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.

CoQ10 Augments Rosuvastatin Neuroprotective Effect in a Model of Global Ischemia via Inhibition of NF-κB/JNK3/Bax and Activation of Akt/FOXO3A/Bim Cues

“…Furthermore, another explanation can be led by the upregulation of p -Akt, where Shao et al (2016) reported that administration of LY294002, a PI3K inhibitor, reversed the hippocampal protective effect of atorvastatin, another HMG-CoA reductase suppressor, through the inhibition of p -Akt and the upregulation of p -JNK3, suggesting the inverse correlation between the two molecules.…”

“…Aside from their destructive role, ROS/RNS initiate apoptotic signaling pathways, such as JNK3 ( Hu et al, 2012 ), which is an important subclass of the mitogen-activated protein kinase family ( Meloni et al, 2014 ). Activated JNK3 aggravates ischemia-induced apoptotic signaling by promoting the expression/activity of crucial proteins involved in apoptosis, such as c-Jun, Bcl-2 associated X protein (Bax), and caspase-3 ( Hetz et al, 2005 ; Shao et al, 2016 ). Hence, inhibition of JNK3 shows a neuroprotective effects against several models of cerebral I/R injury ( Ge et al, 2017 ; Luo et al, 2017 ).…”

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

“…All of these protective effects of atorvastatin are reversed by LY294002 [an inhibitor of phosphatidylinositide 3-kinase (PI3K)]. Pretreatment with JNK inhibitor SP600125 diminishes the phosphorylation of JNK3 and c-Jun, and further inhibits the activation of caspase-3 after cerebral ischemia/reperfusion (Shao et al, 2017 ).…”

Statins and the Brain: More than Lipid Lowering Agents?

“…Ischemia/reperfusion suppresses Akt/nNOS pathway, leading to the activation of JNK3 and induction of apoptosis. In this context, atorvastatin pre-treatment prevents the reduction in Akt phosphorylation mediated by ischemic damage and promotes survival in hippocampal neurons [308]. Statin-mediated neuroprotection in stroke may be also exerted by immunomodulatory actions.…”