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

Abstract Background Glucagon-like peptide-1 receptor (GLP-1R) activation can decrease stroke risk in people with type 2 diabetes (T2D). Moreover, animal studies have shown the efficacy of GLP-1R agonists to counteract stroke-induced acute brain damage. Whether GLP-1R activation can also improve stroke recovery during the post-acute, chronic phase after stroke, however, remains to be determined. We investigated whether post-acute, chronic administration of the GLP-1R agonist Exendin-4 improves poststroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. Methods 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 daily for 8 weeks from day 3 after tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests, while insulin sensitivity and glycemia were evaluated at 4 and 8 weeks after tMCAO. Neuronal cell death, stroke-induced neurogenesis, neuroinflammation, potential atrophy of GABAergic, parvalbumin + interneurons, poststroke vascular remodeling and fibrotic scar formation were investigated by immunohistochemistry. Results Exendin-4 entirely normalized the T2D-induced impairment of forepaw grip strength recovery. The recovery correlated with the normalization of glycemia and insulin sensitivity. We also show that Exendin-4 counteracted the T2D-induced atrophy of parvalbumin + interneurons and decreased microglia activation. In addition, Exendin-4 normalized density and pericyte coverage of microvessels and restored fibrotic scar formation in T2D mice. In non-T2D mice the recovery effect of Exendin-4 was minor. Conclusion This study demonstrates that post-acute, chronic GLP-1R activation mediates neurological recovery after stroke in T2D mice likely through the normalization of glucose metabolism and neuroplasticity mechanisms as well as improved vascular remodeling in the recovery phase. The results promote launching clinical trials investigating whether GLP-1R agonists improve the efficacy of rehabilitation after stroke in people with T2D.