Lee, Ji Ae Kim, Hye Ri Kim, Jiyoung Park, Ki Duk Kim, Dong Jin Hwang, Onyou 2024-01-19T21:34:16Z 2024-01-19T21:34:16Z 2021-09-04 2018-10 1226-2560 https://pubs.kist.re.kr/handle/201004/120864 We have previously reported a novel synthetic compound KMS99220 that prevented degeneration of the nigral dopaminergic neurons and the associated motor deficits, suggesting a neuroprotective therapeutic utility for Parkinson's disease. Microglia are closely associated with neuroinflammation, which plays a key role in the pathogenesis of neurodegenerative diseases. In this study, we investigated the effects of KMS99220 on the signaling involving AMP-activated protein kinase (AMPK) and heme oxygenase-1 (HO-1), the enzymes thought to regulate inflammation. KMS99220 was shown to elevate the enzyme activity of purified AMPK, and phosphorylation of cellular AMPK in BV2 microglia. It increased the level of HO-1, and this was attenuated by AMPK inhibitors. KMS99220 lowered phosphorylation of I kappa B, nuclear translocation of NF kappa B, induction of inducible nitric oxide synthase, and generation of nitric oxide in BV2 cells that had been challenged with lipopolysaccharide. This anti-inflammatory response involved HO-1, because both its pharmacological inhibition and knockdown of its expression abolished the response. The AMPK inhibitors also reversed the anti-inflammatory effects of KMS99220. The induction of HO-1 by KMS99220 occurred within 1 h, and this appeared not to involve the transcription factor Nrf2, because Nrf2 knockdown did not affect the compound's HO-1 inducing-and anti-inflammatory effects in this time window. These findings indicated that KMS99220 leads to AMPK-induced HO-1 expression in microglia, which in turn plays an important role in early anti-inflammatory signaling. Together with its neuroprotective property, KMS99220 may serve as a feasible therapeutic agent against neuroinflammation and neurodegeneration. English KOREAN SOC BRAIN & NEURAL SCIENCE, KOREAN SOC NEURODEGENERATIVE DISEASE ACTIVATED PROTEIN-KINASE HEME OXYGENASE 1 NF-KAPPA-B MICROGLIAL ACTIVATION CHALCONE DERIVATIVES SIGNALING PATHWAY CELLS EXPRESSION INVOLVEMENT INDUCTION The Novel Neuroprotective Compound KMS99220 Has an Early Anti-neuroinflammatory Effect via AMPK and HO-1, Independent of Nrf2 Article 10.5607/en.2018.27.5.408 1 EXPERIMENTAL NEUROBIOLOGY, v.27, no.5, pp.408 - 418 EXPERIMENTAL NEUROBIOLOGY 27 5 408 418 scie scopus kci ART002401680 000449529100008 2-s2.0-85056611857 Medicine, Research & Experimental Neurosciences Research & Experimental Medicine Neurosciences & Neurology Article ACTIVATED PROTEIN-KINASE HEME OXYGENASE 1 NF-KAPPA-B MICROGLIAL ACTIVATION CHALCONE DERIVATIVES SIGNALING PATHWAY CELLS EXPRESSION INVOLVEMENT INDUCTION Microglia Neuroinflammation AMPK HO-1 iNOS