A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro

1 The role of adenosine A(3) receptor activation during ischaemia-like conditions produced by oxygen and glucose deprivation (OGD) was evaluated with extracellular recordings from the CA1 region of rat hippocampal slices. In all, 7 min of OGD evoked tissue anoxic depolarisation ( AD, peak at similar to 7 min from OGD start, n = 20) and were invariably followed by irreversible loss of electrically evoked field epsps (fepsps, n = 42). 2 The selective adenosine A(3) antagonists 3-propyl-6-ethyl-5[(ethylthio) carbonyl]-2-phenyl-4-propyl-3- pyridinecarboxylate (MRS 1523, 1 - 100 nM, n = 31), N-[9-chloro-2-(2-furanyl)[ 1,2,4]- triazolo [1,5-c] quinazolin-5-yl] benzeneacetamide (MRS 1220, 100 nM, n = 7), N-(2-methoxyphenyl)-N'-[2( 3-pyrindinyl)-4-quinazolinyl]- urea, (VUF 5574, 100 nM, n = 3) and 5-[[(4-pyridyl) amino] carbonyl]amino- 8-methyl-2-(2-furyl)- pyrazolo[4,3-e] 1,2,4-triazolo[1,5-c] pyrimidine hydrochloride ( 1 nM, n = 4), prevented the irreversible failure of neurotransmission induced by 7 min OGD ( n 45) and the development of AD in 20 out of 22 monitored slices. 3 When tested on OGD episodes of longer duration ( 8 - 10 min, n 18), 100 nM MRS 1523 prevented or delayed the appearance of AD and exerted a protective effect on neurotransmission for episodes of up to 9 min duration. In the absence of AD, the fepsp recovery was almost total, regardless of OGD episode duration. 4 These findings support the notion that A(3) receptor stimulation is deleterious during ischaemia and suggest that selective A(3) receptor block may substantially increase the resistance of the CA1 hippocampal region to ischaemic damage.