Related expressional change of HIF-1α to the neuroprotective activity of exendin-4 in transient global ischemia.

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.