DPP-4 Inhibitor Linagliptin is Neuroprotective in Hyperglycemic Mice with Stroke via the AKT/mTOR Pathway and Anti-apoptotic Effects

Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-mTOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/mTOR pathway along with anti-apoptotic and anti-inflammatory mechanisms. Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.