H2S-releasing L-DOPA derivatives for Parkinson disease

L-DOPA is the most widely used therapy for Parkinson disease but it does not arrest progression of the disorder. Factors that contribute to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. We have prepared four such L-DOPA hybrids, based on coupling L-DOPA to different hydrogen sulfide donating compounds. They show promise as disease modifying agents. This capability was demonstrated by in vivo results with one of the hybrids where larger increases in brain dopamine levels were observed than with equivalent doses of L-DOPA. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity which could explain why they increased dopamine levels in vivo. The donors themselves were shown to be capable of conversion to H2S or equivalent SH- ions by isolated mitochondria. When human microglia, astrocytes and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H2S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-α, interleukin-6 and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant and neuroprotective properties.