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

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

Regeneration du nerf peripherique chez la souris Trembler, porteuse d'une mutation affectant la cellule de Schwann : influence de l'environnement non neuronal

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Additional file 1: Figure S1. of A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury

Complete PCA solution. To understand the relationship of behavioral outcome and innate immune cell responses, multivariate PC analysis was used. (A) PCA applies eigenvalue decomposition to the entire matrix cross correlations of all outcomes and clusters variables that move together as an integrated, optimally weighted linear composite (PC) to maximally explain the variance in cross-correlation. Once the first eigenvalue decomposition (PC1) is extracted, a second orthogonal (uncorrelated) decomposition calculated accounting for the second highest cluster of variance (PC2) and so on until all of the variance in the data set is partitioned into sequentially numbered PCs. The PC measures are rank ordered by the proportion of the total variance in the dataset that they explain. Standardized statistical PC retention rules are then applied to retain ‘significant’ PCs with eigenvalues > 1 and (B) PCs above the ‘elbow of the scree plot. (C) Interpretation of PC content based on PC loadings, which are equivalent to a pearson correlation between each variable and the PC composites. The PC loading pattern shows the contribution every single variable (outcome measures) on the extracted PCs. This analysis yielded 5 dimensional PC loading patterns (total, 80.55 % of variance). The PC1 module represented the relationship between neurological outcome and pro-inflammatory monocyte responses (27.13 % of variance). The individual PC score (see Fig. 9b) for each subject is the sum of the multiplied loading by the individual raw value of single outcome measures. The individual PC scores are used to define the impact of experimental manipulations on the relationship between outcome measures. (PDF 91 kb

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

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