title: Rho-kinase inhibitor prevents acute injury against transient focal cerebral ischemia by enhancing the expression and function of GABA receptors in rats.
abstract: Studies have shown hydroxyfasudil-mediated inhibition of Rho-kinase (ROCK) has efficacy in rodent models of focal ischemia and in in vitro systems that recapitulate stroke conditions. However, the mechanisms underlying the neuroprotective effects of the ROCK inhibitor on stroke are not well understood. In this study, we examined the role of γ-aminobutyric acid (GABA) interneurons in the effects of hydroxyfasudil on transient middle cerebral artery occlusion (tMCAO) induced acute ischemia-reperfusion injury to explore the mechanisms. tMCAO rats developed marked neurological deficits and impaired long-term potentiation; these effects were attenuated by hydroxyfasudil. Expression of GABAAand GABABreceptors after ischemia was decreased to various extents in three brain regions: the cortex, hippocampus, and striatum. Hydroxyfasudil up-regulated expression in the cortex and hippocampus but not in the striatum. Moreover, hydroxyfasudil could suppress the activation of nuclear factor-κB (NF-κB) in these regions during the acute ischemia. We further found that in tMCAO rats, hydroxyfasudil was able to abolish the decrease in GABAAand GABABreceptor phosphorylation triggered by high-frequency stimulation as well as the activation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In summary, our results suggest ROCK inhibition improved neurological function and mitigated synaptic plasticity deficits caused by transient focal cerebral ischemia through the inactivation of two distinct pathways: (1) a ROCK-NF-κB pathway that leads to the suppression of GABAAand GABABexpression, and (2) a ROCK-PTEN pathway that decreases the phosphorylation of GABAAand GABAB, thereby affecting receptor function by triggering receptor endocytosis and the degradation of internalized receptors.
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing, China.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Wen
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Central laboratory, Peking University People's Hospital, Beijing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Central laboratory, Peking University People's Hospital, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing, China. Electronic address: pkuph_yjk@163.com.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Feng
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D051059:PTEN Phosphohydrolase
keywords: GABA; Hydroxyfasudil; LTP; ROCK; Transient middle cerebral artery occlusion (tMCAO)