Mechanisms underlying striatal vulnerability to 3‐nitropropionic acid

Abstract

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.

Antioxidant properties of xanthones from Calophyllum brasiliense: prevention of oxidative damage induced by FeSO4

“…ROS were detected by DCF fluorescence [34,35]. Aliquots (500 μL) of the homogenates (brain, liver and kidney) were incubated in the absence (control) or presence of 5 μM FeSO 4 and/or xanthones III or V (0.5, 1 and 2.5 μM) at 37°C in a shaking-water bath for 2 h. The final volume for all probes was 1 mL.…”

Convergent mechanisms in etiologically-diverse dystonias

“…The extent of the damage is correlated with the severity of dystonia. It is thought that free radicals produced by 3-NPA react with DA to produce damaging quinone compounds [52], which may account for the selective lesioning of the basal ganglia. Peripheral administration of 3-NPA to rodents and non-human primates results in a motor disorder that is comparable to that seen in humans [51,53,54].…”

Biochemical and Behavioral Evidences for Neuromodulatory Properties of Selaginella prophyalxis Against 3-Nitropropionic Acid in Mice

“…Studies in laboratory animals, suggest that 3NP induces neuronal damage that mainly affects the striatum and mimics most of the histological and neurochemical features of HD [4,6] and hence this phenotypic model is gaining attention as a valuable tool to develop new therapies for HD [4] . The mechanism of 3NP induced neurotoxicity involves inhibition of succinate dehydrogenase (SDH), an enzyme that acts in mitochondrial tricarboxylic acid cycle and the electron transport chain at complex II [7] along with increased oxidative stress, as demonstrated by recent studies leaving scope for use of phytochemicals to reverse the neuronal damage.Although the treatment approaches are limited [1,2] , proposed treatment paradigms generally involve the use of natural antioxidants exhibiting their action by either or combination of speculated processes involving (i) suppression of oxidative/ nitrosative stress (ii) enhancement of mitochondrial function in brain regions and (iii) alleviation of motor deficits. Hence various potent phytochemicals are being explored for HD-therapy owing to their free radical scavenging ability and potency to alleviate oxidative insult in vivo [8] .…”