Project Details
Description
Background: Polyglutamine (polyQ)-mediated spinocerebellar ataxia type 3 (SCA3) is caused by expansion of CAG repeats in the ATXN3 gene. The misfolding and aggregation of polyQ-expanded ATXN3 protein result in a gain of toxicity that are central to pathogenesis and a concomitant increase in ROS level and cellular toxicity. Inflammation is one of the manifestations of oxidative stress and inflammatory process may further induce oxidative stress and reduce cellular antioxidant capacity. Increased numbers of reactive astrocytes and microglia were found in SCA3 pons, suggesting the involvement of inflammatory processes in the disease pathogenesis. Purpose: Previously we identified compounds NC009-1, AM404, VB-037 and LM-031 with anti-inflammatory potential using LPS-activated mouse RAW 264.7 macrophages. In this study, the anti-inflammatory potentials and neuroprotective effects of these compounds were assessed by using mouse BV-2/human HMC3 microglia and inflammation-stimulated human SH-SY5Y ATXN3/Q75 cells to offer a new drug development avenue of SCA3 treatment. Methods: BV-2 and HMC3 microglia were pretreated with test compounds for 8 h followed by activated with LPS and/or IFN-γ for 20 h. The anti-inflammatory potentials of these compounds were assessed by morphology examination, CD68/MHCII stain, NO/TNF-α/IL-1β production in cultured medium or Iba1/CD68 expression. In addition, retinoic acid differentiated SH-SY5Y ATXN3/Q75 cells were pretreated with test compounds followed by stimulation with BV-2 conditioned medium or IFN-γ. The neuroprotective effects of these compounds were evaluated by measuring cell survival, caspase 1 activity and LDH release. Results: Among the four test compounds, AM404 and LM-031 exhibited some radical scavenging activity. In LPS/IFN-γ activated mouse BV-2 cells, all four test compounds displayed anti-inflammatory activity by suppressing NO production. In IFN-γ-activated human HMC3 cells, the four test compounds also displayed anti-inflammatory activity by suppressing NO/IL-1β production in cultured medium and CD68 expression. In inflamed human SH-SY5Y ATXN3/Q75 cells, the decreased cell survival and increased caspase 1 activity and LDH release were mitigated by the treatment with NC009-1, AM404, VB-037 or LM-031. Conclusion: Our results demonstrate the potential of NC009-1, AM404, VB-037 and LM-031 for modifying SCA3 progression by targeting neuroinflammation.
Status | Finished |
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Effective start/end date | 2017/08/01 → 2018/07/31 |
Keywords
- spinocerebellar ataxia type 3
- ATXN3/Q75
- NC009-1
- AM404
- VB-037
- LM-031
- anti-inflammation
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