title: Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway.
abstract: Ischemia-induced brain damage leads to apoptosis like delayed neuronal death in selectively vulnerable regions, which could further result in irreversible damages. Previous studies have demonstrated that neurons in the CA1 area of hippocampus are particularly sensitive to ischemic damage. Atorvastatin (ATV) has been reported to attenuate cognitive deficits after stroke, but precise mechanism for neuroprotection remains unknown. Therefore, the aims of this study were to investigate the neuroprotective mechanisms of ATV against ischemic brain injury induced by cerebral ischemia reperfusion. In this study, four-vessel occlusion model was established in rats with cerebral ischemia. Rats were divided into five groups: sham group, I/R group, I/R+ATV group, I/R+ATV+LY, and I/R+SP600125 group. Cresyl violet staining was carried out to examine the neuronal death of hippocampal CA1 region. Immunoblotting was used to detect the expression of the related proteins. Results showed that ATV significantly protected hippocampal CA1 pyramidal neurons against cerebral I/R. ATV could increase the phosphorylation of protein kinase B (Akt1) and nNOS, diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3. Whereas, all of the aforementioned effects of ATV were reversed by LY294002 (an inhibitor of Akt1). Furthermore, pretreatment with SP600125 (an inhibitor of JNK) diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3 after cerebral I/R. Taken together, our results implied that Akt-mediated phosphorylation of nNOS is involved in the neuroprotection of ATV against ischemic brain injury via suppressing JNK3 signaling pathway that provide a new experimental foundation for stroke therapy.
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China. hzsxxyy2015@sohu.com.|Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China. hzsxxyy2015@sohu.com.|Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China. hzsxxyy2015@sohu.com.
authors.forename: Sen
authors.initials: S
authors.lastname: Shao
authors.affiliation: The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Xu
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Ge
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Guanfeng
authors.initials: G
authors.lastname: Chen
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Lian
authors.initials: L
authors.lastname: Luo
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, 200040, People's Republic of China. hsfayongzhang@163.com.
authors.forename: Fayong
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin / Q000378:metabolism / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D000069059:Atorvastatin; D052248:Nitric Oxide Synthase Type I; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Akt1; Cerebral ischemia; JNK3; LY294002; nNOS