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Suppression of cAMP-responsive element binding protein- (CREB-) dependent transcription, impaired nuclear factor erythroid 2-related factor 2 (NRF2) signaling, and interaction of AMP-activated protein kinase (AMPK) with increased oxidative stress have been implicated to be involved in pathogenic mechanisms of polyQ-mediated diseases. In this study, we demonstrated decreased pCREB and NRF2 and activated AMPK contributing to neurotoxicity in SCA17 SH-SY5Y cells. We also showed that licochalcone A and the related in-house derivative compound 3-benzoyl-5-hydroxy-2<jats:italic>H<\/jats:italic>-chromen-2-one (LM-031) exhibited antiaggregation, antioxidative, antiapoptosis, and neuroprotective effects in TBP\/Q<jats:sub>79<\/jats:sub>-GFP-expressing cell models. LM-031 and licochalcone A exerted neuroprotective effects by upregulating pCREB and its downstream genes, BCL2 and GADD45B, and enhancing NRF2. Furthermore, LM-031, but not licochalcone A, reduced activated AMPK<jats:italic>\u03b1<\/jats:italic>. Knockdown of CREB and NRF2 and treatment of AICAR (5-aminoimidazole-4-carboxamide 1-<jats:italic>\u03b2<\/jats:italic>-D-ribofuranoside), an AMPK activator, attenuated the aggregation-inhibiting and neurite outgrowth promoting effects of LM-031 on TBP\/Q<jats:sub>79<\/jats:sub> SH-SY5Y cells. The study results suggest the LM-031 as potential therapeutics for SCA17 and probable other polyQ diseases.<\/jats:p>","DOI":"10.1155\/2020\/3129497","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T23:34:10Z","timestamp":1587684850000},"page":"1-17","source":"Crossref","is-referenced-by-count":6,"title":["New Synthetic 3-Benzoyl-5-Hydroxy-2<i>H<\/i>-Chromen-2-One (LM-031) Inhibits Polyglutamine Aggregation and Promotes Neurite Outgrowth through Enhancement of CREB, NRF2, and Reduction of AMPK<i>\u03b1<\/i> in SCA17 Cell Models"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0769-0353","authenticated-orcid":true,"given":"Chiung-Mei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, 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