Caffeine and CSC, Adenosine A2 Receptors Antagonists,Protect Dopaminergic Neurons Against

Caffeine and CSC, adenosine A2 receptors antagonists,protect dopaminergic neurons against the 6-OHDA-lesion in rat striatum

Lissiana M. Aguiar, F.C.F. Sousa, Silvania M. M. Vasconcelos, Geanne M. A. Cunha and Glauce S. B. Viana, Department of Physiology and Pharmacology, Federal University of Ceará

Parkinson’s disease (PD) is a neurodegenerative disorder involving the destruction of dopaminergic neurons in the substantia nigra, with subsequent loss of their terminals in the striatum. Current therapies partially alleviate symptoms of PD, but have not been found to avoid the progression of dopaminergic neurons degeneration. Adenosine A2A receptors are predominantly localized in DA-innervated regions such as striatum and nucleus accumbens. In the striatum, these receptors are expressed on GABAergic striatopallidal neurons and co-localized with D2 receptors (1). Neurochemical evidences showed that A2A receptors, functionally oppose the actions of dopamine D2 receptors on GABAergic striatopallidal neurons, and this action together with its unique CNS distribution raised the possibility that A2A antagonists can be used as an alternative therapy to treat PD (2).

Earlier studies reported that A2A receptor stimulation increases GABA release (3, 4), and its blockade decreases extracellular GABA levels (5, 6). Xu et al., 2005 (7) showed that A2A antagonists might facilitate movement by reducing GABA release from striatopallidal axon terminals. As a matter of fact, A2A receptor activation on glutamatergic nerve terminals, might enhance glutamate release and contribute to neuronal death (8, 9). Thus, A2A agonists generally enhance release of glutamate and, A2A receptors antagonists have been found to attenuate glutamate release in the striatum (10).

Caffeine has potential antiparkinsonian properties as demonstrated by its protective effects (11) and the blockade of striatal adenosine receptors. The CNS effectsof caffeine appear to be mediated primarily by its antagonistic actions at the A1 and A2A subtypes of adenosine receptor (12). CSC is a selective and potent A2A antagonist closely related to caffeine. Chen et al. (13)reported that CSC possesses dual actions, MAO B inhibition and A2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

In the present work, we studied in a comparative way the behavioral and neurochemical effects of caffeine and CSC [8-(-3-chlorostyryl)-caffeine]on 6-OHDA-lesioned rats. Animals were administered with caffeine (10 and 20 mg/kg, i.p.) or CSC (1 and 5 mg/kg, i.p.), 1 h after 6-OHDA, injected unilaterally into the striatum. Drugs administration continued for the next 6 days. Two weeks after, animals exhibit a characteristic rotation behavior in response to apomorphine. The number of net rotation/h was recorded and, at the next day, animals were sacrificed and striata used for HPLC measurements of monoamines and amino acids. The increase in body rotation induced by the 6-OHDA-lesion was significantly and dose-dependently decreased by caffeine and CSC.

The stereotaxic injection of 6-OHDA produced oxidative damage resulting in the loss of striatal neurons as indicated by the decrease in monoamines and their metabolites levels, in the ipsilateral side. This decreased striatal levels of NE, DA, DOPAC and 5-HT were significantly attenuated by caffeine and CSC. However, only CSC decreased 5-HIAA contents. Besides, the increased striatal levels of glutamate and GABA observed in 6-OHDA-lesioned rats were also reversed by CSC. In conclusion,we demonstrated that although both drugs were active in reducing behavior and neurochemical alterations in rats after striatal 6-OHDA-lesion, CSC seems to be more effective. Altogether, our data point out to the potential benefit of A2A receptors antagonists as a non-dopaminergic therapeutic target for the treatment of PD.

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