase 2, immune-modulation, and induction of tolerance to gluten using gluten tolerizing vaccines, use of gluten-sequestering polymers, use of anti-inflammatory drugs (glucocorticoids, budesonides) and anti-cytokines such as anti TNF-α, and anti-interleukin-15. While many of these targets are still in the pre-clinical phase, some of them including zonulin antagonist and endopeptidases have already reached phase II and phase III clinical trials. Furthermore, while these targets appear very exciting; they at best are likely to be used as adjunctive therapy rather than a complete replacement for gluten-free diet.
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Affiliation(s)
- Govind K. Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Streijger F, Lee JHT, Duncan GJ, Ng MTL, Assinck P, Bhatnagar T, Plunet WT, Tetzlaff W, Kwon BK. Combinatorial treatment of acute spinal cord injury with ghrelin, ibuprofen, C16, and ketogenic diet does not result in improved histologic or functional outcome. J Neurosci Res 2014; 92:870-83. [PMID: 24658967 DOI: 10.1002/jnr.23372] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 11/28/2013] [Accepted: 01/20/2014] [Indexed: 11/09/2022]
Abstract
Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8-10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI.
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Affiliation(s)
- F Streijger
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
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Hassan K, A-Kader H. Celiac disease: the search for adjunctive or alternative therapies. Expert Rev Gastroenterol Hepatol 2014; 8:313-21. [PMID: 24490653 DOI: 10.1586/17474124.2014.882769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Celiac disease is a widespread disorder caused by intolerance to gluten, a common protein in food. Currently, a life-long gluten-free diet is the only available treatment for patients with celiac disease. However, adherence to gluten-free diet is difficult due to the widespread use of wheat-derived gluten in the food industry. Therefore, there is a pressing need for the development of novel non-dietary therapies. In this article, we will review several promising strategies focusing on reducing gluten immunogenicity or sequestering to gluten prevent its uptake by the intestinal epithelium. Other possible treatment strategies that will be reviewed include the suppression of the adaptive immune response, permeability modulation and the use of systemic T-cell or cytokine blockers.
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Affiliation(s)
- Kareem Hassan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The University of Arizona, Tucson AZ, USA
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Gordon-Weeks PR, Fournier AE. Neuronal cytoskeleton in synaptic plasticity and regeneration. J Neurochem 2013; 129:206-12. [PMID: 24147810 DOI: 10.1111/jnc.12502] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 09/20/2013] [Accepted: 10/17/2013] [Indexed: 11/26/2022]
Abstract
During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system.
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Affiliation(s)
- Phillip R Gordon-Weeks
- The MRC Centre for Developmental Neurobiology, New Hunt's House, Guy's Campus, King's College London, London, UK
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34
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Auer M, Allodi I, Barham M, Udina E, Neiss WF, Navarro X, Klimaschewski L. C3 exoenzyme lacks effects on peripheral axon regeneration in vivo. J Peripher Nerv Syst 2013; 18:30-6. [PMID: 23521641 DOI: 10.1111/jns5.12004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Peripheral nerve injury triggers the activation of the small GTPase RhoA in spinal motor and peripheral sensory neurons. C3 transferase, an exoenzyme produced by Clostridium botulinum that inactivates RhoA by ADP-ribosylation, has been successfully applied in central nervous system (CNS) lesion models to facilitate regeneration functionally and morphologically. Until now it has not been demonstrated if C3bot exerts positive effects on peripheral axon regeneration as well. In organotypic spinal cord preparations, C3bot reduced axonal growth of motoneurons, while no effect on sensory axon outgrowth from dorsal root ganglia (DRG) explants was observed. Enzymatically inactive C3E174Q was ineffective in both culture models. Spinal cord slices exhibited a significant increase in microglia/macrophages after treatment with C3bot suggesting an inflammatory component in the inhibition of axon growth. C3bot or C3E174Q were then applied into conduits implanted after transection of the sciatic nerve in rats. Functional evaluation by electrophysiology, nociception, and walking track tests did not show any significant difference between groups with active or mutant C3E174Q . Transmission electron microscopy of the regenerated nerves revealed no significant differences in the number of myelinated and unmyelinated axons 6 weeks after surgery. Compared to the CNS, the functional significance of RhoA may be limited during nerve regeneration in a growth-promoting environment.
