Dopamine-Derived Cotoxins and the Unique Vulnerability of Dopaminergic Neurons in Parkinson’s Disease

The fundamental problem in Parkinson’s disease is the selective death of dopaminergic neurons in the substantia nigra. This selective death is facilitated by products of dopamine oxidation including a toxin, DHBT-1 (7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2 H -benzo[b][1,4]thiazine-3-carboxylic acid) and a cotoxin, BT-2 (7-(2-aminoethyl)- 2H -benzo[b][1,4]thiazin-5-ol). The cytotoxicity of these compounds was tested both individually and in the presence of the mitochondrial complex I inhibitors rotenone and Paraquat, both of which are implicated as causes of Parkinson’s disease. BT-2 potentiates the toxicities of these inhibitors. It also amplifies the toxicity of DHBT-1, reported to also be a complex I inhibitor. Although BT-2 is somewhat unstable, an analogue (2,2-dimethyl-BT-2) is much more stable than BT-2 itself and also enhances the toxicities of DHBT-1, rotenone and Paraquat. We suggest that DHBT-1 and BT-2 are normally detoxified by polymerization into neuromelanin but may accumulate under certain conditions and contribute, in concert with other stresses, to the selective death of dopaminergic neurons.