Pathomechanism characterization and potential therapeutics identification for SCA3 targeting neuroinflammation.

Abstract

Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are caused by mutant genes with expanded CAG repeats encoding polyQ tracts. The misfolding and aggregation of polyQ proteins result in increased reactive oxygen species (ROS) and cellular toxicity. Inflammation is a common manifestation of oxidative stress and inflammatory process further reduces cellular antioxidant capacity. Increase of activated microglia in the pons of SCA type 3 (SCA3) patients suggests the involvement of neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of indole compound NC009-1, 4-aminophenol-arachidonic acid derivative AM404, quinoline compound VB-037 and chalcone-coumarin derivative LM-031 using human HMC3 microglia and SCA3 ATXN3/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing NO, IL-1β, TNF-α and IL-6 production and CD68 expression of IFN-γ-activated HMC3 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP SH-SY5Y cells inflamed with IFN-γ-primed HMC3 conditioned medium, treatment with the tested compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced polyQ aggregation and ROS and/or promoted neurite outgrowth. Examination of IL-1β- and TNF-α-mediated signaling pathways revealed that the tested compounds decreased IκBα/P65, JNK/JUN and/or P38/STAT1 signaling. The study results suggest the potential of NC009-1, AM404, VB-037 and LM-031 in treating SCA3 and probable other polyQ diseases.

• Authors: Ya-Jen Chiu, Shu-An Lin, Wan-Ling Chen, Te-Hsien Lin, Chih-Hsin Lin, Ching-Fa Yao, Wenwei Lin, Yih-Ru Wu, Kuo-Hsuan Chang, Guey-Jen Lee-Chen, Chiung-Mei Chen
• Journal: Aging (Aging (Albany NY)) Vol. 12 Issue 23 Pg. 23619-23646 (11 10 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 33196459 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Arachidonic Acids
• Coumarins
• Cytokines
• Indoles
• Inflammation Mediators
• NC009-1 compound
• Quinolines
• Reactive Oxygen Species
• N-(4-hydroxyphenyl)arachidonylamide

Topics

• Anti-Inflammatory Agents (pharmacology)
• Arachidonic Acids (pharmacology)
• Cell Line, Tumor
• Coumarins (pharmacology)
• Cytokines (metabolism)
• Humans
• Indoles (pharmacology)
• Inflammation Mediators (metabolism)
• Machado-Joseph Disease (drug therapy, metabolism, pathology)
• Microglia (drug effects, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Quinolines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction