title: An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke.
abstract: Diabetes is a major risk factor for the development of stroke. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been in clinical use for the treatment of diabetes and also been reported to be neuroprotective in ischemic stroke. The quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert- butylaminoquinoxaline (DMB) is an agonist and allosteric modulator of the GLP-1R with the potential to increase the affinity of GLP-1 for its receptor. The aim of this study was to evaluate the neuroprotective effects of DMB on transient focal cerebral ischemia. In cultured cortical neurons, DMB activated the GLP-1R, leading to increased intracellular cAMP levels with an EC50 value about 100 fold that of exendin-4. Pretreatment of neurons with DMB protected against necrotic and apoptotic cell death was induced by oxygen-glucose deprivation (OGD). The neuroprotective effects of DMB were blocked by GLP-1R knockdown with shRNA but not by GLP-1R antagonism. In C57BL/6 mice, DMB was orally administered 30 min prior to middle cerebral artery occlusion (MCAO) surgery. DMB markedly reduced the cerebral infarct size and neurological deficits caused by MCAO and reperfusion. The neuroprotective effects were mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway. DMB exhibited anti-apoptotic effects by modulating Bcl-2 family members. These results provide evidence that DMB, a small molecular GLP-1R agonist, attenuates transient focal cerebral ischemia injury and inhibits neuronal apoptosis induced by MCAO. Taken together, these data suggest that DMB is a potential neuroprotective agent against cerebral ischemia.
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Huinan
authors: H
authors: Zhang
authors: School of Nurse, the Fourth Military Medical University, Xi'an, China.
authors: Yunhan
authors: Y
authors: Liu
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Shaoyu
authors: S
authors: Guan
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Di
authors: D
authors: Qu
authors: Department of Health Statistics, Faculty of Preventative Medicine, the Fourth Military Medical University, Xi'an, China.
authors: Ling
authors: L
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Xinshang
authors: X
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Xubo
authors: X
authors: Li
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Shimeng
authors: S
authors: Zhou
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Ying
authors: Y
authors: Zhou
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Ning
authors: N
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Jingru
authors: J
authors: Meng
authors: Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi'an, China.
authors: Xue
authors: X
authors: Ma
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010455:Peptides / Q000494:pharmacology; D061251:Primary Cell Culture; D011810:Quinoxalines / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000517:prevention & control; D013450:Sulfones / Q000008:administration & dosage*; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D007328:Insulin; D018696:Neuroprotective Agents; D010455:Peptides; D011810:Quinoxalines; D013450:Sulfones; D014688:Venoms; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C517397:3-(tert-butylamino)-6,7-dichloro-2-(methylsulfonyl)quinoxaline; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor