2. Academic Validation
  3. Investigating the therapeutic effects of novel compounds targeting inflammatory IL-1β and IL-6 signaling pathways in spinocerebellar ataxia type 3

Investigating the therapeutic effects of novel compounds targeting inflammatory IL-1β and IL-6 signaling pathways in spinocerebellar ataxia type 3

  • Eur J Pharmacol. 2024 Mar 15:967:176370. doi: 10.1016/j.ejphar.2024.176370.
I-Cheng Chen 1,  Wan-Ling Chen 2,  Kuo-Hsuan Chang 2,  Jun-Wei Lee 2,  Te-Hsien Lin 2,  Wenwei Lin 3,  Chiung-Mei Chen 4,  Guey-Jen Lee-Chen 5
Affiliations

Affiliations

  • 1 High-value Biomaterials Research and Commercialization Center, National Taipei University of Technology, Taipei, 10608, Taiwan; Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, 10608, Taiwan.
  • 2 Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, 33302, Taiwan.
  • 3 Department of Chemistry, National Taiwan Normal University, Taipei, 11677, Taiwan.
  • 4 Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, 33302, Taiwan. Electronic address: [email protected].
  • 5 Department of Life Science, National Taiwan Normal University, Taipei, 11677, Taiwan. Electronic address: [email protected].
PMID: 38320719 DOI: 10.1016/j.ejphar.2024.176370
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, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (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 IL-1β and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (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.

Keywords

IL-1β/IL-6 signaling; JAK2/SOCS3; JNK/NF-κB/P38; Spinocerebellar ataxia 3/ATXN3; Therapeutics.

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