title: Investigation of the mechanisms of neuroprotection mediated by Ro5-4864 in brain injury.
abstract: Increasing evidence has established the involvement of the 18-kDa translocator protein (TSPO) in the process of mitochondrial membrane permeabilization and subsequent apoptosis through modulation of the mitochondrial permeability transition pore. Recent studies have shown that treatment with Ro5-4864, a TSPO ligand, resulted in a neuroprotective effect in traumatic brain injury. Yet, the nature of this effect remained uncertain as mature neurons are considered to be lacking the TSPO protein. In order to investigate the mechanism of Ro5-4864-mediated neuroprotection, the neuro-inflammatory and neurosteroid response to cortical injury was tested in sham-operated, vehicle, cyclosporine A (CsA) and Ro5-4864-treated rats. As anticipated, the levels of interleukin 1β and tumor necrosis factor α, as well as the astrocyte and microglia cellular density in the injured area were all decreased by CsA in comparison with the vehicle group. By contrast, no visible effect could be observed in Ro5-4864-treated animals. None of the groups showed any significant difference with any other in respect with the expression of brain-derived neurotrophic factor. Double immunofluorescence staining with NeuN and TSPO confirmed the absence of TSPO in native neurons though showed clear evidence of co-localization of TSPO in the cytoplasm of NeuN-stained injured neurons. Altogether, this study shows that the neuronal protection mediated by Ro5-4864 in brain injury cannot be solely attributed to an indirect effect of the ligand on glial TSPO but may also represent the consequence of the modulation of upregulated TSPO in injured neurons. This observation may be of importance for future pharmacological research in neurotrauma.
authors.affiliation: Eliachar Research Laboratory, Medical Center of the Galilee, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia 22100, Israel.
authors.forename: Eilam
authors.initials: E
authors.lastname: Palzur
authors.affiliation: Department of Neurosurgery, Medical Center of the Galilee, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia 22100, Israel.
authors.forename: Aviram
authors.initials: A
authors.lastname: Sharon
authors.affiliation: Eliachar Research Laboratory, Medical Center of the Galilee, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia 22100, Israel.
authors.forename: Mona
authors.initials: M
authors.lastname: Shehadeh
authors.affiliation: Eliachar Research Laboratory, Medical Center of the Galilee, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia 22100, Israel; Department of Neurosurgery, Medical Center of the Galilee, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia 22100, Israel. Electronic address: JeanS@gmc.gov.il.
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Soustiel
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005455:Fluorescent Antibody Technique; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D016572:Cyclosporine
keywords: 18-kDa translocator protein; Ro5-4864; cyclosporine A; mitochondrial permeability transition pore; neuroinflammation; traumatic brain injury