Abstract
Chronic exposure to cathinone derivatives increases the risk of severe health hazards, whereas little is known about the detailed pathogenic mechanisms triggered by the derivatives. We have recently shown that treatment with α-pyrrolidinononanophenone (α-PNP, a highly lipophilic cathinone derivative possessing a long hydrocarbon main chain) provokes neuronal cell apoptosis and its 4′-fluorinated analog (F-α-PNP) potently augments the apoptotic effect. In this study, we found that neuronal SK-N-SH cell damage elicited by F-α-PNP treatment is augmented most potently by pre-incubation with an AKR1B1 inhibitor tolrestat, among specific inhibitors of four aldo–keto reductase (AKR) family members (1B1, 1C1, 1C2, and 1C3) expressed in the neuronal cells. In addition, forced overexpression of AKR1B1 remarkably lowered the cell sensitivity to F-α-PNP toxicity, clearly indicating that AKR1B1 protects from neurotoxicity of the derivative. Treatment of SK-N-SH cells with F-α-PNP resulted in a dose-dependent up-regulation of AKR1B1 expression and activation of its transcription factor NF-E2-related factor 2. Metabolic analyses using liquid chromatography/mass spectrometry/mass spectrometry revealed that AKR1B1 is hardly involved in the F-α-PNP metabolism. The F-α-PNP treatment resulted in production of reactive oxygen species and lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) in the cells. The enhanced HNE level was reduced by overexpression of AKR1B1, which also lessened the cell damage elicited by HNE. These results suggest that the AKR1B1-mediated neuronal cell protection is due to detoxification of HNE formed by F-α-PNP treatment, but not to metabolism of the derivative.
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Morikawa, Y., Miyazono, H., Kamase, K. et al. Protective Effect of Aldo–keto Reductase 1B1 Against Neuronal Cell Damage Elicited by 4′-Fluoro-α-pyrrolidinononanophenone. Neurotox Res 39, 1360–1371 (2021). https://doi.org/10.1007/s12640-021-00380-8
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DOI: https://doi.org/10.1007/s12640-021-00380-8