J. Pineal Res. 2000; 29:40–47 Protective effect of melatonin against the 1-methyl-4-phenylpyridinium-induced inhibition of Complex I of the mitochondrial respiratory chain Absi E, Ayala A, Machado A, Parrado J. Protective effect of mela- tonin against the 1-methyl-4-phenylpyridinium-induced inhibition of Complex I of the mitochondrial respiratory chain. J. Pineal Res. 2000; 29:40 – 47. © Munksgaard, Copenhagen Abstract: In the present study, a novel property of melatonin is shown: a protective effect of melatonin on the respiratory chain in isolated rat liver mitochondria and in striatal synaptosomes treated with 1-methyl-4-phenylpyridinium ion (MPP + ). The cellular damage caused by MPP + , a compound that produces a Parkinsonian-like syndrome in humans, is the result of the mitochondrial respiration inhibition at the Complex I level and oxidative stress induction. Treatment of mitochondria with MPP + inhibits the respiration rate. This effect was prevented by the inclusion of melatonin in the incubation mixture. This preventive effect, which is not related to the antioxidative properties of melatonin, seems to be due to the fact that melatonin prevents MPP + interaction with Complex I. These results suggest that melatonin may protect against the effect of several Parkinsonogenic compounds that are associated with progressive impairment of mitochondrial function and increased oxidative damage. Elhadi Absi, Antonio Ayala, Alberto Machado and Juan Parrado Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain Key words: Complex I – melatonin – mitochondria – MPP + – oxidative stress – parkinson disease Address reprint requests to Dr Juan Parrado, Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Univer- sidad de Sevilla, C/.Prof. Garcia Gonzalez, s/n, 41012-Sevilla, Spain. E-mail: parrado@cica.es Received July 1, 1999; accepted September 15, 1999. Introduction Melatonin, a secretory product of the pineal gland, participates in many important physiologi- cal functions [Reiter, 1991; Pierpaoli and Regel- son, 1994]. Its absorption and bioavailability [Reiter, 1991; Menendez-Pelaez and Reiter, 1993; Menendez-Pelaez et al., 1993; Shida et al., 1994] make this pineal product one of the most potent and versatile cellular antioxidants [Poeggeler et al., 1994]. Melatonin has also been described as hav- ing an important role in the protection of DNA and cell membranes from oxidative stress [Tan et al., 1993b; Melchiorri et al., 1995], these effects being a consequence of its ability to scavenge hydroxyl [Tan et al., 1993a] and peroxyl radicals [Pieri et al., 1994]. In addition, melatonin has been shown to exert a protective action against the toxic effect of the neurotoxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) [Acun ˜a- Castroviejo et al., 1997; Iacovitti et al., 1997; Jin et al., 1998]. The administration of MPTP produces exten- sive destruction of nigrostriatal dopaminergic neu- rons. Indeed, this compound is able to produce a severe Parkinsonian-like syndrome in humans and in non-human primates [Burns et al., 1983; Langston et al., 1983]. The toxicity of this drug is due to its conversion into 1-methyl-4-phenylpyri- dinium ion (MPP + ) by the mitochondrial monoamine oxidase B enzyme. MPP + then accu- mulates inside the mitochondria, where it binds to Complex I [Javitch et al., 1985; Ramsay et al., 1986; Nicklas et al., 1987; Davey et al., 1992], causing an inhibition of NAD-linked mitochon- drial respiration [Nicklas et al., 1985; Ramsay et al., 1986]. The cellular damage caused by MPP + is due primarily to energy depletion caused by the specific binding to Complex I, a secondary effect being the damage caused by free radical produc- tion [Hasegawa et al., 1990; Fahn and Cohen, 1992; Tipton and Singer, 1993; Bates et al., 1994]. Due to the implications of oxidative stress in Parkinson disease, melatonin has been studied as a protective substance. It rescues dopamine neurons from cell death in tissue culture treated with MPP + [Iacovitti et al., 1997]. It also produces in vivo neuroprotective effects in rats with a unilat- 40 Printed in Ireland —all rights resered.