NAD(P)H oxidase contributes to neurotoxicity in an excitotoxic/prooxidant model of Huntington's disease in rats: Protective role of apocynin

Abstract

Intrastriatal injection of quinolinic acid (QUIN) to rodents reproduces some biochemical, morphological, and behavioral characteristics of Huntington's disease. NAD(P)H oxidase is an enzymatic complex that catalyzes superoxide anion (O(2).(-)) production from O(2) and NADPH. The present study evaluated the role of NAD(P)H oxidase in the striatal damage induced by QUIN (240 nmol/microl) in adult male Wistar rats by means of apocynin (APO; 5 mg/kg i.p.), a specific NAD(P)H oxidase inhibitor. Rats were given APO 30 min before and 1 hr after QUIN injection or only 30 min after QUIN injection. NAD(P)H oxidase activity was measured in striatal homogenates by O2(*)(-) production. QUIN infusion to rats significantly increased striatal NAD(P)H oxidase activity (2 hr postlesion), whereas APO treatments decreased the QUIN-induced enzyme activity (2 hr postlesion), lipid peroxidation (3 hr postlesion), circling behavior (6 days postlesion), and histological damage (7 days postlesion). The addition of NADH to striatal homogenates increased NAD(P)H oxidase activity in striata from QUIN-treated animals but not from sham rats. Interestingly, O2(*)(-) production in QUIN-lesioned striata was unaffected by the addition of substrates for intramitochondrial O2(*)(-) production, xanthine oxidase and nitric oxide synthase, suggesting that NAD(P)H oxidase may be the main source of O2(*)(-) in QUIN-treated rats. Moreover, the administration of MK-801 to rats as a pretreatment resulted in a complete prevention of the QUIN-induced NAD(P)H activation, suggesting that this toxic event is completely dependent on N-methyl-D-aspartate receptor overactivation. Our results also suggest that NAD(P)H oxidase is involved in the pathogenic events linked to excitotoxic/prooxidant conditions.

RETRACTED: Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity

“…Motor alterations, assessed as rotation behavior, were evaluated in animals from all experimental groups, according to previous reports [20,32]. Six days after QUIN infusion, animals were administered with apomorphine (1 mg/kg, s.c.) and separated into individual acrylic box cages.…”

“…Brain tissues were collected and histologically processed according to previous descriptions [20,32]. Seven days after intrastriatally lesioned, animals from all groups were anesthetized i.p.…”

New Insights onNOXEnzymes in the Central Nervous System

“…However, increased oxidative stress is a known feature of this disease (160). Previous studies have shown increased oxidation, which was attributed to NADPH oxidase in a model of intrastriatal quinolic acid injection (115) and in vitro using the PC12 cell line overexpressing expanded polyQ proteins (17). It was not until very recently that the role of NOX2 was studied in a mouse model of HD consisting of a knock-in introducing 140 glutamine residues in the N-terminal part of endogenous Huntingtin (HD 140Q/140Q mice).…”

Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model

“…Recently, we and others have linked enhanced production of reactive oxygen species (ROS) by transmembrane NADPH oxidase (NOX) enzymes to the oxidative stress and toxicity in polyQ disease [9][10][11][12]. Under normal physiological conditions NOX enzymes generate low, local levels of superoxide, thereby regulating a number of redox-sensitive intracellular signaling molecules like phosphatases, transcription factors and ion channels [8].…”