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Affiliation(s)
- Maria Auer
- Division of Neuroanatomy, Innsbruck Medical University, Innsbruck, Austria
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35
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Local injection of lentivirus encoding LINGO-1-shRNA promotes functional recovery in rats with complete spinal cord transection. Spine (Phila Pa 1976) 2013; 38:1632-9. [PMID: 23759802 DOI: 10.1097/brs.0b013e31829dd58f] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN We used a complete spinal cord transection model and locomotor function, histological, and immunohistochemical examinations to evaluate the effects of local injection of lentivirus/LINGO-1-short hairpin RNA (VL) on rats with spinal cord injury (SCI). OBJECTIVE To demonstrate the neuroregenerative and neuroprotective effects of LINGO-1 RNAi on complete transection SCI rats. SUMMARY OF BACKGROUND DATA LINGO-1 has been reported as a negative regulator of axonal sprouting and its antagonist was determined to improve functional outcomes in SCI rats. However, it has not been assessed whether blockade of LINGO-1 mediated by lentivirus vectors could stimulate neural recovery after SCI. METHODS Complete spinal cord transection was made at T10 level. Suspension of lentivirus vectors encoding LINGO-1-short hairpin RNA was injected into the lesion gap. Controls received control vectors in the same manner and the sham group was subjected to laminectomy only. The Basso-Beattie-Bresnahan scale and surface righting reflex test were used to evaluate functional outcomes. Finally, the spinal cords were harvested for histological and immunohistochemical analysis. RESULTS The treatment with VL improved Basso-Beattie-Bresnahan scores and surface righting reflex after SCI. Tissue repair was facilitated and the cavity area was significantly decreased in VL-treated animals. More sprouting and myelinated nerve fibers were detected within the injured site in the VL group as compared with the control. In addition, the number of survival neurons and oligodendrocytes around the epicenter was notably higher under the VL condition. CONCLUSION Local injection of lentivirus/LINGO-1-short hairpin RNA after complete transection of spinal cord resulted in meaningful histological and functional outcomes in rats. The mechanism of VL protection may be related to its promotion of axonal sprouting, remyelination, and cell survival.
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36
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Razmi A, Jahanabadi S, Sahebgharani M, Zarrindast MR. EPAC–STX interaction may play a role in neurodevelopment/neurogenesis. Med Hypotheses 2013; 81:216-8. [DOI: 10.1016/j.mehy.2013.04.047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 04/17/2013] [Accepted: 04/26/2013] [Indexed: 11/30/2022]
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Shen M, Zhou S, Li Y, Pan P, Zhang L, Hou T. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. MOLECULAR BIOSYSTEMS 2013; 9:361-74. [DOI: 10.1039/c2mb25408e] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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38
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Kusiak AN, Selzer ME. Neuroplasticity in the spinal cord. HANDBOOK OF CLINICAL NEUROLOGY 2013; 110:23-42. [DOI: 10.1016/b978-0-444-52901-5.00003-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Shen M, Yu H, Li Y, Li P, Pan P, Zhou S, Zhang L, Li S, Lee SMY, Hou T. Discovery of Rho-kinase inhibitors by docking-based virtual screening. MOLECULAR BIOSYSTEMS 2013; 9:1511-21. [DOI: 10.1039/c3mb00016h] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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40
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Auer M, Schweigreiter R, Hausott B, Thongrong S, Höltje M, Just I, Bandtlow C, Klimaschewski L. Rho-independent stimulation of axon outgrowth and activation of the ERK and Akt signaling pathways by C3 transferase in sensory neurons. Front Cell Neurosci 2012; 6:43. [PMID: 23087613 PMCID: PMC3468917 DOI: 10.3389/fncel.2012.00043] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 09/23/2012] [Indexed: 11/15/2022] Open
Abstract
Peripheral nerve injury triggers the activation of RhoA in spinal motor and peripheral sensory neurons. RhoA activates a number of effector proteins including the Rho-associated kinase, ROCK, which targets the cytoskeleton and leads to inhibition of neurite outgrowth. Blockade of the Rho/ROCK pathway by pharmacological means improves axon regeneration after experimental injury. C3bot transferase, an exoenzyme produced by Clostridium botulinum, inactivates RhoA by ADP-ribosylation. It has been successfully applied in experimental CNS lesions to facilitate axon regeneration. Up to now it was not investigated thoroughly whether C3bot exerts positive effects on peripheral axon regeneration as well. In the present study, recombinant membrane permeable C3bot produced a small, but significant, axon outgrowth effect on peripheral sensory neurons dissociated from adult dorsal root ganglia (DRG) of the rat. Neuronal overexpression of C3, however, did not enhance axonal growth. Moreover, transfection of plasmids encoding dominant negative RhoA or RhoA specific shRNAs failed to increase axonal growth. Furthermore, we show that the C3bot mutant, C3E174Q, which lacks RhoA inhibitory activity, still stimulates axonal growth. When analyzing possible signaling mechanisms we found that extracellular signal-regulated kinase (ERK) and Akt are activated by C3bot and ERK is induced by the C3E174Q mutant. Upregulation of kinase activities by C3bot occurs significantly faster than inactivation of RhoA indicating a RhoA-independent pathway of action by C3bot. The induction of ERK signaling by C3bot was detected in embryonic hippocampal neurons, too. Taken together, although RhoA plays a central role for inhibition of axon outgrowth by myelin-derived inhibitors, it does not interfere with axonal growth of sensory neurons on a permissive substrate in vitro. C3bot blocks neuronal RhoA activity, but its positive effects on axon elongation and branching appear to be mediated by Rho independent mechanisms involving activation of axon growth promoting ERK and Akt kinases.
