Sulforaphane as an inducer of glutathione prevents oxidative stress‐induced cell death in a dopaminergic‐like neuroblastoma cell line

Abstract

The total GSH depletion observed in the substantia nigra (SN) appears to be responsible for subsequent oxidative stress (OS), mitochondrial dysfunction, and dopaminergic cell loss in patients with Parkinson’s disease. A strategy to prevent the OS of dopaminergic cells in the SN may be the use of chemopreventive agents as inducers of endogenous GSH, antioxidant and phase 2 enzymes. In this study, we demonstrated that treatment of the dopaminergic‐like neuroblastoma SH‐SY5Y cell line with sulforaphane (SF), a cruciferous vegetables inducer, resulted in significant increases of total GSH level, NAD(P)H : quinone oxidoreductase‐1, GSH‐transferase and ‐reductase, but not GSH‐peroxidase, catalase and superoxide dismutase activities. Further, the elevation of GSH levels, GSH‐transferase and NAD(P)H:quinone oxidoreductase‐1 activities was correlated to an increase of the resistance of SH‐SY5Y cells to toxicity induced by H2O2 or 6‐hydroxydopamine (6‐OHDA). The pre‐treatment of SH‐SY5Y cells with SF was also shown to prevent various apoptotic events (mitochondrial depolarization, caspase 9 and 3 activation and DNA fragmentation) and necrosis elicited by 6‐OHDA. Further, the impairment of antioxidant capacity and reactive oxygen species formation at intracellular level after exposure to 6‐OHDA was effectively counteracted by pre‐treatment with SF. Last, both the cytoprotective and antioxidant effects of SF were abolished by the addition of buthionine sulfoximine supporting the main role of GSH in the neuroprotective effects displayed by SF. These findings show that SF may play a role in preventing Parkinson’s disease.

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

“…SF is a known activator of the Nrf2-ARE pathway. It has been reported that SF protects against 6-OHDA-induced oxidative stress by increasing the levels of GSH, NAD(P)H: quinine oxidoreductase-1, GSH-transferase and reductase (23). Whether HO-1 is involved in the SF-mediated protection against 6-OHDA is still unknown.…”

“…SF also has been reported to be a potential candidate for development of treatment and/or prevention of PD (22). SF protects dopaminergic neurons against 6-OHDA-induced cytotoxicity (23,24). However, the molecular mechanisms by which SF protects against 6-OHDA-induced cytotoxicity are poorly elucidated.…”

Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by sulforaphane through the activation of Nrf2 nuclear translocation

“…SF is known to have cytoprotective effects by activating the transcription factor, NF-E2-related factor-2 (Nrf2), which binds to the anti-oxidant response element in the promoter region of a number of genes encoding anti-oxidative and phase 2 enzymes, including heme oxygenase-1, glutathione reductase and NAD(P)H:quinoine oxidoreductase 1 (17)(18)(19). SF first gained attention due to its potential as an anticancer agent (20).…”

Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression

“…In a mouse cytotoxin (malonate) model of Huntington's disease, neuroprotection is observed by intrastriatal implantation of astrocytes with activated Nrf2-mediated gene expression [77]. Pretreatment of either dopaminergic cell lines or nigrostriatal co-cultures with sulforaphane provides neuroprotection against Parkinson's disease neurotoxins, e.g., 6-hydroxydopamine [78,79]. Mechanisms of neuroprotection in these models may include the increased expression of NQO1, which prevents ROS production that is catalyzed by the semiquinone fraction of the increased pool of quinones generated by aberrant dopamine metabolism, and increased levels of glutathione GSH, which detoxify peroxides and protect against oxidation of protein sulfhydryl groups [79].…”

“…Pretreatment of either dopaminergic cell lines or nigrostriatal co-cultures with sulforaphane provides neuroprotection against Parkinson's disease neurotoxins, e.g., 6-hydroxydopamine [78,79]. Mechanisms of neuroprotection in these models may include the increased expression of NQO1, which prevents ROS production that is catalyzed by the semiquinone fraction of the increased pool of quinones generated by aberrant dopamine metabolism, and increased levels of glutathione GSH, which detoxify peroxides and protect against oxidation of protein sulfhydryl groups [79]. In a MPTP mouse model of Parkinson's disease, overexpression of Nrf2 in astrocytes prevents neuronal death and reduces inflammation [80].…”