Normalization of glucose metabolism by Exendin-4 in the chronic phase after stroke promotes functional recovery in diabetes

Background and purpose Glucagon-like peptide-1 receptor (GLP-1R) activation decreases stroke risk in people with type 2 diabetes (T2D) while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1R activation also improves stroke recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1R agonist Exendin-4 improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. Experimental approach We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, poststroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. Key results Exendin-4 entirely normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover Exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, Exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the Exendin-4-mediated recovery was minor. Conclusion and implications Chronic GLP-1R activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results promote launching clinical trials investigating whether GLP-1R agonists improve rehabilitation after stroke in T2D.