Ebselen blocks the quinolinic acid-induced production of thiobarbituric acid reactive species but does not prevent the behavioral alterations produced by intra-striatal quinolinic acid administration in the rat Janine I. Rossato, Gilson Zeni, Carlos F. Mello, Maribel A. Rubin, Joa ˜ o B.T. Rocha * DepartamentodeQuı ´mica,CentrodeCie ˆnciasNaturaiseExatas,UniversidadeFederaldeSantaMaria,97105-900,SantaMaria,RS,Brazil Received 2 October 2001; received in revised form 15 November 2001; accepted 17 November 2001 Abstract Ebselen (EBS) is a seleno-organic compound with glutathione peroxidase-like activity which is neuroprotective in acute stroke ischemia. In this study, we investigated the effect of EBS on quinolinic acid (QA)-induced neurotoxicity. EBS inhibited QA-induced production of thiobarbituric acid reactive species (TBARS) by striatal homogenates in vitro with an IC 50 of 1.85 mM. Intra-striatal injection of QA (360 nmol) increased striatal content of TBARS and induced convulsions and contralateral rotational behavior. Intra-striatal pre-injection of EBS (10 nmol) 15 min before QA abolished QA-induced TBARS production but did not alter QA-induced behavioral effects. The present findings suggest that EBS acts on post- receptor events, neutralizing free radicals produced by overstimulation of N-methyl-d-aspartate receptors. q 2002 Published by Elsevier Science Ireland Ltd. Keywords: Ebselen; Lipid peroxidation; Quinolinic acid; Antioxidant; Seizures Quinolinic acid (QA) is a neuroactive metabolite of tryp- tophan which has been implicated in the pathogenesis of a variety of degenerative, infectious, and inflammatory human neurological diseases [2,16,17]. Accordingly, injec- tion of QA into the rat striatum produces striatal lesions similar to those observed in Huntington’s disease [1,2,5,15] The mechanism underlying QA-induced neurotoxicity seems to involve overactivation of the N-methyl-d-aspartate (NMDA) receptor subtype, which in turn produces excito- toxicity [14,19]. In fact, it has been proposed that oversti- mulation of excitatory amino acid receptors is involved in the pathophysiology of acute brain injury and chronic neurodegenerative diseases [2,12]. Moreover, intra-striatal microinjection of QA increases lipid peroxidation which is completely prevented by pre-treatment with the NMDA receptor antagonist, MK-801 [13,14], supporting the notion that QA-induced lipid peroxidation is mediated by a sustained activation of NMDA receptors. Taking into account that lipid peroxidation is initiated by the attack of free radicals against unsaturated membrane lipids, it is reasonable to assume that QA toxicity is mediated by reac- tive species formed after activation of NMDA receptors [13,14]. Accordingly, melatonin, a natural occurring anti- oxidant, protects against QA-induced lipid peroxidation in rat brain [2]. Recently, it has been demonstrated that ebselen (EBS), a lipid-soluble seleno-organic compound which possesses glutathione peroxidase-like activity [3,10], has a protective role against brain ischemia and stroke [4,18,20]. Of parti- cular importance, glutamate neurotoxicity in primary cultures of cerebellar neurons, which is believed to be mediated by NMDA receptor activation [9,19], is signifi- cantly reduced by EBS [12]. In fact, EBS reverses dithio- threitol potentiation of NMDA-mediated currents in cultured neurons by acting at the redox-sensitive NMDA receptor site, but does not directly antagonize NMDA recep- tor-mediated responses [7]. However, it is not known whether EBS can block NMDA receptor-mediated responses in vitro and in vivo. Therefore, in the present study, we investigated the effect of EBS on QA-induced behavioral changes and lipid perox- idation in rat brain. Moreover, the effect of EBS on QA- induced lipoperoxidation in vitro was also investigated. For in vitro studies, rats were decapitated under mild Neuroscience Letters 318 (2002) 137–140 0304-3940/02/$ - see front matter q 2002 Published by Elsevier Science Ireland Ltd. PII: S0304-3940(01)02504-6 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 121-55-2208140; fax: 121-55- 2208031. E-mail address: jbtrocha@yahoo.com.br (J.B.T. Rocha).