title: Peptidic exenatide and herbal catalpol mediate neuroprotection via the hippocampal GLP-1 receptor/β-endorphin pathway.
abstract: Both peptidic agonist exenatide and herbal agonist catalpol of the glucagon-like peptide-1 receptor (GLP-1R) are neuroprotective. We have previously shown that activation of spinal GLP-1Rs expresses β-endorphin in microglia to produce antinociception. The aim of this study was to explore whether exenatide and catalpol exert neuroprotection via activation of the hippocampal GLP-1R/β-endorphin pathway. The rat middle cerebral artery occlusion model was employed, and the GLP-1R immunofluorescence staining and β-endorphin measurement were assayed in the hippocampus and primary cultures of microglia, neurons and astrocytes. The immunoreactivity of GLP-1Rs on microglia in the hippocampus was upregulated after ischemia reperfusion. Intracerebroventricular (i.c.v.) injection of exenatide and catalpol produced neuroprotection in the rat transient ischemia/reperfusion model, reflected by a marked reduction in brain infarction size and a mild recovery in neurobehavioral deficits. In addition, i.c.v. injection of exenatide and catalpol significantly stimulated β-endorphin expression in the hippocampus and cultured primary microglia (but not primary neurons or astrocytes). Furthermore, exenatide and catalpol neuroprotection was completely blocked by i.c.v. injection of the GLP-1R orthosteric antagonist exendin (9-39), specific β-endorphin antiserum, and selective opioid receptor antagonist naloxone. Our results indicate, for the first time, that the neuroprotective effects of catalpol and exenatide are GLP-1R-specific, and that these effects are mediated by β-endorphin expression probably in hippocampal microglia. We postulate that in contrast to the peripheral tissue, where the activation of GLP-1Rs in pancreas islet β-cells causes secretion of insulin to perform glucoregulation, it leads to β-endorphin expression in microglial cells to produce neuroprotection and analgesia in the central nervous system.
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jia
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Li
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D057888:Iridoid Glucosides / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D001615:beta-Endorphin / Q000378:metabolism*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D057888:Iridoid Glucosides; D018696:Neuroprotective Agents; D010455:Peptides; D011957:Receptors, Opioid; D014688:Venoms; C078040:catalpol; D001615:beta-Endorphin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Catalpol; Exenatide; Glucagon-like peptide-1 receptor (GLP-1R); Microglia; Neuroprotection; β-endorphin