title: Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage.
abstract: The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Hou
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Jakob
authors.initials: J
authors.lastname: Hakon
authors.forename: Jacob
authors.initials: J
authors.lastname: Hansen-Schwartz
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D040761:Biomimetic Materials / Q000493:pharmacokinetics* / Q000494:pharmacology; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D055372:AMP-Activated Protein Kinases; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse