Neuroprotection of resveratrol against cadmium-poisoning acts through dual inhibition of mTORC1/2 signaling. (15th November 2022)

• Record Type: Journal Article
• Authors: Liu, Chunxiao; Zhang, Ruijie; Yang, Liu; Ji, Tong; Zhu, Cuilan; Liu, Beibei; Zhang, Hai; Xu, Chong; Zhang, Nana; Huang, Shile; Chen, Long
• Is Part Of: Neuropharmacology. Volume 219(2022)
• Publication Date: 2022-11-15
• Subjects: Resveratrol -- Neuroprotection -- Cadmium -- Poisoning -- mTOR -- Akt; 4E-BP1 eukaryotic initiation factor 4E binding protein 1 -- AD Alzheimer disease -- Akt protein kinase B (PKB) -- ALS amyotrophic lateral sclerosis -- AMPK AMP-activated protein kinase -- Cd cadmium -- CM-H2DCFDA 5-(and-6)-chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate -- DMEM Dulbecco's Modified Eagle's Medium -- Erk1/2 extracellular signal-regulated kinases 1/2 -- FBS fetal bovine serum -- GSK3β glycogen synthase kinase 3β -- HD Huntington's disease -- JNK c-Jun N-terminal kinase -- MAPKs mitogen-activated protein kinases -- mTOR mammalian target of rapamycin -- mTORC1/2 mTOR complex 1/2 -- PBS phosphate buffered saline -- PD Parkinson disease -- PDL poly-d-lysine -- PI3K phosphatidylinositol-3-hydroxykinase -- PKCα protein kinase Cα -- PP2A protein phosphatase 2A -- PP5 protein phosphatase 5 -- Raptor regulatory-associated protein of mTOR -- Rictor rapamycin insensitive companion of mTOR -- ROS reactive oxygen species -- S6K1 ribosomal p70 S6 kinase 1 -- SGK1 serum and glucocorticoid-induced kinase 1 -- SIRT1 sirtuin 1 -- TUNEL the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109236
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Resveratrol is a natural polyphenol with neuroprotective function. The underlying mechanism is not well understood. Our previous studies have identified that resveratrol antagonizes cadmium (Cd) neurotoxicity via targeting PP2A/PP5-mediated Erk1/2 and JNK pathways. Here we show that resveratrol protected against Cd-poisoning also by blocking Cd-induced activation of mTORC1 and mTORC2 pathways in PC12 cells and murine primary neurons. Co-treatment with inhibitors of mTORC1 (rapamycin), mTORC1/2 (PP242), Erk1/2 (U0126) and/or JNK (SP600125), knockdown of mTOR, or disruption of mTORC1 and/or mTORC2 by silencing raptor, rictor or raptor/rictor, respectively, markedly potentiated the inhibitory effects of resveratrol on Cd-induced phosphorylation of S6K1/4E-BP1 (mTORC1 substrates), Akt (mTORC2 substrate), Erk1/2 and/or JNK/c-Jun, cleavage of caspase-3 and cell death in PC12 cells and/or primary neurons. Knockdown of S6K1 or 4E-BP1, or ectopic expression of constitutively hypophosphorylated 4E-BP1 (4E-BP1-5A) reinforced the resveratrol's inhibition on Cd-evoked cell death, whereas ectopic expression of constitutively active S6K1 or knockdown of 4E-BP1 attenuated the resveratrol's inhibition on Cd-induced cell death. Co-treatment with Akt inhibitor or overexpression of dominant negative Akt (dn-Akt) strengthened the resveratrol's suppression on Cd-induced ROS, Erk1/2 activation and apoptosis, whereas overexpression of constitutively active Akt (myr-Akt) conferred high resistance to the resveratrol's inhibitory effects in the neuronal cells. Taken together, the results indicate that resveratrol attenuates Cd-induced neuronal apoptosis partly through inhibition of mTORC1/2 pathways. Our studies highlight that resveratrol can be exploited for the prevention of Cd toxicity related to neurodegenerative diseases. Highlights: Resveratrol blocks Cd neurotoxicity by targeting mTORC1-mediated S6K1/4E-BP1 pathways. Resveratrol prevents Cd neurotoxicity also through suppressing mTORC2-mediated Akt pathway. Resveratrol exerts neuroprotection against Cd-poisoning via dual inhibition of mTORC1/2 signaling. Resveratrol may be exploited for prevention of Cd toxicity related to neurodegenerative diseases.