Abstract SNACC-43

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The p75 neurotrophin receptor (p75NTR) is essential for secondary brain damage formation after experimental TBI

Sebastiani A, Gölz C, Schaible E, Luh C, Schaefer M, Werner C, Engelhard K, Thal S
University Medical Center of the Johannes Gutenberg-University, Mainz, Rheinland-, Germany

Objective: Traumatic brain injury (TBI) initiates a complex sequence of pathophysiological changes including excessive neurotransmitter and mediator release. Neurotrophins are mediators which promote neuronal survival, differentiation, and modulate synaptic plasticity. While mature forms of neurotrophins promote these beneficial effects, unprocessed forms of neurotrophins (pro-neurotrophins) induce cell death through p75 neurotrophin receptor (p75NTR) signaling. The p75NTR is widely expressed during synaptogenesis and is subsequently downregulated in the adult brain [1]. Secondary processes after cerebral insults e.g. TBI can reactivate the expression of p75NTR [2]. Therefore, the question was addressed whether posttraumatic p75NTR induction contributes to secondary brain damage formation after TBI.
Methods: Following approval of Animal Ethics Committee following experiments were performed: 1) mRNA levels of p75NTR were investigated in the brain tissue 15 minutes, 6, 12, 24, and 48 hours after controlled cortical impact (CCI; n=9-10/group). 2) Histopathological damage (Nissl staining) was determined in p75NTR deficient mice and wildtype-littermates (WT) 24 hours (n=8/group) and 5 days (n=11/group) after CCI. 3) Mice subjected to CCI were treated with thepharmacological p75NTR signaling inhibitor TATPep5 in low dose (LD) or high dose (HD) and compared to TAT peptide (TAT ctrl). Contusion volume (Nissl staining) was evaluated 24 hours after injury (n=11/group). Statistics: Mann-Whitney Rank Sum test; Holm-Bonferroni correction; p < 0.05.
Results: The mRNA levels of p75NTR increased 2fold within 24 hours after CCI (p<0.001). In p75NTR deficient mice contusion volume was decreased by 23.4% (p=0.004) 24 hours and by 33% (p=0.008) 5 days following trauma. Pharmacological inhibition of p75NTR by HD TAT Pep5 reduced lesion volume 24 hours after CCI by 18% compare to the TAT ctrl (p=0.018) group.
Conclusion: The present implicates a role for p75NTR as a key activator of posttraumatic brain damage. Pharmacological inhibition of p75NTR signalling was less potent to prevent secondary brain damage compared to complete genetic depletion of the receptor. Despite this lower efficacy of the pharmacological inhibiton compared with p75NTR knockout, the present data suggests p75NTR to be a promising and clinically relevant target to reduce neuronal cell death after TBI
1. Underwood, Int. J. Biochem Cell Biol. 2008; 40(9): 1664-8
2. Jansen, Nat. Neurosci. 2007 Nov; 10(11):1449-57

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