(R)-(+)-α-lipoic acid protected NG108-15 cells against H₂O₂-induced cell death through PI3K-Akt/GSK-3β pathway and suppression of NF-κβ-cytokines

• Published in: Drug design, development and therapy development and therapy, 2014-10, Vol.8, p.1765-1780
• Main Authors: Kamarudin, Muhamad Noor Alfarizal, Mohd Raflee, Nur Afiqah, Hussein, Sharifah Salwa Syed, Lo, Jia Ye, Supriady, Hadi, Abdul Kadir, Habsah
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; AKT protein; alpha-lipoic acid (LA); Alzheimer's disease; Antioxidants; Apoptosis; Bcl-x protein; Brain; Caspase; Caspase-3; Cell death; Cell Death - drug effects; Cell growth; Cell Survival - drug effects; Cell viability; Cells, Cultured; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Deactivation; Dose-Response Relationship, Drug; Glutathione; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β; Humans; Hydrogen peroxide; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - pharmacology; Inactivation; Inflammation; Interleukin 10; Interleukin 6; Iodides; Kinases; Lipoic acid; Medical treatment; Membrane potential; Mitochondria; Molecular Conformation; Molecular modelling; Morphology; Neurodegeneration; Neurodegenerative diseases; neuroegenerative diseases; Neurological diseases; Neuroprotection; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κβ; Original Research; Oxidative stress; Pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K-Akt; Pretreatment; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reduction; Signal transduction; Signal Transduction - drug effects; Structure-Activity Relationship; Thioctic Acid - chemistry; Thioctic Acid - pharmacology; Translocation; Tumor necrosis factor-TNF
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S67980

Alpha-lipoic acid, a potent antioxidant with multifarious pharmacological benefits has been reported to be neuroprotective in several neuronal models and used to treat neurological disorders such as Alzheimer's disease. Nonetheless, conclusive mechanisms of alpha-lipoic acid for its protective effects particularly in NG108-15 cells have never been investigated. In this study, the intricate neuroprotective molecular mechanisms by (R)-(+)-alpha-lipoic acid (R-LA) against H2O2-induced cell death in an in vitro model of neurodegeneration were elucidated. Pretreatment with R-LA (2 hours) significantly increased NG108-15 cell viability as compared to H2O2-treated cells and mitigated the induction of apoptosis as evidenced by Hoechst 33342/propidium iodide staining. R-LA (12.5-50 μM) aggrandized the reduced glutathione over glutathione disulfide ratio followed by a reduction in the intracellular reactive oxygen species level and an increase in mitochondrial membrane potential following H2O2 exposure. Moreover, pretreatment with R-LA stimulated the activation of PI3K-Akt through mTORC1 and mTORC2 components (mTOR, rictor and raptor) and production of antiinflammatory cytokine, IL-10 which led to the inactivation of glycogen synthase kinase-3β (GSK-3β) and reduction of both Bax/Bcl2 and Bax/Bcl-xL ratios, accompanied by inhibition of the cleaved caspase-3. Additionally, this observation was preceded by the suppression of NF-κβ p65 translocation and production of proinflammatory cytokines (IL-6 and TNF-α). The current findings accentuate new mechanistic insight of R-LA against apoptogenic and brain inflammatory factors in a neuronal model. These results further advocate the therapeutic potential of R-LA for the treatment of neurodegenerative diseases.