Elsevier

Toxicology

Volume 250, Issues 2–3, 4 September 2008, Pages 96-99
Toxicology

Protective effect of captopril and enaraprilat, angiotensin-converting enzyme inhibitors, on para-nonylphenol-induced radical dotOH generation and dopamine efflux in rat striatum

https://doi.org/10.1016/j.tox.2008.06.005Get rights and content

Abstract

We recently reported that para-nonylphenol, an environmental chemical, induced hydroxyl radical (radical dotOH) formation in rat striatum. In this study we examined the antioxidant effects of angiotensin-converting enzyme inhibitors (captopril or enalaprilat) on para-nonylphenol (nonylphenol) and 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (radical dotOH) formation and dopamine (DA) efflux in extracellular fluid of rat striatum, using a microdialysis technique. para-Nonylphenol clearly enhanced radical dotOH formation and DA efflux induced by MPP+. When captopril or enalaprilat was infused in nonylphenol and MPP+-treated rats, DA efflux and radical dotOH formation significantly decreased, as compared with that in the nonylphenol and MPP+-treated control. We compared the ability of non-SH-containing enalaprilat with a SH-containing captopril to scavenge radical dotOH and DA efflux. Both inhibitors were able to scavenge radical dotOH and DA efflux induced by para-nonylphenol and MPP+. The results suggest that angiotensin-converting enzyme inhibitors may protect against nonylphenol and MPP+-induced radical dotOH formation via suppressing DA efflux in the 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 (radical dotOH) 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 radical dotOH 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 (radical dotOH) generation in the rat striatum (Obata and Kubota, 2000). However, whether nonylphenol enhances MPP+-induced radical dotOH generation and DA efflux, and whether angiotensin-converting enzyme inhibitors suppressed radical dotOH 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 radical dotOH 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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