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8e Protects against Acute Cerebral Ischemia by Inhibition of PI3Kγ-Mediated Superoxide Generation in Microglia

by 1,2, 3, 1,2, 4,* and 1,2,*
1
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
2
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
3
Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China
4
Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(11), 2828; https://doi.org/10.3390/molecules23112828
Received: 29 September 2018 / Revised: 28 October 2018 / Accepted: 29 October 2018 / Published: 31 October 2018
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. View Full-Text
Keywords: hydrogen sulfide; cerebral ischemia/reperfusion; microglial activation; NOX2; PI3Kγ hydrogen sulfide; cerebral ischemia/reperfusion; microglial activation; NOX2; PI3Kγ
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MDPI and ACS Style

Wang, L.; Wang, X.; Li, T.; Zhang, Y.; Ji, H. 8e Protects against Acute Cerebral Ischemia by Inhibition of PI3Kγ-Mediated Superoxide Generation in Microglia. Molecules 2018, 23, 2828.

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