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영어

Repeated sublethal hypoxia exposure is reported to accelerate brain inflammation, and to affect the initiation and progression of cognitive dysfunction. Forskolin, an adenylate cyclase activator, is well-known as an inducer of the cAMP/PKA/CREB signaling. It has been shown that forskolin protects against various neuronal complications and induces long term memory; however, the underlying mechanism remains unclear. In this study, we showed that intraperitoneal administration of 200ng/g forskolin for 5 days on zebrafish notably recovered hypoxia-induced social interaction impairment and learning memory deficit. Forskolin suppressed hypoxia-induced neuroinflammation indicated by the decrease of NF-kB signaling and GFAP expression. On mouse neuroblastoma cell line, forskolin notably rescued hypoxia-induced cell death and dysfunction. The hypoxia model either in vivo or in vitro exerted a downregulation of PKA/CREB signaling and its downstream, c-Fos and BDNF expression, which was restored by forskolin. As previous studies proposed that hypoxia-induced hypo-O-GlcNAcylation could be an important causal factor for cognitive defect, we further investigated whether the HBP/O-GlcNAcylation cycling was changed by forskolin. Intriguingly, we observed that following forskolin treatment, OGT protein level (enzyme controls the addition of GlcNAc group to target proteins) induced considerably, which was accompanied by the upregulated O-GlcNAcylation level. Under forskolin treatment, O-GlcNAcylation flux on hypoxia-exposed zebrafish was reserved in line with the recovery of other inflammation and learning/memory markers. Next, we studied further about potential regulation of O-GlcNAcylation on the neuroprotective effect of forskolin. Zebrafish were treated with 500ng/g 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of GFAT1 (enzyme that catalyzes the reaction from fructose-6-P to glucosamine-6-P), to downregulate the O-GlcNAcylation of proteins. It was observed that DON treatment led to learning/memory impairment, which was rescued by forskolin. Moreover, forskolin conserved hypo-O-GlcNAcylation and neuroinflammation following DON administration. Further experiments are being conducted to examine how HBP/O-GlcNAc flux is involved in the beneficial effect of forskolin on cognitive function.