Protective effect of captopril and enaraprilat, angiotensin-converting enzyme inhibitors, on para-nonylphenol-induced OH generation and dopamine efflux in rat striatum
Introduction
The etiology of Parkinson's disease is not fully understood, although 1-methyl-4-phenylpyridinium ion (MPP+), a major metabolite of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to induce a parkinsonian syndrome (Chiueh et al., 1993, Chiba et al., 1984, Markey and Schmuff, 1986). The cytotoxic hydroxyl radical (OH) is involved in dopamine (DA) neurotoxicity caused by MPTP (Chiueh et al., 1993, Hirsch et al., 1988, Youdim et al., 1989).
Angiotensin-converting enzyme (ACE) (E.C. 3.4.15.1), also known as kininase II, is widely distributed in the brain (Poth et al., 1975), and a high level of activity exists in the basal ganglia, including substantia nigra, globus pallidus, and caudate putamen (Chai et al., 1987). In the basal ganglia angiotensin-converting enzyme is associated with neurons in the striatum. Cerebrospinal fluid levels of ACE were affected in Alzheimer's and Parkinson's diseases, so ACE level is suggested to be an index of neuronal dysfunction (Konings et al., 1994, Zubenko et al., 1985). Angiotensin II stimulates striatal dopamine release via the AT1 receptor (Brown et al., 1996, Jenkins et al., 1996). We reported that ACE inhibitors suppress OH formation via suppressing DA efflux in the MPP+-treated rats (Obata, 1999). Jenkins et al. reported that chronic treatment with ACE inhibitor perindopril increases striatal DA levels in MPTP-treated mouse (Jenkins et al., 1999). The activity of ACE inhibitor is considered to be due to the presence of an SH group in its structure (Bagchi et al., 1989), but non-SH-containing angiotensin-converting enzyme inhibitors are also shown to protect cells against free radical-induced lipid peroxidation and injury (Fernandes et al., 1996, Mak et al., 1990).
We recently reported that para-nonylphenol (nonylphenol) stimulates hydroxyl radical (OH) generation in the rat striatum (Obata and Kubota, 2000). However, whether nonylphenol enhances MPP+-induced OH generation and DA efflux, and whether angiotensin-converting enzyme inhibitors suppressed OH generation, and DA efflux induced by nonylphenol and MPP+ remains to be elucidated.
Section snippets
Animals
Adult male Wistar rats (300–400 g) were housed in an environmentally controlled room with food and water available ad libitum. The animals were anesthetized with chloral hydrate (400 mg/kg i.p.; Sigma Chemical, St. Louis, MO, USA) and prepared for intracranial microdialysis brain perfusion. This study was approved by the Ethics Committee for Animal Experiments, Oita Medical University.
Experimental protocol
MPP+ was purchased from Research Biochemicals Inc., MA, USA. Ferrous ammonium sulfate, sodium salicylate and its
Results and discussion
Time-dependent changes in the level of the DA efflux and the formation of 2,3-DHBA were monitored in the dialysates from the rat brain after MPP+ treatment or MPP+ and para-nonylphenol treatment. Fig. 1 shows the effects of nonylphenol (10 μM) on DA efflux and the formation of OH trapped as DHBA induced by 5 mM MPP+. Nonylphenol (10 μM) enhanced DA efflux and the DHBA formation induced by MPP+ (Fig. 1). The dose-response effect of nonylphenol (1, 5, 10 and 50 μM) on DA efflux was also examined.
Acknowledgements
This study was supported by Health Science Research Grants for Research on Environmental Health from the Ministry of Health and Welfare of Japan, and a grant under the Ministry of Education, Science, Sports, and Culture, Japan.
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