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

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.

• Authors: Linna Wang, Xiaoli Wang, Tingting Li, Yihua Zhang, Hui Ji
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 11 (Oct 31 2018) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30384445 (Publication Type: Journal Article)

Chemical References

• Benzofurans
• Nsfl1c protein, rat
• Nuclear Proteins
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
• Superoxides
• 3-n-butylphthalide
• Cybb protein, rat
• NADPH Oxidase 2
• Hydrogen Sulfide

Topics

• Animals
• Benzofurans (administration & dosage, chemistry)
• Brain Ischemia (drug therapy, genetics, physiopathology)
• Disease Models, Animal
• Humans
• Hydrogen Sulfide (administration & dosage, chemistry, metabolism)
• Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
• Microglia (drug effects, metabolism, pathology)
• NADPH Oxidase 2 (genetics)
• Neurons (drug effects, pathology)
• Nuclear Proteins (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering (genetics)
• Rats
• Signal Transduction (drug effects)
• Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
• Stroke (drug therapy, genetics, pathology)
• Superoxides (chemistry, metabolism)