Liraglutide protects against diabetes mellitus complicated with focal cerebral ischemic injury by activating mitochondrial ATP-sensitive potassium channels.

Cerebral infarction is a common disease that threatens the health of humankind worldwide. Diabetes is one of the important causes of cerebral ischemic (CI) injury. CI complicated with diabetes has a worse prognosis and lacks effective treatment. Our preliminary study demonstrated that liraglutide mitigates CI injuries in diabetic rats. However, the essential mechanism underlying this effect remained to be fully investigated. Recent research has shown that damaged mitochondrial ATP-sensitive potassium channels (mitoKATP) play a critical role in diabetes-aggravated CI injury. Therefore, we hypothesized that liraglutide may confer therapeutic effects against CI with diabetes by activating mitoKATP channels. In this study, liraglutide, but not insulin, significantly improved ischemia-induced neurological deficits and decreased infarct volumes following CI in diabetic rats, down-regulated the expression of myeloperoxidase and up-regulated the expression of superoxide dismutase and two subunits of the mitoKATP channel (SUR1 and Kir6.2). However, these effects were weakened by the mitoKATP antagonist 5-hydroxydecanoic acid. Our study demonstrated that the neuroprotective effects of liraglutide on CI injury with diabetes, which occurs by reducing oxidative stress and the inflammatory response, are associated with the activation of the mitoKATP channel.

Liraglutide Activates the Nrf2/HO-1 Antioxidant Pathway and Protects Brain Nerve Cells against Cerebral Ischemia in Diabetic Rats.

This study aimed to determine the effect of liraglutide pretreatment and to elucidate the mechanism of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) signaling after focal cerebral ischemia injury in diabetic rats model. Adult male Sprague-Dawley rats were randomly divided into the sham-operated (S) group, diabetes mellitus ischemia (DM + MCAO) group, liraglutide pretreatment normal blood glucose ischemia (NDM+MCAO+L) group, and liraglutide pretreatment diabetes ischemia (DM + MCAO + L) group. At 48 h after middle cerebral artery occlusion (MCAO), neurological deficits and infarct volume of brain were measured. Oxidative stress brain tissue was determined by superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. The expression levels of Nrf2 and HO-1 of brain tissue were analyzed by western blotting. In the DM + MCAO + L group, neurological deficits scores and cerebral infarct volume seemed to decrease at 48 h after MCAO cerebral ischemia compared with those in DM + MCAO group (P < 0.05). In addition, the expression of Nrf2 and HO-1 increased in 48 h at liraglutide pretreatment groups after MCAO cerebral ischemia if compared with those in the DM + MCAO group (P < 0.05). Furthermore, the DM + MCAO + L group has no significant difference compared with the NDM + MCAO + L group (P > 0.05). To sum up, alleviating effects of liraglutide on diabetes complicated with cerebral ischemia injury rats would be related to Nrf2/HO-1 signaling pathway.

Anti-inflammatory properties of lipoxin A4 protect against diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury.

Lipoxin A4 can alleviate cerebral ischemia/reperfusion injury by reducing the inflammatory reaction, but it is currently unclear whether it has a protective effect on diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury. In this study, we established rat models of diabetes mellitus using an intraperitoneal injection of streptozotocin. We then induced focal cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. After administration of lipoxin A4 via the lateral ventricle, infarction volume was reduced, the expression levels of pro-inflammatory factors tumor necrosis factor alpha and nuclear factor-kappa B in the cerebral cortex were decreased, and neurological functioning was improved. These findings suggest that lipoxin A4 has strong neuroprotective effects in diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury and that the underlying mechanism is related to the anti-inflammatory action of lipoxin A4.

[Effects of puerarin on the neurocyte apoptosis and p-Akt (Ser473) expressions in rats with cerebral ischemia/reperfusion injury].

OBJECTIVE: To observe the effects of puerarin (Pue) on the neurocyte apoptosis and the p-Akt (Ser473) expression in the ischemic penumbra of rats with cerebral ischemia/reperfusion (I/R). METHODS: The 48 Sprague-Dawley rats were randomly divided into four groups, i.e., the sham-operation group, the I/R group, the Pue treatment group, and the Pue + LY294002 treatment group (Pue + LY), 12 in each group. The cerebral I/R rat model was established by Longa's suture method. Pue and Pue + specific P13K kinase inhibitor, i.e., LY294002 were administered. The score of the neurological deficit was estimated 1 h followed by 24 h reperfusion. The infarct volume was measured using TTC staining. The number of apoptotic neurons were detected using Tunel method. The expressions of p-Akt (Ser473) was detected using immunohistochemical assay, and the images were analyzed. RESULTS: The score of the neurological deficit decreased more obviously, the number of apoptosis decreased more significantly, the expressions of p-Akt (Ser473) increased more significantly in the Pue group than in the I/R group (all P < 0.05). The score of the neurological deficit increased more obviously, the number of apoptosis increased more significantly, the expression of p-Akt (Ser473) decreased more significantly in the Pue + LY group than in the Pue group (all P < 0.05). CONCLUSION: Pue reduced the apoptosis of neurocytes and had protective effects against cerebral I/R injury possibly through activating the PI3K/Akt signaling pathway.