Abstract
The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.
Highlights
As one of the major causes of death and serious long-term disability, stroke produces immense health and economic burdens globally
Middle cerebral artery occlusion (MCAO) in rats induces lesions in the cortical and striatal which are involved in the processing of sensorimotor information
The results showed that the numbers of transferase dUTP nick end labeling (TUNEL) positive nuclei, i.e., the apoptotic nuclei, in the 8e-treated groups were much fewer than those in the transient middle cerebral artery occlusion (tMCAO) + vehicle group (10 mg/kg, p < 0.05; 20 mg/kg, p < 0.01)
Summary
As one of the major causes of death and serious long-term disability, stroke produces immense health and economic burdens globally. In 2013, 6.5 million stroke deaths were reported worldwide, 67% of which were caused by ischemic stroke [1]. Intravenous thrombolysis with tissue-type plasminogen activator (tPA) is the only approved treatment for acute ischemic stroke, but the benefit is strongly time-dependent. A tremendous amount of work has been done on developing neuroprotective agents, which appeared to be quite credible on animal models. None of these agents have been demonstrated to be effective where humans are concerned. This may be partly due to overlooking the fact that all cell types
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
