Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist.

We have previously shown that the peripheral administration of an A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) protected the hippocampus against kainate-induced excitotoxicity. The present study utilises the intrahippocampal route to further investigate CGS 21680-mediated protection as well as examining the role of adenosine and both A1 and A2A receptors in kainate-induced excitotoxicity. Injections were made directly into the hippocampus of anaesthetised male Wistar rats. Following surgery and the administration of 0.25 nmol kainate in 1 microl of solution, the animals were left to recover for seven days before perfusion and brain slicing. Haematoxylin and eosin staining revealed substantial damage to the CA3 region. Co-administration of the A2A receptor agonist CGS 21680 over a range of doses did not protect the region to any degree. Similarly neither the A1 receptor agonist R-phenylisopropyladenosine (R-PIA), nor adenosine itself reduced kainate-induced damage. The intrahippocampal injection of the selective A2A receptor antagonist, 4-(2-[7-amino-2-¿2-furyl¿¿1,2, 4¿triazolo¿2,3-a¿¿1,3,5¿triazin-5-yl-amino]ethyl)phenol (ZM241385) however, significantly decreased kainate damage to the CA3 region. These results show that adenosine A2A receptor-induced protection is most likely to be mediated peripherally and is probably not due to activation of A2A receptors within the hippocampus. The lack of protection observed with either R-PIA or adenosine may be due to an inhibitory action of the A2A receptor on the neuroprotective A1 receptor. Importantly, this study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage.