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.
Glucagon-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.



Sixty 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.



The 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.
School of Medicine for International Students, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan. pingchiali@gmail.com.|Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan. pingchiali@gmail.com.
Ping-Chia
PC
Li
School of Medicine for International Students, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
Li-Fen
LF
Liu
School of Medicine for International Students, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
Ming-Jia
MJ
Jou
School of Medicine for International Students, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.|Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
Hao-Kuang
HK
Wang
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018697:Nootropic Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D014555:Urination Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018697:Nootropic Agents; D010455:Peptides; D020011:Protective Agents; D014688:Venoms; D000069450:Liraglutide; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
Cerebral microcirculation; GLP-1 agonist; Middle cerebral artery occlusion; Oxidative stress; Pelvic nerve; Voiding function