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Urolithin A Reverses Intranigral Rotenone-Generated Parkinsonism by Modulating DNA Methyltransferase 1 and
Ankita Devi1, Shashi Bala Singh1,2, Saurabh Srivastava3
1Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
Urolithin A reversed rotenone-induced Parkinson
Area of Science:
- Neuroscience
- Epigenetics
- Pharmacology
Background:
- Epigenetic alterations, including DNA methylation, are implicated in Parkinson's disease (PD) neuropathogenesis.
- DNA methyltransferase 1 (DNMT1) is a key epigenetic regulator whose post-translational modifications are not well understood in PD models.
- Rotenone exposure in rats creates a valid model for studying PD-like motor and non-motor deficits.
Purpose of the Study:
- To investigate the role of DNA methyltransferase 1 (DNMT1) post-translational modifications in a rotenone-induced Parkinson's disease (PD) rat model.
- To evaluate the therapeutic potential of urolithin A (UA) in reversing PD-like symptoms and underlying molecular changes.
- To elucidate the mechanism by which UA exerts its neuroprotective effects, focusing on the SIRT1/DNMT1/5-mC axis.
Main Methods:
- Establishment of a rotenone-induced PD rat model with assessment of motor and non-motor behaviors.
- Analysis of NAD+-dependent sirtuin 1 (SIRT1) and DNMT1 expression, acetylation, and methylation levels in the substantia nigra (SN).
- In-silico molecular dynamics simulation to confirm SIRT1-DNMT1 interaction and assessment of UA's effect on DNA methylation and alpha-synuclein (SNCA) expression.
Main Results:
- Rotenone administration induced motor deficits, depression-like behavior, decreased SIRT1, and increased acetylated DNMT1 (ac-DNMT1) in the SN.
- Urolithin A (UA) treatment reversed behavioral impairments and normalized SIRT1 levels and DNMT1 acetylation.
- UA increased global DNA methylation (5-mC) and SNCA promoter methylation, leading to reduced SNCA gene expression and α-synuclein levels.
Conclusions:
- Urolithin A (UA) demonstrates neuroprotective effects against rotenone-induced Parkinson's disease (PD) in rats.
- UA's mechanism involves the modulation of the SIRT1/ac-DNMT1/5-mC axis, leading to enhanced DNA methylation and reduced α-synuclein.
- Targeting the SIRT1/DNMT1 pathway with UA represents a potential therapeutic strategy for PD.
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