Figure 8.

Proposed mechanisms underlying sildenafil neuroprotection against malonate-induced neurotoxicity. Inhibition of succinate dehydrogenase by malonate administration induces mitochondrial dysfunction, which triggers the generation of ROS. The increase in ROS production leads to the activation of ASK1, which, in turn, activates JNK and p38. Nuclear translocation of p38 contributes to neuronal death. Sildenafil afforded protection is independent of any change in ROS production but appears to be related to the inhibition of the ASK1–MKK3/6–p38 pathway.