Mechanisms underlying striatal vulnerability to 3-nitropropionic acid

The striatum is a cerebral structure particularly susceptible to the metabolic challenge exerted by 3-nitropropionic acid (3-NPA), a toxin that inhibits the respiratory chain at complex II. The striatum, which receives the nerve endings of the nigro-striatal pathway, concentrates the largest amount of 3,4-dihydroxyphenylethylamine or dopamine (DA) in the brain. DA is metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO), an enzyme that contains a redox-active disulfide in the active site. In striatum isolated nerve endings exposed to 3-NPA in vitro, DA increased and DOPAC decreased already after 10 min, and after 2 h also an increase in reactive oxygen species and DA-quinone products formation was detected. These 3-NPA-induced effects resulted in an increase in DA release after 2 h. In striatum homogenates from animals presenting motor disturbances in response to 3-NPA in vivo, the DA metabolites homovanillic acid and DOPAC were increased. It is concluded that in the striatum nerve endings where DA is particularly concentrated, the increase in reactive oxygen species induced by 3-NPA, oxidizes DA generating DA-quinones. These DA-quinones may form adducts with the active site of MAO type A reducing its activity. The DA not metabolized to DOPAC is both, used to unchain generation of more of the harmful DA-oxidation products and released to the external medium, where is metabolized by the non-neuronal enzymes MAO type B and catechol-O-methyltransferase.