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Baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating ATP-sensitive potassium channels

Acta Pharmacologica Sinica volume 45, pages 480–489 (2024)Cite this article

Abstract

Dopaminergic neurons in the substantia nigra (SN) expressing SUR1/Kir6.2 type ATP-sensitive potassium channels (K-ATP) are more vulnerable to rotenone or metabolic stress, which may be an important reason for the selective degeneration of neurons in Parkinson’s disease (PD). Baicalein has shown neuroprotective effects in PD animal models. In this study, we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells. K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp recording. Drugs dissolved in the external solution at the final concentration were directly pipetted onto the cells. We showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC50 values of 0.438 μM and 6.159 μM, respectively. K-ATP channel blockers glibenclamide (50 μM) or 5-hydroxydecanoate (5-HD, 250 μM) attenuated the protective effects of baicalein in reducing reactive oxygen species (ROS) content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells, suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP channels. Administration of baicalein (150, 300 mg·kg−1·d−1, i.g.) significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of rats. We conducted surface plasmon resonance assay and molecular docking, and found that baicalein had a higher affinity with SUR1 protein (KD = 10.39 μM) than glibenclamide (KD = 24.32 μM), thus reducing the sensitivity of K-ATP channels to rotenone. Knockdown of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells, confirming that SUR1 was an important target for slowing dopaminergic neuronal degeneration in PD. Taken together, we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.

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Fig. 1: Rotenone and baicalein activated K-ATP channels in vitro.
Fig. 2: K-ATP channels blockers abolished the effect of baicalein on preventing rotenone-induced mitochondrial disruption in SH-SY5Y cells.
Fig. 3: Baicalein inhibits rotenone-induced SH-SY5Y viability damage and apoptosis.
Fig. 4: Baicalein bound to SUR1 and reduced K-ATP channels response sensitivity to rotenone.
Fig. 5: Baicalein downregulated the overexpression of SUR1 induced by rotenone.
Fig. 6: SUR1 knockdown reversed the survival and apoptosis of SH-SY5Y cells by weakening IK-ATP.
Fig. 7: Diagram showing the proposed mechanisms of baicalein against Parkinson’s disease via regulating K-ATP channels.

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Acknowledgements

This work was supported by the Beijing Natural Science Foundation (7232258) and the CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-005, 2022-I2M-JB-010).

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    De-wen Kong, Run-zhe Liu, Tian-yi Yuan, Yue-hua Wang, Lian-hua Fang & Guan-hua Du

  2. Beijing Key Laboratory of Drug Targets Identification and Drug Screening, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    De-wen Kong, Run-zhe Liu, Shou-bao Wang, Yue-hua Wang, Lian-hua Fang & Guan-hua Du

  3. Shandong Soteria Pharmaceutical Co Ltd., Jinan, 250022, China

    Li-da Du

  4. Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Yang Lu

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Contributions

DWK performed most of the experiments, analyzed the data and wrote the draft. LDD and RZL assisted in animal experiments. TYY and SBW carried out the Western blotting. YHW and YL provided baicalein (98% purity, crystal β form). LHF and GHD designed the project and revised the draft.

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Correspondence to Lian-hua Fang or Guan-hua Du.

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Kong, Dw., Du, Ld., Liu, Rz. et al. Baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating ATP-sensitive potassium channels. Acta Pharmacol Sin 45, 480–489 (2024). https://doi.org/10.1038/s41401-023-01187-3

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