Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A 2A receptor antagonist

Abstract

We have previously shown that the peripheral administration of an A 2A 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 A 1 and A 2A 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 μl 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 A 2A receptor agonist CGS 21680 over a range of doses did not protect the region to any degree. Similarly neither the A 1 receptor agonist R-phenylisopropyladenosine (R-PIA), nor adenosine itself reduced kainate-induced damage. The intrahippocampal injection of the selective A 2A 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 A 2A receptor-induced protection is most likely to be mediated peripherally and is probably not due to activation of A 2A receptors within the hippocampus. The lack of protection observed with either R-PIA or adenosine may be due to an inhibitory action of the A 2A receptor on the neuroprotective A 1 receptor. Importantly, this study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage.