Unexpected neuroprotection observed with the adenosine A(2A) receptor agonist CGS 21680

The selective adenosine A(2A) receptor agonists 2-[p-(2-carboxethyl)phenylethylamino]-5'-N-ethylcarboxyamidoadenosine (CGS 21680), N-[2-(3,5-dimethoxyphenyl)ethyl]adenosine (DPMA) and metrifudil were investigated for their ability to prevent the loss of pyramidal CA1 neurons in the hippocampus following 5 min of severe temporary forebrain ischemia in mongolian gerbils. CGS 21680, when administered at 18.7 mu mol/kg 30 and 120 min following reperfusion, exhibited highly significant protection against neuronal loss, but was inactive at 5.6 mu mol/kg. DPMA, a more potent agonist at A(1) and A(2A) receptors, was inactive up to a dose of 19 mu mol/kg. Metrifudil (equipotent with CGS 21680 at A(2A) > 25 times more potent at A(1)) gave a modest degree of protection at 26 mu mol/kg and was inactive at 7.8 mu mol/kg. CCS 21680 showed an equal degree of hypothermia at 5.6 and 18.7 mu mol/kg, suggesting that this was not the prime mode of action. While the effect of metrifudil may be the result of its higher A(1) receptor affinity, the mode of action of CCS 21680 has not been established; the data, however, suggest that a non-A(1) non-A(2A) receptor mechanism may possibly be involved. (C) 1997 Wiley-Liss, Inc.