Abstract
Previous studies have shown that metformin not only is a hypoglycemic agent but also has neuroprotective effects. However, the mechanism of action of metformin in ischemic stroke is unclear. Oxidative stress is an important factor in the pathogenesis of cerebral ischemia-reperfusion injury. It has been reported that metformin is associated with stroke risk in the clinical population. This study is aimed at investigating the effect and mechanism of metformin in an experimental model of oxidative stress induced by ischemia/reperfusion (I/R) in vivo and oxygen glucose deprivation/reperfusion (OGD/R) in vitro. Metformin (100, 200, and 300 mg/kg) was administered intraperitoneally immediately after induction of cerebral ischemia. The indicators of oxidative stress selected were antioxidant enzyme activities of catalase, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione peroxidation enzyme (GSHPx). First, we demonstrated that metformin can significantly alleviate acute and chronic cerebral I/R injury and it has a strong regulatory effect on stroke-induced oxidative stress. It can reduce the elevated activities of MDA and NO and increase the levels of GSHPx and SOD in the cerebrum of mice and N2a cells exposed to I/R. Furthermore, real-time PCR and western blot were used to detect the expression of long noncoding RNA H19 (lncRNA-H19), microRNA-148a-3p (miR-148a-3p), and Rho-associated protein kinase 2 (Rock2). The direct interaction of lncRNA-H19, miR-148a-3p, and Rock2 was tested using a dual luciferase reporter assay. lncRNA-H19 altered OGD/R-induced oxidative stress by modulating miR-148a-3p to increase Rock2 expression. The expression of lncRNA-H19 and Rock2 could be downregulated with metformin in vivo and in vitro. In conclusion, our study confirmed that metformin exerts neuroprotective effects by regulating ischemic stroke-induced oxidative stress injury via the lncRNA-H19/miR-148a-3p/Rock2 axis. These results provide new evidence that metformin may represent a potential treatment for stroke-related brain injury.
Highlights
Stroke is a serious and common disease that is one of the main causes of disability and death worldwide [1, 2]
No significant neurobehavioral impairment or differences in brain water content were found in the sham group, while a more serious lack of neurobehavioral function and increased brain water content were shown in the middle cerebral artery occlusion (MCAO)/R group
We found that metformin exerts neuroprotective effects on I/R injury induced by oxygen glucose deprivation/reperfusion (OGD/R) or MCAO/R
Summary
Stroke is a serious and common disease that is one of the main causes of disability and death worldwide [1, 2]. It is increasingly understood that an excessive inflammatory response and oxidative stress are closely related to the pathogenesis of cerebral ischemia-reperfusion (I/R) injury [3]. Oxidative Medicine and Cellular Longevity polyunsaturated fatty acid (PUFA) content, the brain is extremely susceptible to oxidative stress-induced damage [5]. Many studies have shown that lncRNAs affect many physiological and pathological processes of the nervous system and they have been determined as potential biomarkers for stroke [8]. There is evidence that elevated expression of lncRNA-H19 is closely related to the progression of cerebral ischemia [9]. LncRNA-H19 protects H9c2 cells from hypoxia-induced damage by regulating miR-139 and acts as a positive regulator of autophagy in cerebral ischemia [11]. Based on miRNA expression profiling in ischemic stroke, it has been shown that some miRNAs may be potential biomarkers for the diagnosis of stroke or prediction of prognosis
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