Neuroprotective effect of Ro5-4864 following brain injury.
The 18 kDa translocator protein (TSPO) is a protein complex located at the outer mitochondrial membrane and interacting with the mitochondrial permeability transition pore (mPTP), indicating its involvement in the control of mPTP opening. We intended to explore the effect of TSPO ligands, PK 11195 and Ro5-4864 on apoptosis in a rat model of cortical injury. Sprague-Dawley rats received a daily intraperitoneal injection of dimethylsulfoxide (vehicle), PK 11195, or Ro5-4864, starting 2 days prior the injury and a third injection after the injury. At 6 weeks, immunohistochemistry analysis showed that Ro5-4864 resulted in a significant increase in the number of surviving neurons and in the density of the neurofilament network in the perilesional cortex in comparison with animals of the vehicle and PK 11195 groups. In tissue samples dissected from the injured area, Ro5-4864 caused a significant reduction in activation of caspases 3 and 9 but not of caspase 8 in comparison with the vehicle and PK 11195 groups. In addition, measurements of transmembrane mitochondrial potential of mitochondria (Deltapsi(M)) isolated from normal rat brain showed that loss of Deltapsi(M) induced by recombinant Bax could be significantly reduced by Ro5-4864 in a concentration-dependent manner. Our findings indicate that the neuroprotective effect shown by Ro5-4864 in the present model of brain injury involves the mitochondrial pathway of apoptosis modulation of mPTP.
Soustiel
Jean F
JF
Acute Brain Injury Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. j_soustiel@rambam.health.gov.il
Zaaroor
Menashe
M
Vlodavsky
Eugene
E
Veenman
Leo
L
Weizman
Abraham
A
Gavish
Moshe
M
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D002352:Carrier Proteins; D003292:Convulsants; D007546:Isoquinolines; D008024:Ligands; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D020169:Caspases; C037850:PK 11195