title: Neuroprotection against permanent focal cerebral ischemia by ginkgolides A and B is associated with obstruction of the mitochondrial apoptotic pathway via inhibition of c-Jun N-terminal kinase in rats.
abstract: We have previously reported that ginkgolides containing ginkgolides A and B (GKAB) reduce infarct size in a rat model of focal ischemia. c-Jun N-terminal kinase (JNK), also known as stress-activated kinase (SAPK), is a critical stress-responsive kinase activated by various brain insults. Previous studies have demonstrated a brief increase in p-SAPK/JNK levels after focal ischemic brain injuries. In this study, we sought to investigate whether the neuroprotective effects of GKAB in rat models of permanent focal cerebral ischemia are associated with the JNK signaling pathway. Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion by intraluminal suture blockade. GKAB was injected intravenously immediately after ischemia onset. Here we demonstrate in rats that GKAB reduces neuronal apoptosis and blocks the increase of p-SAPK/JNK levels and nuclear translocation after cerebral ischemia in a dose-dependent manner. Furthermore, we report that cerebral ischemia increases ischemia-induced induction of reactive oxygen species, and this effect was blocked by GKAB. In addition, we show that BimL is induced and attenuated by GKAB. GKAB also repressed the ischemia-induced increase in the expression of Bax and reversed the decline in expression of Bcl-2. Likewise, there was a reduction in the release or activation of several mitochondrial proapoptotic molecules, including cytochrome c, caspases 3 and 9, and PARP. Taken together, our findings strongly suggest that GKAB-mediated neuroprotective effects against focal ischemia act through the inhibition of p-SAPK/JNK activation, in which the obstruction of the mitochondrial apoptotic pathway via the JNK signaling pathway is a key downstream mechanism of GKAB.
authors: Department of Pharmacy, Putuo People's Hospital, Shanghai, China.
authors: Xuan
authors: X
authors: Wang
authors: Cui-Min
authors: CM
authors: Jiang
authors: Hai-Ying
authors: HY
authors: Wan
authors: Jun-Lu
authors: JL
authors: Wu
authors: Wen-Qiang
authors: WQ
authors: Quan
authors: Kai-Yin
authors: KY
authors: Wu
authors: Dong
authors: D
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D046934:Ginkgolides / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008928:Mitochondria; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
chemical_list: D046934:Ginkgolides; D007783:Lactones; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C045856:ginkgolide B; D048031:JNK Mitogen-Activated Protein Kinases; C477042:ginkgolide A
keywords: GKAB; c-Jun N-terminal kinase; mitochondrial apoptotic pathway; neuroprotection; permanent focal cerebral ischemia