Canagliflozin ameliorates neuronal injury after cerebral ischemia reperfusion by targeting SGLT1 and AMPK-dependent apoptosis

Abstract

Currently, the treatment of acute ischemic stroke is still limited. In clinical studies, the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on stroke risk is controversial. This preclinical study was conducted to determine whether canagliflozin, a SGLT2 inhibitor, has neuroprotective effects on ischemic stroke and the underlying mechanisms. The middle cerebral artery occlusion (MCAO) model was established in Sprague Dawley rats, and canagliflozin was administered by gavage before reperfusion. Canagliflozin treatment significantly reduced infarct volume, improved neurological deficits, lessened brain edema, alleviated neuronal damage and reduced apoptosis. SGLT2 inhibitors which are commonly used in the clinic have different degrees of affinity for SGLT1 and SGLT2 receptors, the expression levels of SGLT1 and SGLT2 were detected using immunofluorescence in the cortex and hippocampus. SGLT2 was barely detectable in these regions regardless of MCAO or canagliflozin treatment or not. The SGLT1 expression levels were significantly elevated in the cortex and hippocampus after MCAO, and further significantly reduced by canagliflozin administration. In vitro experiments, the oxygen-glucose deprivation/reoxygenation (OGD/R) model of the HT-22 mouse hippocampal neurons was established. Canagliflozin treatment increased cell viability and attenuated lactate dehydrogenase (LDH) release. Additionally, canagliflozin activated AMP-activated protein kinase (AMPK) and subsequently inhibited apoptosis in a SGLT1 inhibition dependent manner. The present study shows that canagliflozin could attenuate cerebral ischemia-reperfusion injury in experimental ischemic stroke via SGLT1/AMPK signaling, leading to anti-apoptotic effects in neuron. These findings might serve as evidence for the further application of canagliflozin in the treatment of acute ischemic stroke.