Nitro-oleic acid (OA-NO2), a nitroalkene formed in nitric oxide-dependent oxidative reactions, has been found in human plasma and is thought to regulate pathophysiological functions. Recently, accumulating evidence suggests that OA-NO2 may function as an anti-inflammatory mediator, and ameliorate the progression of diabetes and cardiovascular diseases. However, the role of OA-NO2 in ischemic brain injury remains unexplored. In this study, C57BL/6 mice were subjected to 1 h transient middle cerebral artery occlusion (MCAO) and followed by 1- 7 days of reperfusion. These mice were treated with vehicle, OA, or OA-NO2 (10 mg/kg) via tail vein injection at 2 h after the onset of MCAO. Our results show that intravenous administration of OA-NO2 led to reduced BBB leakage in ischemic brains, reduced brain infarct, and improved sensorimotor functions in response to ischemic insults when compared to OA and vehicle controls. Also, OA-NO2 significantly reduced BBB leakage-triggered infiltration of neutrophils and macrophages in the ischemic brains. Moreover, OA-NO2 treatment reduced the M1-type microglia and increased M2-type microglia. Mechanistically, OA-NO2 alleviated the decline of mRNA and protein level of major endothelial TJs including ZO-1 in stroke mice. Treatment of OA-NO2 also significantly inhibited stroke-induced inflammatory mediators, iNOS, E-selectin, P-selectin, and ICAM1, in mouse brains. In conclusion, OA-NO2 preserves BBB integrity and confers neurovascular protection in ischemic brain damage. OA-NO2-mediated brain protection may help us to develop a novel therapeutic strategy for the treatment of ischemic stroke.
Keywords: BBB; Brain infarction; Cerebral ischemia; Neuroinflammation; Nitro-oleic acid.
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