Abstract
BackgroundPrevious studies had showed that Apelin 13 could protect against apoptosis induced by ischemic/reperfusion (I/R). However, the mechanisms whereby Apelin 13 protected brain I/R remained to be elucidated. The present study was designed to determine whether Apelin 13 provided protection through AMPK/GSK-3β/Nrf2 pathway.MethodsIn vivo, the I/R model was induced and Apelin 13 was given intracerebroventricularly 15 min before reperfusion. The neurobehavioral scores, infarction volumes, and some cytokines in the brain were measured. For in vitro study, PC12 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Protein levels were investigated by western blotting.ResultsThe results showed that Apelin 13 treatment significantly reduced infarct size, improved neurological outcomes, decreased brain edema, and inhibited cell apoptosis, oxidative stress, and neuroinflammation after I/R. Apelin 13 significantly increased the expression of Nrf2 and the phosphorylation levels of AMPK and GSK-3β. Furthermore, in cultured PC12 cells, the same protective effects were also observed. Silencing Nrf2 gene with its siRNA abolished the Apelin 13’s prevention of I/R-induced PC12 cell injury, oxidative stress, and inflammation. Inhibition of AMPK by its siRNA decreased the level of Apelin 13-induced Nrf2 expression and diminished the protective effects of Apelin 13. The interplay relationship between GSK-3β and Nrf2 was also verified with relative overexpression. Using selective inhibitors, we further identified the upstream of AMPK/GSK-3β/Nrf2 is AR/Gα/PLC/IP3/CaMKK.ConclusionsIn conclusion, the previous results showed that Apelin 13 protected against I/R-induced ROS-mediated inflammation and oxidative stress through activating the AMPK/GSK-3β pathway by AR/Gα/PLC/IP3/CaMKK signaling, and further upregulated the expression of Nrf2-regulated antioxidant enzymes.
Highlights
Previous studies had showed that Apelin 13 could protect against apoptosis induced by ischemic/reperfusion (I/R)
Apelin 13 protected the brain from Middle cerebral artery occlusion (MCAO)/R-induced injuries In sham group, no infarction was observed
Apelin significantly improved the neurological scores compared with the MCAO and reperfusion (MCAO/R) group and ameliorated mental status in rats subjected to MCAO/R (Fig. 1b)
Summary
Previous studies had showed that Apelin 13 could protect against apoptosis induced by ischemic/reperfusion (I/R). Apelin 13 has the highest activity than other apelin forms [2, 3]. Oxidative stress and post-ischemic inflammatory response are considered to be the key pathogenic mechanisms of the brain injury. Oxygen and glucose levels rise suddenly during reperfusion, which can potentially aggravate the inflammation, oxidative stress, and cell death already underway due to the initial ischemia [7, 8]. Chronic oxidative stress will lead to the decreased expression of anti-oxidative enzymes and induce the insufficient of antioxidant defense systems, further aggravate inflammation and neuron injuries [9]. Inhibiting the production of ROS or inducing the expression of antioxidant proteins may be useful to inhibit oxidative and inflammation induced by ischemic stroke
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