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<p>Parkinson’s disease (PD) is the second most common multifactorial neurodegenerative disorder caused by several genetics and environmental factors. Rotenone a pesticide with mitotoxicity causes cytosolic proteopathy resulting in PD-associated apoptosis and modulations in cell survival pathways. Shikonin, a naphthoquinone compound extracted from the <i>Lithospermum erythrorhizon</i> herb, was investigated in this study for its neuroprotective properties and underlying molecular mechanisms against rotenone-induced cellular apoptosis and survival in SH-SY5Y cells. The molecular docking analysis of apoptotic proteins against Shikonin revealed that they showed a binding affinity with BAD. Shikonin effectively countered the loss of cell viability induced by rotenone, rescued annexin-positive apoptotic cells, and dose-dependently suppressed the generation of reactive oxygen species. Pre-treatment with Shikonin prevented the morphological aberrations like shrining of neurites leading to decreased LDH leakage and NO release caused due to the rotenone treatment. The α-synucleinopathy is a prime hallmark of PD, Shikonin mitigated the rotenone-induced aggregation of α-synuclein as seen from confocal imaging. Furthermore, Shikonin treatment reversed the rotenone-induced excessive production of reactive oxygen species, activation of caspases (-8 and -3), and mitochondrial dysfunction, as evidenced by the restoration of mitochondrial membrane potential and cellular ATP levels. Western blot and qPCR analysis revealed that Shikonin heightened the IGF1R/PI3K/AKT signaling associated with cell survival while concurrently downregulating rotenone-induced intrinsic apoptotic pathways. These findings underscore Shikonin as a promising candidate to prevent the onset of pesticide-induced Parkinson’s disease and potentially other oxidative stress-related neurodegenerative disorders.</p>

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Shikonin Ameliorates Rotenone-Induced Neurotoxicity Through Inhibition of Apoptosis via IGF-1R/PI3K/AKT Pathway in a Parkinson’s Disease-Associated SH-SY5Y Cell Model

  • 期刊论文

  • 发表日期：

    2025年3月8日

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  • Aparna Anandan,
  • Mohammed Unais AK,
  • Surovi Saika,
  • Marthandam Asokan Shibu,
  • Vijaya Padma Viswanadha

摘要

Parkinson’s disease (PD) is the second most common multifactorial neurodegenerative disorder caused by several genetics and environmental factors. Rotenone a pesticide with mitotoxicity causes cytosolic proteopathy resulting in PD-associated apoptosis and modulations in cell survival pathways. Shikonin, a naphthoquinone compound extracted from the Lithospermum erythrorhizon herb, was investigated in this study for its neuroprotective properties and underlying molecular mechanisms against rotenone-induced cellular apoptosis and survival in SH-SY5Y cells. The molecular docking analysis of apoptotic proteins against Shikonin revealed that they showed a binding affinity with BAD. Shikonin effectively countered the loss of cell viability induced by rotenone, rescued annexin-positive apoptotic cells, and dose-dependently suppressed the generation of reactive oxygen species. Pre-treatment with Shikonin prevented the morphological aberrations like shrining of neurites leading to decreased LDH leakage and NO release caused due to the rotenone treatment. The α-synucleinopathy is a prime hallmark of PD, Shikonin mitigated the rotenone-induced aggregation of α-synuclein as seen from confocal imaging. Furthermore, Shikonin treatment reversed the rotenone-induced excessive production of reactive oxygen species, activation of caspases (-8 and -3), and mitochondrial dysfunction, as evidenced by the restoration of mitochondrial membrane potential and cellular ATP levels. Western blot and qPCR analysis revealed that Shikonin heightened the IGF1R/PI3K/AKT signaling associated with cell survival while concurrently downregulating rotenone-induced intrinsic apoptotic pathways. These findings underscore Shikonin as a promising candidate to prevent the onset of pesticide-induced Parkinson’s disease and potentially other oxidative stress-related neurodegenerative disorders.