Metabolism of endogenous neurotoxins in neurodegenerative disease.

摘要

Oxidative stress can produce many damaging products that may contribute to neurodegenerative disease. The metabolism of these endogenous compounds is one way in which the brain may protect itself and one mechanism that may be altered in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). We have studied the metabolism of two endogenous neurotoxins, the oxidized form of the neurotransmitter dopamine (DA) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE), in brain in the context of PD and AD, respectively.; Oxidized DA can cause damage to neurons both through reduction-oxidation cycling and by conjugating to cellular components. Mercapturic acid pathway (MAP) metabolism of oxidized DA may result in more damaging products than the parent compound. We found that MAP metabolism of oxidized DA occurs in human brain but is not increased in a disease that is thought to represent preclinical PD, Dementia with Lewy bodies (DLB). One MAP product of oxidized DA, cysteinyl-DA, was shown to disrupt DA trafficking in two model systems, both in vitro synaptosomes and in vivo microdialysis. As others have shown that cysteinyl-DA is increased in late stage PD patients who have been treated with L-3,4-dihydroxyphenylalanine (L-DOPA) therapy, this compound may contribute to the disease process in these instances. Human brain has a reduced capacity to produce the less active mercapturyl-DA compared with rat brain.; HNE metabolism results in a less reactive and therefore less damaging product. HNE metabolism occurs in rat and human brain at a slower rate than rat liver. MAP metabolism of HNE occurred to a greater extent than oxidation of HNE, and reduction of HNE was not detectable. The synaptic compartment metabolized HNE less efficiently and therefore may be more vulnerable to the toxic effects of HNE.; In conclusion, we have found that the enzymes capable of metabolizing endogenous neurotoxins are not distributed homogenously in brain. We have also found that while MAP metabolism of HNE is a detoxifying event, MAP metabolism of DA produces at least one potentially neurotoxic compound.