title: Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain.
abstract: Recently, some studies suggested that inhibition of Rho-kinase (ROCK) prevented cerebral ischemia injury through inhibiting inflammatory reaction, increasing cerebral blood flow, modulating the neuronal actin cytoskeleton polymerization, and preventing tau hyperphosphorylation and p25/CDK5 increase. However, there is little information regarding the effects of ROCK inhibitor on the neuronal apoptosis in ischemic brain injury. In this study, we determined whether ROCK inhibitor, fasudil, inhibited ischemic neuronal apoptosis through phosphatase and tensin homolog deleted on chromosome10 (PTEN)/Akt/signal pathway in vivo. Adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion. Rats received ROCK inhibitor, fasudil (10 mg/kg), at 30 min before middle cerebral artery occlusion. The infarct area, neuronal apoptosis and caspase-3 activity was significantly decreased by fasudil with improvement of neurological deterioration. However, the beneficial effects of fasudil were attenuated by the co-application of LY294002 (PI3K inhibitor). Fasudil maintained postischemic Akt activity at relatively proper level and decreased the augmentation of PTEN and ROCK activity in the penumbra area. Furthermore, fasudil inhibited attenuation of GSK-β and Bad phosphorylation in the penumbra area. In conclusion, the findings provide another consideration that fasudil protects the brain against ischemia injury through decreasing neuronal apoptosis and reveals the link between the ROCK inhibition and the PTEN/Akt pathway.
authors.affiliation: Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wu
authors.forename: Jianzhe
authors.initials: J
authors.lastname: Li
authors.forename: Hankun
authors.initials: H
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Fang
authors.forename: Dongfang
authors.initials: D
authors.lastname: Wu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; C049347:fasudil