Environmental Research 94 (2004) 276–282 Protective role of aryl and alkyl diselenides on lipid peroxidation $ F.C. Meotti, E.C. Stangherlin, G. Zeni, C.W. Nogueira,  and J.B.T. Rocha Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, CEP 97105-900, Brazil Received 10 February 2003; received in revised form 14 May 2003; accepted 27 May 2003 Abstract The concept that selenium-containing molecules may be better nucleophiles (and therefore antioxidants) than classical antioxidants has led to the design of synthetic organoselenium compounds. In the present study we appraised the antioxidant potential, thiol peroxidase activity, and rate of dithiotreitol and reduced glutathione oxidation of simple organodiselenide compounds in rats and mice. The present results demonstrate that alkyl and aryl diselenides are antioxidant compounds. We verified that the substitution on the aromatic moiety of diphenyl diselenide or the replacement of on aryl group by an alkyl substitute on diselenides changes their antioxidant and thiol peroxidase-like properties. The diaryl diselenides (PhSe) 2 and (p-ClPhSe) 2 presented higher thiol peroxidase activity and demonstrated better antioxidant potential than the other diselenides tested. In fact, the results revealed that alkyl diselenides, at low concentrations, were prooxidants and that aryl diselenides did not present this effect. Alkyl diselenides [(C 2 H 5 Se) 2 and (C 3 H 7 Se) 2 ] demonstrated a higher potential for –SH group oxidation than aryl diselenides. In addition, this study demonstrated that diselenide protection against lipid peroxidation was different in mice and rats. The compounds tested acted more as antioxidants in the brains of mice than in the brains of rats. r 2003 Elsevier Inc. All rights reserved. Keywords: Diselenides; Antioxidant; Lipid peroxidation; Thiol peroxidase mimic 1. Introduction Partially reduced derivatives of oxygen, which are produced in aerobic organisms as part of normal physiological and metabolic processes, are toxic species, oxidizing numerous biomolecules, which leads to tissue injury and cell death. These reactive oxygen species are continuously formed in the human body and removed by enzymatic and nonenzymatic antioxidant defense systems under normal conditions (Yu, 1994). The balance between prooxidants and antioxidants is critical for survival and functioning of aerobic organ- isms. An imbalance favoring prooxidants and/or dis- favoring antioxidants, potentially leading to damage, has been called oxidative stress (Sies, 1986). Accumulat- ing evidence has linked the pathogenesis of a variety of human diseases to oxidative stress (Haddad, 2002). In the pathologic condition an overproduction or scaven- ger diminution of these reactive oxygen species can occur. There is increasing evidence that oxygen-free radicals contribute to cerebral ischemic injury by promoting membrane lipid peroxidation and oxidative damage to DNA and proteins (Siesjo et al., 1989; Taystman et al., 1991). In fact, the generation of reactive oxygen species has been implicated in cerebral tissues damage due to central nervous system trauma, ische- mia–reperfusion injury, seizures, cerebral hemorrhage, and Parkinson’s disease (Bankson et al., 1993; Lynch et al., 2000; Pazdernik et al., 1992). Thus, when the natural protective systems against reactive oxygen species are overrun, exogenous antiox- idative compounds must be delivered. Consequently, the search for new antioxidants as potential drugs is an active field of medicinal chemistry (Devillers et al., 2001). The concept that selenium-containing molecules may be better nucleophiles (and therefore antioxidants) than classical antioxidants has led to the design of synthetic organoselenium compounds (Arteel and Sies, 2001). Several reports have been published on glutathione peroxidase (GSH-px)-mimetic compounds, which, like the native enzyme, rely on the redox cycling of selenium. ARTICLE IN PRESS $ The animals were used according to the guidelines of the Committee on Care and Use of Experimental Animal Resources, School of Medicine, Veterinary, and Animal Science of the University of Sao Paulo, Brazil.  Corresponding author. Fax: +5555-220-8031. E-mail address: criswn@quimica.ufsm.br (C.W. Nogueira). 0013-9351/03/$-see front matter r 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0013-9351(03)00114-2