Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

Abstract

Evidence suggests oxidative and electrophilic stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/ electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10-100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and electrophilic stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H 2 O 2 , agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and electrophilic neurocytotoxicity.

Oxidative stress in spinal cord injury and antioxidant-based intervention

“…107 Oxidative stress in spinal cord injury Z Jia et al that D3T increases multiple cellular antioxidants including glutathione and NQO1, two crucial cellular defenses against oxidative and electrophilic stress in human neuroblastoma cells (SH-SY5Y), human primary neurons and astrocytes, suggesting that D3T-mediated antioxidant induction is not cell-type specific. [60][61][62] In addition, D3T treatment of the neuronal cells also results in a marked elevation of glutathione content in the mitochondrial compartment, 62 a critical intracellular target for oxidative and electrophilic stress. 63 It is important to note that the D3T upregulated endogenous defenses are accompanied by increased cellular resistance to neurocytotoxicity elicited by ROS and several well-known neurotoxins including acrolein, suggesting a potential therapeutic value in SCI.…”

“…63 It is important to note that the D3T upregulated endogenous defenses are accompanied by increased cellular resistance to neurocytotoxicity elicited by ROS and several well-known neurotoxins including acrolein, suggesting a potential therapeutic value in SCI. [60][61][62] Other compounds: several epidemiological studies have demonstrated that increased consumption of antioxidant-rich fruits and vegetables is associated with reduced risk of ischemic stroke, dementia and SCI. 64,65 In this context, identification and study of the biologically active compounds may be of importance for developing strategies to inhibit, retard or reverse the pathophysiological processes underlying SCI.…”

Interconnection of Antitoxic and Antioxidant Systems of the Organism under the Action of Natural Low Molecular Complex – Fungidol

“…It was found that the induction of free radical production, that can further lead an oxidative stress, is nonspecific reaction to a wide range a stress factors [9][10].…”

Pathology of Neurodegenerative Diseases

“…Induction of NQO1 by sulforaphane, dimethyl fumarate, 3H-1,2-dithiole-3-thione, tert-butylhydroquinone (tBHQ), and butylated hydroxyanisole protected against neurocytotoxicity associated with DA quinone in vitro (H.J. Choi et al, 2003;Duffy et al, 1998;Han et al, 2007;Hara et al, 2003;Jia et al, 2009;Jia et al, 2008;Miyazaki et al, 2006;Siebert et al, 2009);; and against MPTP-elicited toxicity in vivo (Jazwa et al, 2011). In addition, NQO1 is known to maintain both -tocopherol and coenzyme Q10 in their reduced, antioxidant state (Siegel et al, 1997).…”

“…Indeed, the toxic accumulation of the DA quinone (as well as L-DOPA quinone) can be prevented by the action of NQO1. NQO1 protected against damaging effects of cyclized quinones and oxidative stress induced during their redox cycling (Zafar, Inayat-Hussain, et al, 2006), and against DA (Zafar, Siegel, et al, 2006) and 6-hydroxyDA (Jia et al, 2008). Induction of NQO1 by sulforaphane, dimethyl fumarate, 3H-1,2-dithiole-3-thione, tert-butylhydroquinone (tBHQ), and butylated hydroxyanisole protected against neurocytotoxicity associated with DA quinone in vitro (H.J.…”