Alpha Omega Alpha Honor Medical Society

2012 Research Abstract

Effects of p75 and TrkB Signaling on Cognitive and Motor Function Following Traumatic Brain Injury

Investigators: Wendy Fujioka, David Crockett, Smita Thakker-Varia, Janet Alder, Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School

Mentor: Janet Adler, MD, Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School

Traumatic Brain Injury (TBI) may lead to severe and permanent impairment of nervous tissue, causing deficits in cognition and motor-sensory skills. While mature neurotrophin’s regulate neural development, precursor pro-neurotrophins control neuronal apoptosis. Our previous studies indicate that the toxic proBDNF/p75NTR pathway is predominantly upregulated after injury. We have further demonstrated that genetic inhibition of the p75 toxic pathway promotes recovery from TBI. We are now testing the role of these pathways using pharmaceutical agents. TAT-Pep5(p75 antagonist), 7,8dihydroxyflavone(7,8-DHF) (TrkB agonist), or vehicle was administered to sham and lateral fluid percussion (LFP) injured mice. We observed reduced neuronal degeneration at 1day post-injury as assayed by FluoroJade-C staining in the cortex of mice treated with 7,8DHF, and in the cortex and hippocampus of mice administered TAT-Pep5 relative to vehicle controls. Cell death was detected using activated caspase-3 immunohistochemistry and demonstrated that both 7,8DHF and TAT-Pep5 significantly reduces the number of apoptotic cells in the cortex relative to vehicle. This suggests that pharmacological inhibition of the p75 pathway or activating the TrkB pathway attenuates the cellular effects of LFP. We then performed behavioral studies and observed a longer latency to fall on the Rotarod test indicating improved motor skills in mice treated with TAT-Pep5 relative to vehicle, but no significant effect of 7,8DHF was observed. Cognitive function was measured using the Morris Water Maze and found that the mice administered with TAT-Pep5 located the hidden platform faster and had better memory recall than vehicle controls. Thus both motor function and spatial memory were improved in mice treated with p75 antagonist. Inhibiting the p75/proBDNF pathway appears to be more effective than activating the TrkB pathway although future studies will examine a combinatorial effect. By targeting different components of the neurotrophic pathway we have shown a possible clinical paradigm to counteract the damaging effects of TBI.

Updated on August 5, 2013.

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