A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury
| Autor: | Isabelle Lamarche, Nathalie Delesque-Touchard, Michael S. Beattie, Pierre Savi, Benoit Canolle, Jacqueline C. Bresnahan, Jean-Marc Herbert, Jeffrey Sacramento, Badia Ferzaz, Sandrine Delbary-Gossart, Sangmi Lee, Adam R. Ferguson, Marie-Noelle Castel, Antoine Alam, Baroni Marco, Patricia Laboudie, Ernesto A. Salegio, Geoffrey T. Manley, Michele Arnone, Françoise Bono, Amity Lin |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Traumatic 0301 basic medicine Cell Count Apoptosis Neurodegenerative Tropomyosin receptor kinase A Receptor Nerve Growth Factor Medical and Health Sciences Tropomyosin receptor kinase C Piperazines Radioligand Assay 0302 clinical medicine Injury - Trauma - (Head and Spine) Brain Injuries Traumatic Nerve Growth Factor TBI 2.1 Biological and endogenous factors EVT901 Low-affinity nerve growth factor receptor Aetiology Phosphorylation Cells Cultured Neurons Cultured Oligodendroglia Neuroprotective Agents medicine.anatomical_structure 5.1 Pharmaceuticals trkA Neurological Development of treatments and therapeutic interventions Drug Signal transduction Receptor Neurite Cells Primary Cell Culture Biology Dose-Response Relationship p75NTR 03 medical and health sciences medicine Animals Humans Receptor trkA Cell Proliferation Neurology & Neurosurgery Dose-Response Relationship Drug Psychology and Cognitive Sciences Neurosciences Original Articles Recovery of Function neuron Oligodendrocyte Brain Disorders Rats 030104 developmental biology Nerve growth factor nervous system Brain Injuries Injury (total) Accidents/Adverse Effects sense organs Neurology (clinical) Neuron Neuroscience oligodendrocyte 030217 neurology & neurosurgery Demyelinating Diseases |
| Zdroj: | Brain : a journal of neurology, vol 139, iss Pt 6 Brain |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | The p75 neurotrophin receptor (p75NTR) is a member of the TNF-receptor superfamily. Delbary-Gossart, Lee et al. describe the neuroprotective effects of a novel piperizine derivative that blocks p75NTR. In two rodent models of traumatic brain injury, EVT901 protects neurons and glia, reduces inflammation and seizure susceptibility, and improves neurological outcomes. The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro. Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-β. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected. |
| Databáze: | OpenAIRE |
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