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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

ABSTRACT: 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-?. 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.

SUBMITTER: Delbary-Gossart S

PROVIDER: S-EPMC4892754 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

Delbary-Gossart Sandrine S Lee Sangmi S Baroni Marco M Lamarche Isabelle I Arnone Michele M Canolle Benoit B Lin Amity A Sacramento Jeffrey J Salegio Ernesto A EA Castel Marie-Noelle MN Delesque-Touchard Nathalie N Alam Antoine A Laboudie Patricia P Ferzaz Badia B Savi Pierre P Herbert Jean-Marc JM Manley Geoffrey T GT Ferguson Adam R AR Bresnahan Jacqueline C JC Bono Françoise F Beattie Michael S MS

Brain : a journal of neurology 20160415 Pt 6

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 c ...[more]

PMID: 27084575

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Project description:BackgroundInjuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2?, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.MethodsAccordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.ResultsMorphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.ConclusionThis study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.

Project description:There is a significant need for novel treatments that will improve traumatic brain injury (TBI) outcomes. One potential neuroprotective mechanism is to increase oxygen binding proteins such as neuroglobin. Neuroglobin has a high affinity for oxygen, is an effective free radical scavenger, and is neuroprotective within the brain following hypoxia and ischemia. The purpose of this study was to determine whether neuroglobin overexpression improves sensorimotor outcomes following TBI in transgenic neuroglobin overexpressing (NGB) mice. Additional study aims were to determine if and when an endogenous neuroglobin response occurred following TBI in wild-type (WT) mice, and in what brain regions and cell types the response occurred. Controlled cortical impact (CCI) was performed in adult (5 month) C57/BL6 WT mice, and NGB mice constitutively overexpressing neuroglobin via the chicken beta actin promoter coupled with the cytomegalovirus distal enhancer. The gridwalk task was used for sensorimotor testing of both WT and NGB mice, prior to injury, and at 2, 3, and 7 days post-TBI. NGB mice displayed significant reductions in the average number of foot faults per minute walking at 2, 3, and 7 days post-TBI when compared to WT mice at each time point. Neuroglobin mRNA expression was assessed in the injured cortex of WT mice prior to injury, and at 1, 3, 7, and 14 days post-TBI using quantitative real time polymerase chain reaction (qRT-PCR). Neuroglobin mRNA was significantly increased at 7 days post-TBI. Immunostaining showed neuroglobin primarily localized to neurons and glial cells in the injured cortex and ipsilateral hippocampus of WT mice, while neuroglobin was present in all brain regions of NGB mice at 7 days post-TBI. These results showed that overexpression of neuroglobin reduced sensorimotor deficits following TBI, and that an endogenous increase in neuroglobin expression occurs during the subacute period. Increasing neuroglobin expression through novel therapeutic interventions during the acute period after TBI may improve recovery.

Project description:The rat high-impact free weight drop model mimics the diffuse axonal injury caused by severe traumatic brain injury in humans, while severe controlled cortical impact can produce a severe traumatic brain injury model using precise strike parameters. In this study, we compare the pathological mechanisms and pathological changes between two rat severe brain injury models to identify the similarities and differences. The severe controlled cortical impact model was produced by an electronic controlled cortical impact device, while the severe free weight drop model was produced by dropping a 500 g free weight from a height of 1.8 m through a plastic tube. Body temperature and mortality were recorded, and neurological deficits were assessed with the modified neurological severity score. Brain edema and blood-brain barrier damage were evaluated by assessing brain water content and Evans blue extravasation. In addition, a cytokine array kit was used to detect inflammatory cytokines. Neuronal apoptosis in the brain and brainstem was quantified by immunofluorescence staining. Both the severe controlled cortical impact and severe free weight drop models exhibited significant neurological impairments and body temperature fluctuations. More severe motor dysfunction was observed in the severe controlled cortical impact model, while more severe cognitive dysfunction was observed in the severe free weight drop model. Brain edema, inflammatory cytokine changes and cortical neuronal apoptosis were more substantial and blood-brain barrier damage was more focal in the severe controlled cortical impact group compared with the severe free weight drop group. The severe free weight drop model presented with more significant apoptosis in the brainstem and diffused blood-brain barrier damage, with higher mortality and lower repeatability compared with the severe controlled cortical impact group. Severe brainstem damage was not found in the severe controlled cortical impact model. These results indicate that the severe controlled cortical impact model is relatively more stable, more reproducible, and shows obvious cerebral pathological changes at an earlier stage. Therefore, the severe controlled cortical impact model is likely more suitable for studies on severe focal traumatic brain injury, while the severe free weight drop model may be more apt for studies on diffuse axonal injury. All experimental procedures were approved by the Ethics Committee of Animal Experiments of Tianjin Medical University, China (approval No. IRB2012-028-02) in February 2012.

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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

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