title: Related expressional change of HIF-1α to the neuroprotective activity of exendin-4 in transient global ischemia.
abstract: Transient global ischemia induces selective hippocampal pyramidal neuronal death. Under conditions of severe ischemic hypoxia, hypoxia-inducible factor-1α (HIF-1α) induces apoptosis. Exendin-4 (Ex-4), the glucagon-like peptide-1 receptor (GLP-1R) agonist, provides neuroprotection against brain damage after cerebral ischemia. We investigated the relationship between Ex-4 and HIF-1α by examining Ex-4-induced changes in HIF-1α expression in the gerbil hippocampus following global brain ischemia (in vivo) and in neuroblastoma cells (SH-SY5Y) and cortical primary neurons (in vitro). Twice-daily administration of Ex-4 (1 μg/kg) for 3 days after ischemia (30 min before and 30 min after ischemia on the day of surgery and 2 more days) decreased the number of Fluoro-Jade B-stained cells in the CA1 pyramidal region of the hippocampus of the ischemic brain. Western blot analysis indicated a significant decrease in HIF-1α expression in the ischemic compared with the Sham brain following Ex-4 treatment. These in-vivo results were confirmed in vitro in SH-SY5Y cells and primary cortical neurons treated with 100 nM of Ex-4 under hypoxic conditions (0.1%>O2). We found that Ex-4 decreased the HIF-1α expression in the SH-SY5Y cell line and primary cortical neurons under hypoxic conditions, and this effect was reversed by cotreatment with exendin (9-39), a GLP-1R antagonist. These results suggest that HIF-1α may be involved in the neuroprotective effect of Ex-4 in the hypoxia-damaged brain.
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Biomedical Science Institute, Kyung Hee University, Seoul, Korea.
authors.forename: Jizi
authors.initials: J
authors.lastname: Jin
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Junyang
authors.initials: J
authors.lastname: Jung
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Jeong
authors.forename: Chan
authors.initials: C
authors.lastname: Park
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D000077270:Exenatide; D005849:Gerbillinae; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide