Normalisation of glucose metabolism by exendin‐4 in the chronic phase after stroke promotes functional recovery in male diabetic mice

BACKGROUND AND PURPOSE: Glucagon‐like peptide‐1 (GLP‐1) receptor 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‐1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post‐acute, chronic administration of the GLP‐1 receptor 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, post‐stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. KEY RESULTS: Exendin‐4 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‐1 receptor 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 warrant clinical trial of GLP‐1 receptor agonists for rehabilitation after stroke in T2D. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc