title: Neuroprotective and anti-apoptotic effects of liraglutide in the rat brain following focal cerebral ischemia.
abstract: Stroke is a leading cause of death and serious, long-term disability worldwide. We report that rats receiving liraglutide show markedly attenuated infarct volumes and neurological deficit following ischemic insult. We have also investigated the effect of liraglutide on apoptosis and oxidative stress pathways after ischemic injury in diabetic and non-diabetic rats. Male Sprague-Dawley rats weighing 300-350g were used. Diabetes was induced by streptozotocin. Rats were pretreated with either vehicle or liraglutide (50μg/kg, s.c.) for 14days and thereafter subjected to middle cerebral artery occlusion (MCAO). Twenty-four hours after occlusion, rats were assessed for neurological deficit, motor function and subsequently sacrificed for estimation of infarct volume, oxidative stress and apoptotic markers. Vehicle-treated non-diabetic and diabetic rats showed significant (p<0.001) neurological deficit following cerebral ischemia. Liraglutide pretreatment resulted in significantly (p<0.001) less neurological deficit compared to vehicle-treated MCAO rats. Cerebral ischemia produced significant (p<0.0001) infarction in vehicle-treated rats; however, the infarct volume was significantly (p<0.001) less in liraglutide-pretreated rats. Oxidative stress markers were increased following ischemia but were attenuated in liraglutide-treated rats. Anti-apoptotic protein Bcl-2 expression was decreased and pro-apoptotic protein Bax expression was increased in vehicle-treated MCAO rats compared to sham (p<0.0001). On the other hand liraglutide pretreatment showed significantly (p<0.01) increased expression of Bcl-2 and decreased expression of Bax in MCAO rats. In vehicle-treated group, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells significantly (p<0.0001) increased in the ischemic hemisphere compared to sham-operated group. The number of TUNEL-positive cells in vehicle group was 73.5±3.3 and 85.5±5.2/750μm(2) in non-diabetic and diabetic vehicle-treated MCAO rats, respectively. Following liraglutide treatment the number of TUNEL-positive cells was remarkably attenuated to 25.5±2.8 and 41.5±4.1/750μm(2) (p<0.001) in non-diabetic and diabetic rats, respectively. The results demonstrate that glucagon-like peptide 1 (GLP-1) agonist, liraglutide, is a neuroprotective agent and attenuates the neuronal damage following cerebral ischemia in rats by preventing apoptosis and decreasing oxidative stress.
authors.affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA.
authors.forename: S
authors.initials: S
authors.lastname: Briyal
authors.affiliation: Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA. Electronic address: AGULAT@midwestern.edu.
authors.forename: A
authors.initials: A
authors.lastname: Gulati
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D000069450:Liraglutide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: GLP-1 receptor; apoptosis; cerebral ischemia; liraglutide; oxidative stress