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Affiliation(s)
- Maria Auer
- Division of Neuroanatomy, Innsbruck Medical University Innsbruck, Austria
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41
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Mukherjee R, Kelly CP, Schuppan D. Nondietary therapies for celiac disease. Gastrointest Endosc Clin N Am 2012; 22:811-31. [PMID: 23083995 DOI: 10.1016/j.giec.2012.09.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Currently, the only available therapy for celiac disease is strict lifelong adherence to a gluten-free diet (GFD). Although safe and effective, the GFD is not ideal. It is frequently expensive, of limited nutritional value, and not readily available in many countries. Consequently, a need exists for novel, nondietary therapies for celiac disease. Based on the current understanding of celiac disease pathogenesis, several potential targets of therapeutic intervention exist. These novel strategies provide promise of alternative, adjunctive treatment options but also raise important questions regarding safety, efficacy, and monitoring of long-term treatment effect.
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Affiliation(s)
- Rupa Mukherjee
- Department of Medicine, Division of Gastroenterology, The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Lee JY, Choi SY, Oh TH, Yune TY. 17β-Estradiol inhibits apoptotic cell death of oligodendrocytes by inhibiting RhoA-JNK3 activation after spinal cord injury. Endocrinology 2012; 153:3815-27. [PMID: 22700771 DOI: 10.1210/en.2012-1068] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A delayed oligodendrocyte cell death after spinal cord injury (SCI) contributes to chronic demyelination of spared axons, leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent oligodendrocyte cell death after SCI should be considered. Estrogens are well known to have a broad neuroprotective effect, but the protective effect of estrogens on oligodendrocytes after injury is largely unknown. Here, we demonstrated that 17β-estradiol attenuates apoptosis of oligodendrocytes by inhibiting RhoA and c-Jun-N-terminal kinase activation after SCI. Estrogen receptor (ER)-α and -β were expressed in oligodendrocytes of the spinal cord, and 17β-estradiol treatment significantly inhibited oligodendrocyte cell death at 7 d after injury as compared with vehicle (cyclodextrin) control. 17β-Estradiol also attenuated caspase-3 and -9 activation at 7 d and reduced the loss of axons from progressive degeneration. In addition, 17β-estradiol inhibited RhoA and JNK3 activation, which were activated and peaked at 3 and/or 5 d after injury. Furthermore, administration of Rho inhibitor, PEP-1-C3 exoenzyme, inhibited RhoA and JNK3 activation, and decreased phosphorylated c-Jun level at 5 d after injury. Additionally, the attenuation of RhoA and JNK3 activation as well as oligodendrocyte cell death by 17β-estradiol was reversed by ER antagonist, ICI182780. Our results thus indicate that 17β-estradiol treatment improves functional recovery after SCI in part by reducing oligodendrocyte cell death via inhibition of RhoA and JNK3 activation, which were ER dependent. Furthermore, improvement of hindlimb motor function by posttreatment of 17β-estradiol suggests its potential as a therapeutic agent for SCI patients.
