Both Stereoselective (R)- and (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline Enantiomers Protect Striatal Terminals Against Rotenone-Induced Suppression of Dopamine Release

Lucyna Antkiewicz-Michaluk 0 1 Agnieszka Wasik 0 1 Irena Roman ska 0 1 Andrzej Bojarski 0 1 Jerzy Michaluk 0 1 0 A. Bojarski Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, 31-343 Krakow, Poland 1 L. Antkiewicz-Michaluk (&) A. Wasik I. Romanska J. Michaluk Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, 31-343 Krakow, Poland 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is present in the human and rodent brain as a mixture of stereospecific (R)- and (S)-1MeTIQ enantiomers. The racemate, (R,S)-1MeTIQ, exhibits neuroprotective activity as shown in the earlier study by the authors, and In addition, it was suggested to play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. In this article, we investigated the influence of stereospecific enantiomers of 1MeTIQ, (R)- and (S)-1MeTIQ (50 mg/kg i.p.) on rotenone-induced (3 mg/kg s.c.) behavioral and neurochemical changes in the rat. In behavioral study, in order to record dynamic motor function of rats, we measured locomotor activity using automated locomotor activity boxes. In biochemical studies, we analyzed in rat striatum the concentration of dopamine (DA) and its metabolites: intraneuronal DOPAC, extraneuronal 3-MT, and final HVA using HPLC with electrochemical detection. Otherwise, DA release was estimated by in vivo microdialysis study. The behavioral study has demonstrated that both acute and repeated (3 times) rotenone administration unimportantly depressed a basic locomotor activity in rat. (R)- and (S)-1MeTIQ stereoisomers (50 mg/kg i.p.) produced a modest behavioral activation both in nave and rotenone-treated rats. - The data from ex vivo neurochemical experiments have shown stereospecificity of 1MeTIQ enantiomers in respect of their effects on DA catabolism. (R)-1MeTIQ significantly increased both the level of the final DA metabolite, HVA (by about 70%), and the rate of DA metabolism (by 50%). In contrast to that, (S)-1MeTIQ significantly depressed DOPAC, HVA levels (by 60 and 40%, respectively), and attenuated the rate of DA metabolism (by about 60%). On the other hand, both the enantiomers increased the concentrations of DA and its extraneuronal metabolite, 3-MT in rat striatum. In vivo microdialysis study has shown that repeated but not acute administration of rotenone produced a deep and significant functional impairment of striatal DA release. Both (R)- and (S)- stereospecific enantiomers of 1MeTIQ antagonized rotenone-induced suppression of DA release; however, the effect of (R)-1MeTIQ was more strongly expressed in microdialysis study. In conclusion, we suggest that both chiral isomers of 1MeTIQ offer neuroprotection against rotenone-induced disturbances in the function of dopaminergic neurons and (R,S)-1MeTIQ will be useful as a drug with marked neuroprotective activity in the brain. Parkinsons disease (PD) is a neurological disorder, and the most of its cases are idiopathic in nature even though in the last few decades, many familial cases have been described as well, and in some of them the underlying genetic defect has been identified. Parkinsons disease is caused by mitochondrial complex I deficiency and neurodegeneration of dopaminergic neurons in the substantia nigra (Schapira et al. 1990). At present, it is believed that both genetic and environmental factors are responsible for Parkinsons disease. Its classical cardinal signs include rigidity and bradykinesia, resting tremor, and postural instability. The environmental neurotoxins may largely contribute to the development of this illness. One of the most famous toxins of dopaminergic neurons is 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) which after injection to humans and animals produces rapid, irreversible parkinsonism (Langston et al. 1983; Bankiewicz et al. 1986). MPTP, acting through its metabolite, 1-methyl-4phenylpyridinium ion (MPP?), induces degeneration of dopaminergic neurons, predominantly in the substantia nigra. It was believed that the main mechanism by which MPP? caused neuronal damage involved mitochondrial dysfunction produced by the inhibition of mitochondrial complex I activity that led to mitochondrial depolarization and generation of reactive oxygen species (Nakamura et al. 2000). However, Lotharius and OMalley (2000) indicated that the generation of reactive oxygen species during the oxidation of dopamine released by MPP? was the main consequence of MPP?-induced neurotoxicity. MPTP has frequently been used to provide an animal model of Parkinsons disease (Gerlach and Riederer 1996). More recently, it has been found that another, much more frequently encountered environmental toxin, rotenone may be used to produce a more realistic animal model of Parkinsons disease (Betarbet et al. 2000). Rotenone, a natural compound, is a classical lipophilic inhibitor of mitochondrial complex I (Gutman et al. 1970; Horgan et al. 1968), and is selectively toxic to dopaminergic neurons (Marey-Semper et al. 1993; Testa et al. 2005). Injected directly into brain structures, rotenone acts similarly to MPTP (Heikkila et al. 1985). Rotenone is the only neurotoxin known today that induces the formation of Lewy bodies, which are the most characteristic histopathological feature of Parkinsons disease (Betarbet et al. 2000). As in the case of MPTP, a defect of mitochondrial function due to complex I inhibition was postulated to be the cause of rotenone-induced neurodegeneration (Betarbet et al. 2000; Jenner 2001; Greenamyre et al. 2001). Rotenone used in a high concentration also causes dopamine release, as evidenced by microdialysis and neurochemical data (Santiago et al. 1995; Thiffault et al. 2000), and this may also contribute to the degeneration of dopaminergic neurons. Chronic administration of a low dose of rotenone in rats reproduces most of the motor, neurochemical, and pathological features of PD shown to be attenuated by L-DOPA (Alam and Schmidt 2002). In addition to the exogenous neurotoxins which have been widely used as convenient and acceptable models for the induction of experimental Parkinsons disease, endogenous amines present in the human and animal brain, such as salsolinol or 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) and to a lesser extent 1,2,3,4-tetrahydroisoquinoline (TIQ) (Lorenc-Koci et al. 2000, 2004) may participate in the pathogenesis of Parkinsons disease (Abe et al. 2005; Antkiewicz-Michaluk et al. 2000a, b; Antkiewicz-Michaluk and Vetulani 2001; Kotake et al. 1995, 1996; Nagatsu 1997; Niwa et al. 1987). However, among them TIQ, and its close methyl derivative, 1-methyl1,2,3,4-tetrahydroisoquinoline (1MeTIQ) was found to be a neuroprotective (Antkiewicz-Michaluk et al. 2006; LorencKoci et al. 2000, 2005; Kohno et al. 1986; Tasaki et al. 1991; Yamakawa and Ohta 1999; Yamakawa et al. 1999) and antiaddictive compound (Antkiewicz-Michaluk et al. 2 (...truncated)