Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with loss of dopaminergic neurons in the substantia nigra pars compacta. Although aging is the primary cause, environmental and genetic factors have also been implicated in its etiology. In fact, the sporadic nature of PD (i.e., unknown etiology) renders the uncovering of the exact pathogenic mechanism(s) or development of effective pharmacotherapies challenging. In search of novel neuroprotectants, we showed that butyrate (BUT), a short-chain fatty acid, protects against salsolinol (SALS)-induced toxicity in human neuroblastoma-derived SH-SY5Y cells, which are considered an in-vitro model of PD. Dihydromyricetin (DHM), a flavonoid derived from Asian medicinal plant, has also shown effectiveness against oxidative damage and neuroinflammation, hallmarks of neurodegenerative diseases. Here we show that pretreatment of SH-SY5Y cells with DHM concentration-dependently prevented SALS-induced toxicity and that a combination of DHM and BUT resulted in a synergistic protection. The effects of both DHM and BUT in turn could be completely blocked by flumazenil (FLU), a GABAA antagonist acting at benzodiazepine receptor site, and by bicuculline (BIC), a GABAA antagonist acting at orthosteric site. Beta-hydroxybutyrate (BHB), a free fatty acid 3 (FA3) receptor antagonist, also fully blocked the protective effect of DHM. BHB was shown previously to only partially block the protective effect of BUT. Thus, there are some overlaps and some distinct differences in protective mechanisms of DHM and BUT against SALS-induced toxicity. It is suggested that a combination of DHM and BUT may have therapeutic potential in PD. However, further in-vivo verifications are necessary.
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The study was supported by NIH/NIAAA R03AA022479 (Y. T.) and NIH/NIA 1R25AG047843-01 (A. B. C., K. F. M.).
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All authors confirmed they have contributed to the intellectual content of this paper including significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; drafting or revising the article for intellectual content; final approval of the published article; and agreement to be accountable for all aspects of the article. The initial concept was developed by Y. T. and discussed with all other co-authors. Cell culture studies were conducted by B. G. and A. B. C. Interpretation and data analysis were done by Y. T., B. G., A. B. C., R. L. C., and K. F. M. All authors contributed to the writing of the final draft.
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Getachew, B., Csoka, A.B., Copeland, R.L. et al. Dihydromyricetin Protects Against Salsolinol-Induced Toxicity in Dopaminergic Cell Line: Implication for Parkinson’s Disease. Neurotox Res 41, 141–148 (2023). https://doi.org/10.1007/s12640-022-00631-2
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DOI: https://doi.org/10.1007/s12640-022-00631-2