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Orientin Modulates Nrf2-ARE, PI3K/Akt, JNK-ERK1/2, and TLR4/NF-kB Pathways to Produce Neuroprotective Benefits in Parkinson's Disease

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Abstract

Parkinson's disease (PD) is characterized by oxidative stress and neuroinflammation as key pathological features. Emerging evidence suggests that nuclear factor erythroid 2 related factor 2-antioxidant response element (Nrf2-ARE), phosphatidylinositol 3‑kinase-protein kinase B (PI3K-Akt), c-Jun N-terminal kinase-extracellular signal-regulated kinase 1/2 (JNK-ERK1/2), and toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kB) pathways play pivotal roles in PD pathogenesis. Orientin, a phenolic phytoconstituent, has demonstrated modulatory potential on these pathways in various experimental conditions other than PD. In this study, we aimed to evaluate the neuroprotective effects of Orientin against rotenone-induced neurodegeneration in SH-SY5Y cell lines and the Swiss albino mice model of PD. Orientin was administered at doses 10 and 20 µM in cell lines and 10 and 20 mg/kg in mice, and its effects on rotenone-induced neurodegeneration were investigated. Oxidative stress markers including mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as inflammatory markers including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured. The expression levels of genes related to Nrf2-ARE (Nrf2), PI3K/Akt (Akt), JNK-ERK1/2 (TNF-α), and TLR4/NF-kB (TNF-α) pathways were measured to understand the modulatory effect of Orientin on these pathways. Additionally, behavioral studies assessing locomotor activity, muscle coordination, and muscle rigidity were conducted with mice. Our results indicate that Orientin dose-dependently attenuated rotenone-induced changes in oxidative stress markers, inflammatory markers, gene expression levels, and behavioral parameters. Therefore, our study concludes that Orientin exhibits significant neuroprotective benefits against rotenone-induced PD by modulating Nrf2-ARE, PI3K-Akt, JNK-ERK1/2, and TLR4/NF-kB pathways.

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The datasets generated during and/or analyzed during the current study will be provided on request.

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Acknowledgements

The authors would like to acknowledge the Indian Council of Medical Research (ICMR), New Delhi, India for providing financial support for the study and the Department of Science and Technology – Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi, India for their infrastructure support to our department.

Funding

This work was supported by the Indian Council of Medical Research (ICMR), New Delhi, India. Grant No: 3/1/2/138/Neuro/2020-NCD-I. Author Deepak Vasudevan Sa**i has received research support from ICMR.

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  1. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, 643 001, India

    Deepak Vasudevan Sa**i, Praveen Thaggikuppe Krishnamurthy, Amritha Chakkittukandiyil & Ravi Naik Mudavath

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Contributions

DVS conceptualized and designed the study. Material preparation, data collection, and analysis were performed by DVS and AC. The statistical analysis was performed by DVS and MRN. The work was supervised by PTK. The first draft of the manuscript was written by DVS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Praveen Thaggikuppe Krishnamurthy.

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Ethical Approval

This study was performed as per the guidelines of the CCSEA, India and the study was approved by the IAEC at JSS College of Pharmacy, Ooty (Approval number JSSCP/OT/IAEC/40/2019-20).

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Vasudevan Sa**i, D., Thaggikuppe Krishnamurthy, P., Chakkittukandiyil, A. et al. Orientin Modulates Nrf2-ARE, PI3K/Akt, JNK-ERK1/2, and TLR4/NF-kB Pathways to Produce Neuroprotective Benefits in Parkinson's Disease. Neurochem Res 49, 1577–1587 (2024). https://doi.org/10.1007/s11064-024-04099-8

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