title: Proneurotrophin Binding to P75 Neurotrophin Receptor (P75ntr) Is Essential for Brain Lesion Formation and Functional Impairment after Experimental Traumatic Brain Injury.
abstract: Traumatic 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.
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Anne
authors: A
authors: Sebastiani
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Christina
authors: C
authors: Gölz
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Christian
authors: C
authors: Werner
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Michael K E
authors: MK
authors: Schäfer
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Kristin
authors: K
authors: Engelhard
authors: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
authors: Serge C
authors: SC
authors: Thal
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse
keywords: BDNF; CCI; TBI; neurotrophins, NGF; p75NTR; traumatic brain injury