A 3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro

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 ∼7 min from OGD start, n =20) and were invariably followed by irreversible loss of electrically evoked field epsps (fepsps, n =42). The selective adenosine A 3 antagonists 3‐propyl‐6‐ethyl‐5[(ethylthio)carbonyl]‐2‐phenyl‐4‐propyl‐3‐pyridinecarboxylate (MRS 1523, 1–100 n M , n =31), N ‐[9‐chloro‐2‐(2‐furanyl)[1,2,4]‐triazolo[1,5‐c]quinazolin‐5‐yl]benzeneacetamide (MRS 1220, 100 n M , n =7), N ‐(2‐methoxyphenyl)‐ N ′‐[2‐(3‐pyrindinyl)‐4‐quinazolinyl]‐urea, (VUF 5574, 100 n M , 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 n M , 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. When tested on OGD episodes of longer duration (8–10 min, n =18), 100 n M 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. 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.British Journal of Pharmacology (2006) 147 , 524–532. doi: 10.1038/sj.bjp.0706646