Investigating the Therapeutic Effects of Novel Compounds Targeting Inflammasome and IL-1β and IL-6 Signaling Pathways in Spinocerebellar Ataxia Type 3

Abstract

Abstract At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1 and LMDS-2, and pharmacological chaperone tafamidis that stabilizes the correctly folded tetrameric transthyretin protein, using mouse BV-2 microglia and SCA3 ATXN3/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing NO, IL-1β, IL-6 and TNF-α production and CD68, MHCII expression in LPS/IFN-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q75 aggregation, and promoted neurite outgrowth. Examination of inflammasome, IL-1β and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2 and tafamidis decreased NLRP1, JNK/JUN, IκBα/P65, P38/STAT1 and/or JAK2/STAT3 signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2 and tafamidis in treating SCA3 and probable other polyQ diseases.