Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity.

ACS6, a novel hydrogen sulfide (H2S)-releasing sildenafil, has been demonstrated to inhibit superoxide formation through donating H2S. We have previously found that ACS6 antagonizes homocysteine-induced apoptosis and cytotoxicity. The aim of the present study is to explore the molecular mechanisms underlying ACS6-exerted protective action against the neurotoxicity of homocysteine. In the present work, we used PC12 cells to explore whether paraoxonase-1 (PON-1) is implicated in ACS6-induced neuroprotection against homocysteine neurotoxicity. We show that ACS6 treatment results in prevention of homocysteine-caused neurotoxicity and overproduction of reactive oxygen species (ROS). Homocysteine downregulates the expression and activity of PON-1; however, this effect is significantly blocked by co-treatment with ACS6. The specific inhibitor of PON-1 2-hydroxyquinoline reverses the inhibitory effect of ACS6 on homocysteine-induced neurotoxicity and intracellular ROS accumulation. These results indicate that ACS6 protects PC12 cells against homocysteine-induced neurotoxicity by upregulating PON-1 and suggest a promising role of PON-1 as a novel therapeutic strategy for homocysteine-induced toxicity.