GLP-1R activation for the treatment of stroke: Updating and future perspectives

Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP-1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients.