Hydrogen sulfide reduces oxidative stress in Huntington’s disease via Nrf2

Abstract

Abstract The pathophysiology of Huntington’s disease involves high levels of the neurotoxin quinolinic acid (Quin). Quin accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which Quin contributes to Huntington’s disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington’s disease by administering Quin to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide (H2S) in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for H2S production. However, treatment with NaHS (a H2S donor) increased H2S levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Finally, treatment with the Nrf2 inhibitor ML385 reversed the beneficial impact of exogenous H2S on Quin-induced oxidative stress. Taken together, our findings show that H2S reduces oxidative stress in Huntington’s disease by activating Nrf2, suggesting that H2S is a novel neuroprotective drug candidate for treating patients with Huntington’s disease.