Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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MLKL Inhibitor Reduces Oxidative Stress, Inflammation, and Dopaminergic Neuronal Cell Death in MPTP-Induced Parkinson's Disease Mouse Model

  • Do-Yeon Kim (Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, School of Medicine, Ewha Womans University) ;
  • Yea-Hyun Leem (Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, School of Medicine, Ewha Womans University) ;
  • Hee-Sun Kim (Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, School of Medicine, Ewha Womans University)
  • Received : 2025.03.18
  • Accepted : 2025.04.04
  • Published : 2025.05.01
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Abstract

Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have shown that necroptosis is involved in the development of inflammatory and neurodegenerative diseases. Receptor-interacting protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) play key roles in necroptosis, with MLKL being the final executor of necroptosis. Necrosulfonamide (NSA) is a specific inhibitor of MLKL, and its therapeutic effects in various inflammatory and neurological disorders have been previously reported. However, its role in PD has not yet been clearly demonstrated. In this study, we examined the effects of NSA in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. NSA reduced dopaminergic cell death and restored the expression of neurotrophic factors, such as BDNF, GDNF, and PGC-1α, in the SN region of MPTP mice. In addition, NSA inhibited microglial/astrocyte activation and the expression of proinflammatory markers, such as iNOS, TNF-α, IL-1β, and IL-6. NSA also reduced oxidative stress markers, such as 8-OHdG and 4-HNE, while enhancing Nrf2-driven antioxidant enzymes, including HO-1, catalase, MnSOD, GCLC, and GCLM. We found that NSA inhibited MLKL phosphorylation in dopaminergic neurons and microglia, which may have reduced neuronal cell death and inflammation. Therefore, NSA-mediated suppression of dopaminergic neuronal cell death, inflammation, and oxidative stress may have therapeutic potential in PD.

Keywords

Acknowledgement

This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (Grant No. NRF-2020R1A5A2019210).

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