Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice

TY - JOUR

T1 - Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice

AU - Alder, Janet

AU - Fujioka, Wendy

AU - Giarratana, Anna

AU - Wissocki, Jenna

AU - Thakkar, Keya

AU - Vuong, Phung

AU - Patel, Bijal

AU - Chakraborty, Trisha

AU - Elsabeh, Rami

AU - Parikh, Ankit

AU - Girn, Hartaj S.

AU - Crockett, David

AU - Thakker-Varia, Smita

N1 - Publisher Copyright: © 2016 Taylor & Francis Group, LLC.

PY - 2016/1/2

Y1 - 2016/1/2

N2 - Primary objective: Neurotrophin levels are elevated after TBI, yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signalling improves recovery following TBI.Research design: Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function.Main outcomes and results: p75 was up-regulated and TrkB was down-regulated 1 day post-LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist.Conclusions: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.

AB - Primary objective: Neurotrophin levels are elevated after TBI, yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signalling improves recovery following TBI.Research design: Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function.Main outcomes and results: p75 was up-regulated and TrkB was down-regulated 1 day post-LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist.Conclusions: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.

KW - Animal models

KW - learning and memory

KW - locomotor function

KW - neurotrophic factors

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U2 - 10.3109/02699052.2015.1088963

DO - 10.3109/02699052.2015.1088963

M3 - Article

C2 - 26579945

SN - 0269-9052

VL - 30

SP - 48

EP - 65

JO - Brain injury

JF - Brain injury

IS - 1

ER -