Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats
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.
References (25)
- et al.
8-(3-Chlorostyryl) caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism
J Biol Chem
(2002) - et al.
Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats
Brain Res
(1993) - et al.
Biochemical and immunocytochemical changes induced by intrastriatal 6-hydroxydopamine injection in the rat nigrostriatal dopamine neuron system: evidence for cell death in the substantia nigra
Exp Neurol
(1994) - et al.
Protective effect of caffeine against neurodegeneration in a model of Parkinson's disease in rat: behavioral and histochemical evidence
Parkinsonism Relat Disord
(2004) Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorpting capacity and inhibition of LDL peroxidation
Clin Chim Acta
(2000)- et al.
Caffeine and muscarinic antagonists act in synergy to inhibit haloperidol-induced catalepsy
Neuropharmacology
(2003) Adenosine A2A antagonists: potential preventive and palliative treatment for Parkinson's disease
Exp Neurol
(2003)- et al.
KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse
Neuropharmacology
(2005) - et al.
Therapeutic potential of adenosine A2A receptor antagonists in Parkinson's disease
Pharmacol Ther
(2005) - et al.
Cross-sensitization between caffeine- and l-dopa-induced behaviors in hemiparkinsonian mice
Neurosci Lett
(2006)
The pesticide retonone induces caspase-3-mediated apoptosis in ventral mesencephalic dopaminergic neurons
J Neurochem
Effect of free radicals on adenosine A (2A) and dopamine D2 receptors in the striatum of young adult and aged rats
Neurochem Int
Cited by (61)
Targeting the adenosine A<inf>2A</inf> receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease
2023, Chinese Journal of Traumatology - English EditionA purine derivative, paraxanthine, promotes cysteine uptake for glutathione synthesis
2023, Journal of Pharmacological SciencesCaffeine prevents neurodegeneration and behavioral alterations in a mice model of agitated depression
2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryNeuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A<inf>2A</inf> receptors
2016, NeuroscienceCitation Excerpt :Moreover, caffeine’s metabolites, paraxanthine and theophylline, also provide protection against MPTP neurotoxicity (Xu et al., 2010). Other preclinical studies have shown that caffeine protects against dopaminergic neuron degeneration, dopamine loss and/or associated behavioral changes induced by 6-hydroxydopamine (6-OHDA) in rats (Joghataie et al., 2004; Aguiar et al., 2006; Kelsey et al., 2009) and by the pesticide combination of paraquat and manebin mice (Kachroo et al., 2007). Interestingly, the neuroprotective effect of caffeine could be dissociated from its psychomotor stimulant properties (Xu et al., 2002; Yu et al., 2008); whereas the latter showed tolerance to repeated administration, under the same conditions caffeine’s neuroprotective action persisted unabated (Xu et al., 2002).
Neuroprotective effects of caffeine in MPTP model of Parkinson's disease: A <sup>13</sup>C NMR study
2016, Neurochemistry InternationalCitation Excerpt :Neuroprotection by caffeine has been demonstrated in many studies involving neurotoxin models of PD. Caffeine has been shown to attenuate dopaminergic lesions induced by MPTP (Chen et al., 2008; Gevaerd et al., 2001; Singh et al., 2009), 6-hydroxydopamine (Aguiar et al., 2006; Joghataie et al., 2004), and the pesticide combination of Paraquat plus Maneb (Kachroo et al., 2010). Moreover, caffeine is believed to provide neuroprotection by acting as an antagonist of adenosine A2A receptor that reduces adenosine transmission and reverses motor deficits (Ho, 2002).
Therapeutic Viewpoint on Rat Models of Locomotion Abnormalities and Neurobiological Indicators in Parkinson's Disease
2024, CNS and Neurological Disorders - Drug Targets