Journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia ~ 1997 International Society for Neurochemistry Neuroprotective Effect of the Iron Chelator Desferrioxamine Against MPP + Toxicity on Striatal Dopaminergic Terminals M. Santiago, E. R. Matarredona, L. Granero, J. Cano, and A. Machado Departamento de BioquImica, Bromatologla y Toxicologla, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain Abstract: Microdialysis was used to evaluate the effect of desferrioxamine (DES) against 1 -methyl-4-phenylpyri- dinium (MPP~) toxicity. The presence of DES (40 fmol— 40 nmol/15 mm for a total of 90 mm) in the Ringer solu- tion, coperfused with MPP~ (40 nmol/15 mm) on day 1, produced on day 2a higher extracellular dopamine output after perfusion of MPP~ than in control MPP~ perfusion experiments, in which no DES was administered on day 1. Both Ringer perfusion alone (control Ringer) and co- perfusion of 40 nmol DES with 40 nmol MPP~ on day 1 produced on day 2 similar increases in extracellular dopamine output after a second MPP~ perfusion. In the control Ringer experiment, note that the MPP~ on day 2 is the first MPP~ perfusion. Perfusion of 800 fmol FeCI 3/ 15 mm along with 40 nmol MPP~ and 400 fmol DES on day 1 completely abolished on day 2 the neuroprotective effect found with 40 nmol MPP~ and 400 fmol DES; 800 fmol FeCl3 did not increase the neurotoxic effect of 40 nmol MPP~perfusion. The ability of DES to protect against MPP + toxicity may indicate a therapeutic strategy in the treatment of diseases when iron is implicated. Key Words: Microdialysis—Dopamine—1 -Methyl-4-phenyl- pyridinium—Iron chelator—Striatum—Rat. J. Neurochem. 68, 732—738 (1997). 1 - Methyl -4- phenyl - 1, 2, 3, 6- tetrahydropyridine (MPTP) is a remarkably selective neurotoxin; i.e., its systemic administration to experimental animals pro- duces extensive destruction of nigrostriatal dopaminer- gic neurons. Indeed, this compound is capable of pro- ducing a severe parkinsonian-like syndrome in human and nonhuman primates (Davis et al., 1979; Heikkila et al., 1984; Langston et al., 1984). The toxicity of this drug is produced by its conver- sion to MPP + by mitochondrial monoamine oxidase- B (MAO-B) (Chiba et al., 1984). Intracerebral admin- istration of 1-methyl-4-phenylpyridinium (MPP ~) was shown to be neurotoxic in rats (Heikkila et al., 1985), a species that is virtually insensitive to peripherally administered MPTP (Chiueh et al., 1984). Microdialy- sis has also been used to study the acute neurotoxic effects of MPP + on striatal dopaminergic (Rollema et al., 1986, 1988) and serotonergic (Miyake and Chiueh, 1989) neurons, as well as on neurons in the substantia nigra (Santiago et al., 1991a). Intranigral infusion with high MPP~concentrations can be used as a chronic animal model for severe and clinically manifest parkin- sonism (Santiago et al., 1991b). Several reports have indicated that free radicals can be generated in the presence of MPTP, MPP ~, or 1- methyl-4-phenyl-2,3-dihydropyridine (Sinha et al., 1986; Chacon et al., 1987; Akenaya et al., 1995; Am- brosio et al., 1996). The principal free radicals that can be produced by MPP + are superoxide and hydrogen peroxide. Under normal physiological conditions, su- peroxide does not oxidize all organic substances (Fee and Valentine, 1977). In a similar manner, hydrogen peroxide, although a strong oxidizing agent, interacts with organic substances only sluggishly, being rela- tively inert and nontoxic to the cell (Halliwell, 1992). The damage is produced when these free radicals react with transition metals, such as iron with the creation of even more reactive species such as hydroxyl radicals (Yu, 1994). Hydroxyl radicals react at great speed, with affinity for almost every molecule found in living cells, leading to a cascade of events with subsequent damage to the mitochondrial electron transport system, induction of proteases, increased membrane lipid per- oxidation, and finally cell death (Halliwell, 1992; You- dim et al., 1993). This suggests the importance of iron in the possible damage of MPP + through oxidative stress or the possible protective action of iron chelators. The present study investigates the effect of the iron chelator desferrioxamine (DES) on MPP + -induced dopaminergic toxicity by means of a striatal MPP + challenge perfusion, 24 h after another MPP + perfu Received May 13, 1996; revised manuscript received October 7, 1996; accepted October 7, 1996. Address correspondence and reprint requests to Dr. A. Machado, c/Prof. G. Gonzalez, s/n, at Departamento de Bioqulmica, Bromato- logIa y Toxicologla, Facultad de Farmacia, Universidad de Sevilla, 41012-Sevilla, Spain. Abbreviations used: DES, desferrioxamine; MAO, monoamine oxidase; MPP~,l-methyl-4-phenylpyridinium; MPTP, 1-methyl-4- phenyl-1 ,2,3,6-tetrahydropyridine. 732