The GLP-1 receptor agonists exendin-4 and liraglutide alleviate oxidative stress and cognitive and micturition deficits induced by middle cerebral artery occlusion in diabetic mice

Abstract

BackgroundGlucagon-like peptide 1 (GLP-1) analogs protect a variety of cell types against oxidative damage and vascular and neuronal injury via binding to GLP-1 receptors. This study aimed to investigate the effects of the GLP-1 analogs exendin-4 and liraglutide on cerebral blood flow, reactive oxygen species production, expression of oxidative stress-related proteins, cognition, and pelvic sympathetic nerve-mediated bladder contraction after middle cerebral artery occlusion (MCAO) injury in the db/db mouse model of diabetes.ResultsSixty minutes of MCAO increased blood and brain reactive oxygen species counts in male db/db mice, as revealed by dihydroethidium staining. MCAO also increased nuclear factor-κB and intercellular adhesion molecule-1 expression and decreased cerebral microcirculation. These effects were attenuated by treatment with exendin-4 or liraglutide. MCAO did not affect basal levels of phosphorylated Akt (p-Akt) or endothelial nitric oxide synthase (p-eNOS); however, exendin-4 and liraglutide treatments significantly enhanced p-Akt and p-eNOS levels, indicating activation of the p-Akt/p-eNOS signaling pathway. MCAO-induced motor and cognitive deficits and micturition dysfunction, indicated by reduced pelvic nerve-mediated voiding contractions and increased nonvoiding contractions, were also partially attenuated by exendin-4 treatment.ConclusionsThe above data indicate that treatment with GLP-1 agonists exerts protective effects against oxidative, inflammatory, and apoptotic damage in brain areas that control parasympathetic/pelvic nerve-mediated voiding contractions and cognitive and motor behaviors in a diabetic mouse model.

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

“…The timing of drug administration varied between studies. Eight studies administered GLP‐1RAs pre‐ischaemia , eight post‐ischaemia and four both pre‐ and post‐ischaemia . For the seven studies involving DPP‐4Is, one study applied the drugs pre‐ischaemia , one post‐ischaemia and five studies both pre‐ and post‐ischaemia .…”

“…Mouse (C57BL/6), rat (Sprague Dawley/Wistar/Wistar albino) and gerbil (Mongolian) animal models were used (n = 1766). Fifteen studies tested non‐diabetic animals , six used diabetic/hyperglycaemic animals , and six studies included both non‐diabetic and diabetic . Diabetes was induced by streptozotocin , high‐fat diet or genetically modified animal strains including db/db mice , Goto‐Kakizaki rats and hyperglycaemia induced by infusion of 50% dextrose .…”

“…All studies but one used a non‐active vehicle as a control, and some studies also investigated sham‐operated animals , other kinds of GLP‐1‐based therapies , other administration routes or other drug classes . Five studies observed the effects of GLP‐1R suppression using knockout animals or specific short hairpin ribonucleic acid (RNA) sequences to target the GLP‐1R .…”

“…Neutrophil infiltration was reduced by exenatide and sitagliptin , as shown in the latter study by reduced labelling of myeloperoxidase (MPO). Exenatide , liraglutide and sitagliptin all reduced expression of the pro‐inflammatory gene, nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB).…”

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

“…Similar to the antidiabetic drugs mentioned above (biguanides, meglitinides, sulphonylureas and glitazones), GLP-1 analogues also improve endothelial function. Li et al [85] demonstrated that infusion of liraglutide or exendin-4, two GLP-1 receptor agonists, for 12 hr improves cerebral microcirculation after cerebral artery occlusion in diabetic mice. This result was associated with increased levels of Akt and eNOS phosphorylation, as well as reduced ROS generation.…”