Pre-stroke weight loss by glucagon-like peptide 1 receptor and neuropeptide Y receptor Y2 activation improves post-stroke functional recovery in male diabetic mouse models.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with worsened stroke outcome and lasting disability. The underlying mechanisms are undetermined, and no therapy is available. We experimentally investigated whether pharmacologically targeting obesity, which is highly prevalent in type 2 diabetes, before stroke enhances neurological recovery in type 2 diabetes. To induce weight loss, we employed the glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide and the neuropeptide Y receptor Y2 (NPY2R) agonist BI8271, which potentiates GLP-1R-mediated weight loss. We also investigated potential acute neuroprotective effects induced by these treatments, independently of metabolic regulation. METHODS: C57BL/6J mice were fed with a high-fat diet for 5 months to induce obesity and features of type 2 diabetes (i.e. hyperglycaemia and insulin resistance). Weight loss was induced by 4-week administration of semaglutide and/or BI8271. As a control for the effect of weight loss, a vehicle (PBS)-treated group was switched to standard diet to achieve the same weight range and the same percentage weight loss within the same time frame as those receiving semaglutide/BI8271. Thereafter, mice were subjected to stroke by transient middle cerebral artery occlusion (tMCAO). Stroke recovery (the primary outcome) was assessed by measuring the recovery of grip strength and the lateralised sensorimotor integration. Brains and serum were collected, and stroke volume and serum IGF-1 levels were quantified (secondary outcomes). In additional studies, type 2 diabetic mice were subjected to tMCAO and injected with semaglutide and/or BI8271 1 and 24 h after reperfusion. Acute neuroprotection (the primary outcome) was assessed by a grip strength test and by quantifying stroke volume and the number of surviving neuronal nuclear marker (NeuN)-positive neurons. RESULTS: We report that pre-stroke weight loss by GLP-1R activation, and more potently by dual co-activation of GLP-1 and NPY2 receptors, is a pharmacologically targetable mechanism, upstream of glycaemic regulation, through which post-stroke recovery is achieved. Moreover, we show that post-stroke recovery in type 2 diabetes is inversely associated with peripheral IGF-1 levels. Finally, GLP-1R and NPY2R activation can also improve stroke recovery through acute neuroprotection if they are given acutely after stroke, independently of their metabolic effects. CONCLUSIONS/INTERPRETATION: The diabetes and obesity epidemics are increasing the incidence of stroke, and consequently the need for treatments to improve stroke outcome. Our results indicate that clinically used type 2 diabetes treatments could be employed in a preventive role to improve stroke outcome by exerting dual pharmacological action: weight loss and acute neuroprotection. These findings could have novel therapeutic implications for many people.