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Affiliation(s)
- Jee Y Lee
- Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Medical Building 10th Floor, Dongdaemun-gu, Hoegi-dong 1, Seoul 130-701, Korea
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Otsuka S, Adamson C, Sankar V, Gibbs KM, Kane-Goldsmith N, Ayer J, Babiarz J, Kalinski H, Ashush H, Alpert E, Lahav R, Feinstein E, Grumet M. Delayed intrathecal delivery of RhoA siRNA to the contused spinal cord inhibits allodynia, preserves white matter, and increases serotonergic fiber growth. J Neurotrauma 2012; 28:1063-76. [PMID: 21443453 DOI: 10.1089/neu.2010.1568] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
RhoA is a key regulator of the actin cytoskeleton that is upregulated after spinal cord injury (SCI). We analyzed different methods for siRNA delivery and developed siRNAs targeting RhoA (siRhoA) for SCI treatment. Cy 3.5-labeled siRNA delivered at the time of SCI yielded fluorescence in several cell types in the injury site. Intraspinal injections of chemically stabilized siRhoA into the spinal cord of injured rats reduced RhoA protein levels after 1 week and improved hindlimb walking over 6 weeks. To explore a less invasive route, we tested intrathecal injection of Cy 3.5-labeled siRNA via lumbar puncture 1 day after SCI, which resulted in robust uptake in the T9-T10 injury site. Lumbar injection of siRhoA 1 day after SCI reduced RhoA mRNA and protein levels 3 days after injection. Although siRhoA treatment did not yield significant improvement in locomotion, it decreased tactile hypersensitivity significantly compared to controls. Histological analysis at 8 weeks showed significant improvement in white matter sparing with siRhoA compared to control siRNA. siRhoA treatment also resulted in less accumulation of ED1+macrophages, increased PKC-γ immunoreactivity in the corticospinal tract rostral to the injury site, and increased serotonergic fiber growth 12 mm caudal to the contusion site. The ability of siRhoA to preserve white matter and promote serotonergic axonal regrowth caudal to the injury site is likely to suppress allodynia. This provides justification for considering clinical development of RhoA inhibitors to treat SCI sub-acutely to reduce allodynia, which occurs frequently in SCI patients.
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Affiliation(s)
- Seiji Otsuka
- W.M. Keck Center for Collaborative Neuroscience, Rutgers Stem Cell Research Center, Department of Cell Biology & Neuroscience, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854-8082, USA
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Kopp MA, Liebscher T, Niedeggen A, Laufer S, Brommer B, Jungehulsing GJ, Strittmatter SM, Dirnagl U, Schwab JM. Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell Tissue Res 2012; 349:119-32. [PMID: 22350947 DOI: 10.1007/s00441-012-1334-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 01/16/2012] [Indexed: 01/16/2023]
Abstract
Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of "small molecules" from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting "tissue at risk" (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.
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Affiliation(s)
- M A Kopp
- Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
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45
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Loske P, Boato F, Hendrix S, Piepgras J, Just I, Ahnert-Hilger G, Höltje M. Minimal essential length of Clostridium botulinum C3 peptides to enhance neuronal regenerative growth and connectivity in a non-enzymatic mode. J Neurochem 2012; 120:1084-96. [PMID: 22239108 DOI: 10.1111/j.1471-4159.2012.07657.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
C3 ADP-ribosyltransferase is a valuable tool to study Rho-dependent cellular processes. In the current study we investigated the impact of enzyme-deficient peptides derived from Clostridium botulinum C3 transferase in the context of neuronal process elongation and branching, synaptic connectivity, and putative beneficial effects on functional outcome following traumatic injury to the CNS. By screening a range of peptidic fragments, we identified three short peptides from C3bot that promoted axon and dendrite outgrowth in cultivated hippocampal neurons. Furthermore, one of these fragments, a 26-amino acid peptide covering the residues 156-181 enhanced synaptic connectivity in primary hippocampal culture. This peptide was also effective to foster axon outgrowth and re-innervation in organotypical brain slice culture. To evaluate the potential of the 26mer to foster repair mechanisms after CNS injury we applied this peptide to mice subjected to spinal cord injury by either compression impact or hemisection. A single local administration at the site of the lesion improved locomotor recovery. In addition, histological analysis revealed an increased serotonergic input to lumbar motoneurons in treated compared with control mice. Pull-down assays showed that lesion-induced up-regulation of RhoA activity within the spinal cord was largely blocked by C3bot peptides despite the lack of enzymatic activity.
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Affiliation(s)
- Peter Loske
- Center for Anatomy, Functional Cell Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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46
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Shulga A, Magalhães AC, Autio H, Plantman S, di Lieto A, Nykjær A, Carlstedt T, Risling M, Arumäe U, Castrén E, Rivera C. The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons. J Neurosci 2012; 32:1757-70. [PMID: 22302815 PMCID: PMC6703341 DOI: 10.1523/jneurosci.3282-11.2012] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 11/28/2011] [Accepted: 12/05/2011] [Indexed: 01/09/2023] Open
Abstract
Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA(A)-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75(NTR). The increase in intracellular Ca(2+) triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75(NTR). We further show that high levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.
