• Anne Sebastiani, Christina Gölz, Christian Werner, Michael K E Schäfer, Kristin Engelhard, and Serge C Thal.
• Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
• J. Neurotrauma. 2015 Oct 15; 32 (20): 159916071599-607.

AbstractTraumatic brain injury (TBI) initiates an excessive mediator release of e.g. neurotrophins, which promote neuronal survival, differentiation, and modulate synaptic plasticity. Paradoxically, mature forms of neurotrophins promote neuronal survival, whereas unprocessed forms of neurotrophins induce cell death through p75 neurotrophin receptor (p75NTR) signaling. p75NTR is widely expressed during synaptogenesis and is subsequently downregulated in adulthood. Repair mechanisms after acute cerebral insults can reactivate its expression. Therefore, the influence of p75NTR on secondary brain damage was addressed. mRNA levels of p75NTR and its ligands were quantified in brain tissue up to 7 days after experimental TBI (controlled cortical impact; CCI). Brain damage, motor function and inflammatory marker gene expression were determined in mice lacking the proneurotrophin-binding site of the p75NTR protein (NGFR(-/-)) and wild type littermates (NGFR(+/+)) 24 h and 5 days after CCI. In addition, the effect of TAT-Pep5 (pharmacological inhibitor of the intracellular p75NTR death domain) on lesion volume was evaluated 24 h after insult. p75NTR mRNA levels were induced nine-fold by TBI. In NGFR(-/-) mice, lesion volume was reduced by 29% at 24 h and by 21% 5 days after CCI. Motor coordination was significantly improved 24 h after trauma compared with the wild type. Pharmacological inhibition of the p75NTR signaling reduced lesion volume by 18%. The present study presents first time evidence that genetic mutation of the neurotrophin interaction site of p75NTR strongly limits post-traumatic cell death. In addition, we revealed pharmacological targeting of the intracellular p75NTR cell death domain as a promising approach to limit acute brain damage.

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