Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: potential for treating 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 antiinflammatory properties. Here we demonstrate the properties of four such L-DOPA hybrids based on coupling L-DOPA to four different hydrogen sulfide-donating compounds. The donors themselves were shown to be capable of conversion by isolated mitochondria to H(2)S or equivalent SH(-) ions. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. When human microglia, astrocytes, and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H(2)S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-alpha, 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. The H(2)S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties.
Lee
Moonhee
M
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Tazzari
Valerio
V
Giustarini
Daniela
D
Rossi
Ranieri
R
Sparatore
Anna
A
Del Soldato
Piero
P
McGeer
Edith
E
McGeer
Patrick L
PL
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D015850:Interleukin-6 / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009457:Neuroglia / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007980:Levodopa; D006862:Hydrogen Sulfide