title: 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-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.
authors.affiliation: 1 Evotec, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delbary-Gossart
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Lee
authors.affiliation: 3 Sanofi Research, Exploratory Unit, Via Gaetano Sbodio 2, 20134 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Baroni
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamarche
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Arnone
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Canolle
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Amity
authors.initials: A
authors.lastname: Lin
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sacramento
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Salegio
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Castel
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delesque-Touchard
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Alam
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Laboudie
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Badia
authors.initials: B
authors.lastname: Ferzaz
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Savi
authors.affiliation: 4 From Sanofi Research, Early to Candidate, 195 route d'Espagne, 31036 Toulouse cedex, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Bresnahan
authors.affiliation: 1 Evotec, 195 route d'Espagne, 31036 Toulouse cedex, France Michael.Beattie@ucsf.edu Francoise.Bono@evotec.com.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.affiliation: 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA Michael.Beattie@ucsf.edu Francoise.Bono@evotec.com.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Beattie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D061251:Primary Cell Culture; D011869:Radioligand Assay; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020917:Receptor, trkA / Q000378:metabolism; D020127:Recovery of Function
chemical_list: C000612942:EVT901; C000611485:NTRK1 protein, human; D018696:Neuroprotective Agents; D010879:Piperazines; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA
keywords: EVT901; TBI; neuron; oligodendrocyte; p75NTR