Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats

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Abstract

The work shows the effects of caffeine after the intrastriatal injection of 6-OHDA in rats, considered as a model of Parkinson disease (PD). Two weeks after the 6-OHDA lesion, rats exhibit a characteristic rotation behavior as a response to the apomorphine challenge. Our results showed significant increases in the number of apomorphine-induced rotations in 6-OHDA-lesioned rats, as compared to sham-operated animals. A partial recovery was observed in 6-OHDA-lesioned rats, after caffeine (10 and 20 mg/kg, i.p., daily for 14 days) treatment. The stereotaxic injection of 6-OHDA produced loss of striatal neurons, as indicated by the decrease in monoamines levels, in the ipsilateral side (75–85%) when compared to the contralateral side. Significant decreases in noradrenaline levels were seen in the ipsilateral side of 6-OHDA group (62%), and this effect was not significantly reversed in caffeine-treated groups. While significant decreases in dopamine levels were seen in the ipsilateral side of 6-OHDA group (78%), in the caffeine-treated group (10 and 20 mg/kg, i.p.) the decreases were only 53 and 18%, indicating significant recoveries. In conclusion, our data demonstrated beneficial effects of caffeine in this model of PD, suggesting the potential use of A2A antagonists as a novel treatment for this neurodegenerative disease.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, with severe dopamine depletion in the striatum. Current therapies with antiparkinsonian agents partially alleviate the symptoms of the disease, but have not been found to avoid the progression of dopaminergic neurons degeneration. Another major limitation of PD medications is their sometimes disabling side effects. The most irreversible adverse effect of the chronic dopaminergic therapy is dyskinesia. This side effect limits symptomatic therapy, thus increasing the search for new nondopaminergic alternative or adjunctive treatments for PD.

Adenosine, an endogenous modulator of biological functions, interacts with at least four receptors classified as A1, A2A, A2B and A3. Several data showing the co-localization of A2A and D2 receptors suggest that the blockade of A2A receptors produces direct effects on D2 receptors (Fredholm and Svenningsson, 2003). Evidence that adenosine A2A antagonists could constitute a potential therapeutic tool for the therapy of PD, is provided by results obtained in rodent and primate models of PD, which report that A2A antagonists exert antiparkinsonian activity (Morelli, 2003). Adenosine A2A receptors are abundant in the caudate-putamen, and involved in the motor control in several species.

Caffeine is an alkaloid widely consumed for its CNS stimulating properties (Moo-Puc et al., 2003). Several studies revealed an inverse association between risk of PD and caffeine intake (Ross et al., 2000, Ross and Petrovitch, 2001, Schwarzschild et al., 2002, Baraldi et al., 2003). Experimental evidence also suggests that caffeine has potential antiparkinsonian properties, as demonstrated by its protective effects (Joghataie et al., 2004) and the blockade of striatal adenosine receptors. The CNS effects of caffeine appear to be mediated primarily by its antagonistic actions at the A1 and A2A subtypes of adenosine receptors (Fredholm et al., 1999). A2A receptors are particularly relevant to PD because their expression in the brain is largely restricted to the striatum (Fisone et al., 2004), the main target of dopaminergic neurons that degenerate in PD. The presence of A2A receptors was also reported in the human brain (caudate nucleus and putamen) by Ishiwata and collaborators (Ishiwata et al., 2005).

The unilateral 6-hydroxydopamine nigrostriatal lesion has been widely used as a rodent model of Parkinson's disease. It has been reported that reactive oxygen radicals are involved in the toxicity of 6-OHDA-induced nigrostriatal lesions. Increased free radicals levels occur on aging and are proposed to be a contributing factor for Parkinson's disease (Alfavaro et al., 2004). Methylxanthines, including caffeine and their metabolites, have proven to inhibit oxidative damage induced by these reactive species (Lee, 2000). Joghataie et al. (2004) reported that 6-OHDA-induced loss of nigral neurons and associated alterations in behavioral responses to dopaminergic stimulation can be attenuated by caffeine. Together, the protective effects of caffeine and its metabolites in rodent models of PD support a causal basis for the inverse relationship between human caffeine consumption and the subsequent risk of PD development (Xu et al., 2005). The present study was designed to investigate the beneficial effect of caffeine in a model of PD, using unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats.

Section snippets

Drugs

Caffeine, 6-hydroxydopamine, ascorbic acid, apomorphine, sodium octanesulfonic acid, acetonitrile and tetrahydrofuran were purchased from Sigma Chemical Co. USA. All other drugs were of analytical grade.

Animals and experimental procedures

Adult male Wistar rats (from the Animal House of the Federal University of Ceará), weighing 200–250 g at the start of the experiment, were housed five to six per cage, maintained in a 12 h light/dark cycle with free access to water and standard food. All experiments were performed according to

Results

Two weeks after the intrastriatal injection of 6-OHDA, rats exhibited rotational behavior in the direction opposite to the lesion (contralateral rotation), following the apomorphine administration. Significant increases in the number of apomorphine-induced rotations were seen in 6-OHDA-lesioned controls, as compared to the sham-operated group (178.7 ± 7.8 vs. 7.0 ± 0.5 turns/h; F (3, 34) = 172.8; p < 0.001). A partial motor recovery was observed in 6-OHDA-lesioned rats treated with caffeine, that

Discussion

Adenosine A2A receptor antagonists, including the non-specific adenosine antagonist caffeine, are a novel non-dopaminergic therapeutic strategy for PD treatment (Yu et al., 2006). For instance, istradefylline is the first of several A2A receptor antagonists in development for PD and is now under clinical trials. Results indicate that the drug reduces motor fluctuation induced by l-Dopa.

Epidemiological studies have linked the consumption of coffee and other caffeinated beverages to a reduced

Acknowledgements

The work had financial support from the Brazilian National Research Council (CNPq) and was orthographically revised by Prof. M.O.L. Viana.

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