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Molecules. 2018 Oct 31;23(11). pii: E2828. doi: 10.3390/molecules23112828.

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

Wang L1,2, Wang X3, Li T4,5, Zhang Y6, Ji H7,8.

Author information

1
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. aprilwln@stu.cpu.edu.cn.
2
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. aprilwln@stu.cpu.edu.cn.
3
Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China. xiaoliwang@jiangnan.edu.cn.
4
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. lttcpu@cpu.edu.cn.
5
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. lttcpu@cpu.edu.cn.
6
Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. zyhtgd@163.com.
7
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. huiji@cpu.edu.cn.
8
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. huiji@cpu.edu.cn.

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.

KEYWORDS:

NOX2; PI3Kγ; cerebral ischemia/reperfusion; hydrogen sulfide; microglial activation

PMID:
30384445
PMCID:
PMC6278485
DOI:
10.3390/molecules23112828
[Indexed for MEDLINE]
Free PMC Article

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