Synthesis and neuroprotective effects of HS-donor-peptide hybrids on hippocampal neuronal cells.

Hydrogen sulfide (HS) has emerged as an endogenous signaling molecule that functions in many physiological and pathological processes of human cells in health and disease, including neuromodulation and neuroprotection, inflammation, angiogenesis, and vasorelaxation. The limited clinical applications of current HS donors have led to the development of HS donor hybrid compounds that combine current HS donors with bioactive molecules. Finely tuned multi-targeting hybrid molecules have been shown to have complementary neuroprotective effects against reactive oxygen species (ROS)-induced oxidative stress. In this study, we developed hybrid molecules combining a dithiolethione-based slow-releasing HS donor that exerts neuroprotective effects, with the tripeptides glycyl-L-histidyl-l-lysine (GHK) and L-alanyl-L-cystinyl-l-glutamine (ACQ), two natural products that exhibit powerful antioxidant effects. In particular, a hybrid combination of a dithiolethione-based slow-releasing HS donor and ACQ exhibited significant neuroprotective effects against glutamate-induced oxidative damage in HT22 hippocampal neuronal cells. This hybrid remarkably suppressed Ca accumulation and ROS production. Furthermore, it efficiently inhibited apoptotic neuronal cell death by blocking apoptosis-inducing factor release and its translocation to the nucleus. These results indicate that the hybrid efficiently inhibited apoptotic neuronal cell damage by complementary neuroprotective actions.