Journal of Biochemical Toxicology  1997 John Wiley & Sons, Inc. 0887-2082/97/040197-05 197 J BIOCHEM TOXICOLOGY Volume 11, Number 4, 1996 Chronic Fenfluramine Treatment of Rats with Different Ages: Effects on Brain Oxidative Stress-Related Parameters V. D’Almeida, R. Camarini,* L. A. Azzalis, V. B. C. Junqueira, and E. A. Carlini* Departamento de Bioquı ´mica, Instituto de Quı ´mica, Universidade de Sa ˜o Paulo, Brasil. *Departamento de Psicobiologia, Universidade Federal de Sa ˜o Paulo—Escola Paulista de Medicina, Brasil ABSTRACT: Fenfluramine is an anorectic drug widely used for the regulation of food intake that presents some adverse effects at the central and peripheral lev- els. d-Fenfluramine, an isomer of dl-fenfluramine, is postulated to be more effective and to induce less side effects than the racemic compound. These drugs act preferentially on the serotonergic system. Some au- thors have suggested that fenfluramine causes a de- generation of serotonergic neurons. Alterations of the serotonergic system are also observed during the aging process, and in this case, a relationship with reactive oxygen species has been already established. In view of these data, the present study was conducted to in- vestigate the relationship between fenfluramine and brain antioxidant defense system in mature and aged animals. Rats aged 4 and 17 months were chronically treated with dl-fenfluramine, d-fenfluramine, or saline. Brain activity of superoxide dismutase and glutathione peroxidase was significantly affected by aging. Cata- lase activity was altered by the treatment. Total gluta- thione content and chemiluminescence in the brains were also altered by aging. Glutathione levels were altered as a function of the interaction between age and treatment. These findings suggest that treatment with d- or dl-fenfluramine results in alteration of the anti- oxidant system that could be exacerbated when asso- ciated with the aging process.  1997 John Wiley & Sons, Inc. KEYWORDS: Fenfluramine, Anorectic Drugs, Antioxi- dant Defense, Oxidative Stress, Reactive Oxygen Spe- cies, Aging. INTRODUCTION Fenfluramine (N-ethyl--methyl-3-trifluorometh- yl-b-phenylethylamine), an amphetamine deriva- Received May 24, 1996. Address correspondence to Virgı ´nia Berlanga Campos Jun- queira, Ph.D., Departamento de Bioquı ´mica, Instituto de Quı ´mica, Universidade de Sa ˜ o Paulo, Av. Lineu Prestes, 748 Bloco 12-Inferior, Sa ˜o Paulo, SP-05599, Brazil. Tel.: (55-11) 815-3286; Fax: (55-11) 815- 5579. tive, has been widely used as a short-term auxiliary for the management of obesity (1). Fenfluramine and am- phetamine exert different actions on central biogenic amines. Neither drug alters dopamine (DA) concentra- tion in rat striatum; however, both of them increase striatal levels of homovanillic acid levels with opposite stereoisomeric specificity and by different mechanisms (2). Fenfluramine blocks DA receptors, whereas am- phetamine acts indirectly stimulating the release of DA from dopaminergic terminals (2). The anorectic effects of fenfluramine occur by a dif- ferent mechanism from that of amphetamine. An intact serotonergic system appears to be necessary for fen- fluramine to induce anorexia, whereas catecholami- nergic pathways appear to be involved in ampheta- mine anorexia (2). Fenfluramine has been demonstrated to release se- rotonin from nerve endings and to its inhibit reuptake into these neurons (3–5). However, its neurochemical effects vary according to whether the parent drug or the main metabolite, norfenfluramine, is given and also depend upon the administration of the d- or l- isomer (4,6,7). Some adverse effects associated to the use of fen- fluramine include dizziness, drowsiness, diarrhea, nausea, dry mouth, among others (8,9). It has also been suggested that fenfluramine causes degeneration of se- rotonergic neurons (6,7). The isomer dl-fenfluramine, which acts on the do- paminergic and serotonergic systems, appears to result in more side effects than d-fenfluramine, which has only a serotonergic action (10,11). Thus, d-fenfluramine appears to be more efficient in its anorectic action and less harmful than the other forms of the drug (10,12). The serotonergic system can be affected by both fenfluramine and the aging process, since a decrease of 5-HT binding sites was demonstrated in aged brains (13). In addition, reactive oxygen species are involved in the aging process, as well as in the toxicity of some drugs (14–17).