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Affiliation(s)
- Anastasia Shulga
- Institute of Biotechnology
- Neuroscience Center, and
- Department of Neurological Sciences, University of Helsinki, FI-00014 Helsinki, Finland
| | | | | | - Stefan Plantman
- Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | | | - Anders Nykjær
- The Lundbeck Foundation Research Center MIND, Department of Medical Biochemistry, Aarhus University, DK-8000C Aarhus, Denmark
| | - Thomas Carlstedt
- Department of Hand Surgery, Karolinska Institutet, Södersjukhuset, SE-118 83 Stockholm, Sweden, and
| | - Mårten Risling
- Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | | | | | - Claudio Rivera
- Institute of Biotechnology
- Neuroscience Center, and
- Université de la Méditerranée, UMR S901 Aix-Marseille 2, Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France
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47
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Becker D, McDonald JW. Approaches to repairing the damaged spinal cord: overview. HANDBOOK OF CLINICAL NEUROLOGY 2012; 109:445-61. [PMID: 23098730 DOI: 10.1016/b978-0-444-52137-8.00028-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Affecting young people during the most productive period of their lives, spinal cord injury (SCI) is a devastating problem for modern society. In the past, treating SCI seemed frustrating and hopeless because of the tremendous morbidity and mortality, life-shattering impact, and limited therapeutic options associated with the condition. Today, however, an understanding of the underlying pathophysiological mechanisms, the development of neuroprotective interventions, and progress toward regenerative interventions are increasing hope for functional restoration. In this chapter, we provide an overview of various repair strategies for the injured spinal cord. Special attention will be paid to strategies that promote spontaneous regeneration, including functional electrical stimulation, cell replacement, neuroprotection, and remyelination. The concept that limited rebuilding can provide a disproportionate improvement in quality of life is emphasized throughout. New surgical procedures, pharmacological treatments, and functional neuromuscular stimulation methods have evolved over the last decades and can improve functional outcomes after spinal cord injury; however, limiting secondary injury remains the primary goal. Tissue replacement strategies, including the use of embryonic stem cells, become an important tool and can restore function in animal models. Controlled clinical trials are now required to confirm these observations. The ultimate goal is to harness the body's own potential to replace lost central nervous system cells by activation of endogenous progenitor cell repair mechanisms.
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Affiliation(s)
- Daniel Becker
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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48
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Reier PJ, Lane MA, Hall ED, Teng YD, Howland DR. Translational spinal cord injury research: preclinical guidelines and challenges. HANDBOOK OF CLINICAL NEUROLOGY 2012; 109:411-33. [PMID: 23098728 PMCID: PMC4288927 DOI: 10.1016/b978-0-444-52137-8.00026-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Advances in the neurobiology of spinal cord injury (SCI) have prompted increasing attention to opportunities for moving experimental strategies towards clinical applications. Preclinical studies are the centerpiece of the translational process. A major challenge is to establish strategies for achieving optimal translational progression while minimizing potential repetition of previous disappointments associated with clinical trials. This chapter reviews and expands upon views pertaining to preclinical design reported in recently published opinion surveys. Subsequent discussion addresses other preclinical considerations more specifically related to current and potentially imminent cellular and pharmacological approaches to acute/subacute and chronic SCI. Lastly, a retrospective and prospective analysis examines how guidelines currently under discussion relate to select examples of past, current, and future clinical translations. Although achieving definition of the "perfect" preclinical scenario is difficult to envision, this review identifies therapeutic robustness and independent replication of promising experimental findings as absolutely critical prerequisites for clinical translation. Unfortunately, neither has been fully embraced thus far. Accordingly, this review challenges the notion "everything works in animals and nothing in humans", since more rigor must first be incorporated into the bench-to-bedside translational process by all concerned, whether in academia, clinical medicine, or corporate circles.
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Affiliation(s)
- Paul J Reier
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.
