PROTECTION AGAINST HIPPOCAMPAL KAINATE EXCITOTOXICITY BY INTRACEREBRAL ADMINISTRATION OF AN ADENOSINE A(2A) RECEPTOR ANTAGONIST

We have previously shown that the peripheral administration of an A(2A ) receptor agonist thyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) protected the hippocampus against kainate-in duced 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 k ainate-induced excitotoxicity. Injections were made directly into the hippocampus of anaesthetised male Wistar rats. Following surgery and t he administration of 0.25 nmol kainate in 1 mu l of solution, the anim als were left to recover for seven days before perfusion and brain sli cing. Haematoxylin and eosin staining revealed substantial damage to t he CA3 region. Go-administration of the A(2A) receptor agonist CGS 216 80 over a range of doses did not protect the region to any degree. Sim ilarly neither the A(1) receptor agonist R-phenylisopropyladenosine (R -PIA), nor adenosine itself reduced kainate-induced damage. The intrah ippocampal injection of the selective A(2A) receptor antagonist, azolo {2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385) however, sign ificantly decreased kainate damage to the CA3 region. These results sh ow 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 wi th either R-PIA or adenosine may be due to an inhibitory action of the A(2A) receptor on the neuroprotective A(1) receptor. Importantly, thi s study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage. (C) 1998 Elsevier Science B.V. All rights reserved.