TY - JOUR
T1 - Investigating the therapeutic effects of novel compounds targeting inflammatory IL-1β and IL-6 signaling pathways in spinocerebellar ataxia type 3
AU - Chen, I. Cheng
AU - Chen, Wan Ling
AU - Chang, Kuo Hsuan
AU - Lee, Jun Wei
AU - Lin, Te Hsien
AU - Lin, Wenwei
AU - Chen, Chiung Mei
AU - Lee-Chen, Guey Jen
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/3/15
Y1 - 2024/3/15
N2 - 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.
AB - 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.
KW - IL-1β/IL-6 signaling
KW - JAK2/SOCS3
KW - JNK/NF-κB/P38
KW - Spinocerebellar ataxia 3/ATXN3
KW - Therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85184576082&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85184576082&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2024.176370
DO - 10.1016/j.ejphar.2024.176370
M3 - Article
C2 - 38320719
AN - SCOPUS:85184576082
SN - 0014-2999
VL - 967
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 176370
ER -