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49
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Kubo T, Tokita S, Yamashita T. Repulsive guidance molecule-a and demyelination: implications for multiple sclerosis. J Neuroimmune Pharmacol 2011; 7:524-8. [PMID: 22183806 DOI: 10.1007/s11481-011-9334-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/06/2011] [Indexed: 12/23/2022]
Abstract
Drug development for neurodegenerative and neuroinflammatory diseases such as multiple sclerosis and traumatic brain injury is challenging. One promising strategy is to target a molecule with multiple biological actions affecting divergent pathophysiological disease phases simultaneously since these diseases arise from multiple pathological phases. In recent years, we pursued this strategy with a focus on multiple sclerosis and spinal cord injury and found that repulsive guidance molecule-a (RGMa) inhibits regeneration of injured CNS axons following spinal cord injury. We also found that RGMa enhances CD4(+) T cell activation facilitating CNS demyelination in an animal model of MS, mouse experimental autoimmune encephalomyelitis (EAE), which supports the idea that RGMa has distinct pathological actions. The multiple functions of RGMa in the CNS and the immune system would provide a therapeutic opportunity to concurrently block the autoimmune reactions and axon injury in neurodegenerative and neuroinflammatory diseases. In this article, we introduce the therapeutic potential of targeting RGMa as a novel intervention for MS and spinal cord injury.
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Affiliation(s)
- Takekazu Kubo
- Molecular Function and Pharmacology Laboratories, Pharmaceutical Business, Taisho Pharmaceutical Co., Ltd, 403, Yoshino-cho 1-Chome, Kita-ku, Saitama-shi, Saitama, 331-9530, Japan.
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50
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Haque RM, Malone HR, Bauknight MW, Kellner MA, Ogden AT, Martin JH, Tanji K, Winfree CJ. Spinal cord bypass surgery with intercostal and spinal accessory nerves: an anatomical feasibility study in human cadavers. J Neurosurg Spine 2011; 16:178-86. [PMID: 22136392 DOI: 10.3171/2011.9.spine10378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Despite extensive study, no meaningful progress has been made in encouraging healing and recovery across the site of spinal cord injury (SCI) in humans. Spinal cord bypass surgery is an unconventional strategy in which intact peripheral nerves rostral to the level of injury are transferred into the spinal cord below the injury. This report details the feasibility of using spinal accessory nerves to bypass cervical SCI and intercostal nerves to bypass thoracolumbar SCI in human cadavers. METHODS Twenty-three human cadavers underwent cervical and/or lumbar laminectomy and dural opening to expose the cervical cord and/or conus medullaris. Spinal accessory nerves were harvested from the Erb point to the origin of the nerve's first major branch into the trapezius. Intercostal nerves from the T6-12 levels were dissected from the lateral border of paraspinal muscles to the posterior axillary line. The distal ends of dissected nerves were then transferred medially and sequentially inserted 4 mm deep into the ipsilateral cervical cord (spinal accessory nerve) or conus medullaris (intercostals). The length of each transferred nerve was measured, and representative distal and proximal cross-sections were preserved for axonal counting. RESULTS Spinal accessory nerves were consistently of sufficient length to be transferred to caudal cervical spinal cord levels (C4-8). Similarly, intercostal nerves (from T-7 to T-12) were of sufficient length to be transferred in a tension-free manner to the conus medullaris. Spinal accessory data revealed an average harvested nerve length of 15.85 cm with the average length needed to reach C4-8 of 4.7, 5.9, 6.5, 7.1, and 7.8 cm. The average length of available intercostal nerve from each thoracic level compared with the average length required to reach the conus medullaris in a tension-free manner was determined to be as follows (available, required in cm): T-7 (18.0, 14.5), T-8 (18.7, 11.7), T-9 (18.8, 9.0), T-10 (19.6, 7.0), T-11 (18.8, 4.6), and T-12 (15.8, 1.5). The number of myelinated axons present on cross-sectional analysis predictably decreased along both spinal accessory and intercostal nerves as they coursed distally. CONCLUSIONS Both spinal accessory and intercostal nerves, accessible from a posterior approach in the prone position, can be successfully harvested and transferred to their respective targets in the cervical spinal cord and conus medullaris. As expected, the number of axons available to grow into the spinal cord diminishes distally along each nerve. To maximize axon "bandwidth" in nerve bypass procedures, the most proximal section of the nerve that can be transferred in a tension-free manner to a spinal level caudal to the level of injury should be implanted. This study supports the feasibility of SAN and intercostal nerve transfer as a means of treating SCI and may assist in the preoperative selection of candidates for future human clinical trials of cervical and thoracolumbar SCI bypass surgery.
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Affiliation(s)
- Raqeeb M Haque
- Department of Neurological Surgery, Columbia University Medical Center, New York, USA
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