Lee, Ji Ae Son, Hyo Jin Choi, Ji Won Kim, Jinwoo Han, Se Hee Shin, Nari Kim, Ji Hyun Kim, Soo Jeong Heo, Jun Young Kim, Dong Jin Park, Ki Duk Hwang, Onyou 2024-01-19T23:34:01Z 2024-01-19T23:34:01Z 2021-09-03 2018-01 0197-0186 https://pubs.kist.re.kr/handle/201004/121855 The transcription factor Nrf2 is known to induce gene expression of antioxidant enzymes and proteasome subunits. Because both oxidative stress and protein aggregation have damaging effects on neurons, activation of the Nrf2 signaling should be beneficial against neurodegeneration. In this study, we report a novel synthetic morpholine-containing chalcone KMS99220 that confers neuroprotection. It showed high binding affinity to the Nrf2 inhibitory protein Keap-1 and increased nuclear translocation of Nrf2 and gene expression of the antioxidant enzymes heme oxygenase-1, NAD(P)H: quinone oxidoreductase-1, and the catalytic and modifier subunits of glutamate-cysteine ligase in dopaminergic CATH.a cells. KMS99220 also increased expression of the proteasome subunits PSMB5, PSMB7, PSMB8 and PSMA1, and the respective chymotrypsin and trypsin-like proteasomal enzyme activities, and reduced alpha-synuclein aggregate in GFP-alpha-syn A53T-overexpressing cells. KMS99220 exhibited a favorable pharmacokinetic profile with excellent bioavailability and metabolic stability, did not interfere with activities of the cytochrome p450 isotypes, and showed no apparent in vivo toxicity when administered up to 2000 mg/kg. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, oral administration of KMS99220 prevented degeneration of the nigral dopaminergic neurons, induced the Nrf2 target genes, and effectively prevented the associated motor deficits. These results suggest KMS99220 as a potential candidate for therapy against Parkinson's disease. (C) 2017 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD PARKINSONS-DISEASE MODELS INDUCED CELL-DEATH ALPHA-SYNUCLEIN OXIDATIVE STRESS SUBSTANTIA-NIGRA IN-VIVO PROTEASOMAL FUNCTION NEUROBLASTOMA-CELLS OXIDIZED PROTEINS ANIMAL-MODEL Activation of the Nrf2 signaling pathway and neuroprotection of nigral dopaminergic neurons by a novel synthetic compound KMS99220 Article 10.1016/j.neuint.2017.11.006 1 NEUROCHEMISTRY INTERNATIONAL, v.112, pp.96 - 107 NEUROCHEMISTRY INTERNATIONAL 112 96 107 scie scopus 000423649300010 2-s2.0-85034668850 Biochemistry & Molecular Biology Neurosciences Biochemistry & Molecular Biology Neurosciences & Neurology Article PARKINSONS-DISEASE MODELS INDUCED CELL-DEATH ALPHA-SYNUCLEIN OXIDATIVE STRESS SUBSTANTIA-NIGRA IN-VIVO PROTEASOMAL FUNCTION NEUROBLASTOMA-CELLS OXIDIZED PROTEINS ANIMAL-MODEL Parkinson&apos s disease Substantia nigra Oxidative stress Protein aggregation Neuroprotection