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

Autor: David P. Crockett, Bijal Patel, Hartaj S Girn, Rami Elsabeh, Jenna Wissocki, Keya Thakkar, Anna O. Giarratana, Smita Thakker-Varia, Phung Vuong, Trisha Chakraborty, Wendy Fujioka, Janet Alder, Ankit Parikh
Rok vydání: 2015
Předmět:
Male
0301 basic medicine
Morris water navigation task
Apoptosis
Tropomyosin receptor kinase B
Mice
Cognition
0302 clinical medicine
Neurotrophic factors
Brain Injuries
Traumatic
Locomotors function
Developmental and Educational Psychology
skin and connective tissue diseases
biology
Animal Models
Neurotrophin
musculoskeletal diseases
Agonist
medicine.medical_specialty
Sensory Receptor Cells
Traumatic brain injury
medicine.drug_class
Neurotropic factor
Neuroscience (miscellaneous)
Receptors
Nerve Growth Factor
Learning and memory
03 medical and health sciences
Internal medicine
medicine
Animals
Receptor
trkB
Nerve Growth Factors
business.industry
Brain-Derived Neurotrophic Factor
Antagonist
Flavones
medicine.disease
biological factors
Mice
Mutant Strains
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
nervous system
Astrocytes
Trk receptor
biology.protein
sense organs
Neurology (clinical)
business
Neuroscience
030217 neurology & neurosurgery
Zdroj: Brain Injury. 30:48-65
ISSN: 1362-301X
0269-9052
DOI: 10.3109/02699052.2015.1088963
Popis: 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 signaling 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 upregulated and TrkB is downregulated 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.
Databáze: OpenAIRE
Externí odkaz: