Novel neuroprotective hydrogen sulfide-releasing L-DOPA derivatives for the treatment of Parkinson disease

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (L-DOPA) is the most widely used therapy but it does not arrest disease progression. Some possible contributing factors 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 anti-inflammatory properties. Here we describe the syntheses and the properties of four such L-DOPA hybrids based on coupling L-DOPA methyl ester to four different hydrogen sulfide donating compounds, which were shown to be capable of conversion by isolated mitochondria to H2S or equivalent SH- ions; other hybrids are in development. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. 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 and interleukin-6 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. The significant antiinflammatory, antioxidant and neuroprotective properties of these new compounds make them potentially useful agents for the treatment of PD.