Targeting oxidative/nitrergic stress ameliorates motor impairment, and attenuates synaptic mitochondrial dysfunction and lipid peroxidation in two models of Huntington's disease.

In this study, we reproduced two toxic models resembling some motor/kinetic deficits of Huntington's disease induced by bilateral intrastriatal injections of either quinolinic acid (QUIN, 120 nmol/microl per side) or 3-nitropropionic acid (3-NP, 250 nmol/microl per side) to rats. Motor skills (including total distance walked/traveled and total horizontal and vertical activities) were evaluated in a box-field system at 1 and 7 days post-lesion. In order to investigate whether these alterations were associated with the oxidative/nitrergic stress evoked by the nitrogen reactive species peroxynitrite (ONOO(-)) in the striatum, some rats were pretreated with the ONOO(-) decomposition catalyst iron porphyrinate (Fe(TPPS), 10 mg/kg, i.p.) 120 min prior to toxins infusion. With the aim to further characterize some possible mechanisms by which motor tasks were affected and/or preserved, biochemical analysis of peroxidative damage to lipids and mitochondrial dysfunction were both assessed in synaptic membranes isolated from the striata of QUIN-, 3-NP- and/or Fe(TPPS)-treated animals. Our results show that targeting oxidative/nitrergic stress by Fe(TPPS) in these toxic models results in amelioration of motor deficits linked to inhibition of peroxidative damage and recovery of mitochondrial function in synaptic membranes. Based on these findings, we hypothesize that the protection exerted by Fe(TPPS) on the biochemical markers analyzed reflects the possible preservation of the functional status of the nerve tissue by limiting the deleterious actions of ONOO(-), further accounting for partial recovery of integrative motor functions.