Brief, repeated, oxygen‐glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptors

Ischemic preconditioning in the brain consists of reducing the sensitivity of neuronal tissue to further, more severe, ischemic insults. We recorded field epsps (fepsps) extracellularly from hippocampal slices to develop a model of in vitro ischemic preconditioning and to evaluate the role of A 1 , A 2A and A 3 adenosine receptors in this phenomenon. The application of an ischemic insult, obtained by glucose and oxygen deprivation for 7 min, produced an irreversible depression of synaptic transmission. Ischemic preconditioning was induced by four ischemic insults (2 min each) separated by 13 min of normoxic conditions. After 30 min, an ischemic insult of 7 min was applied. This protocol substantially protected the tissue from the irreversible depression of synaptic activity. The selective adenosine A 1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 100 n M ), completely prevented the protective effect of preconditioning. The selective adenosine A 2A receptor antagonist 4‐(2‐[7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[2,3‐ a ][1,3,5]triazin‐5‐ylamino]ethyl)phenol (ZM 241385, 100 n M ) did not modify the magnitude of fepsp recovery compared to control slices. The selective A 3 adenosine receptor antagonists, 3‐propyl‐6‐ethyl‐5[ethyl(thio)carbonyl]‐2‐phenyl‐4‐propyl‐3‐pyridinecarboxylate (MRS 1523, 100 n M ) significantly improved the recovery of fepsps after 7 min of ischemia. Our results show that in vitro ischemic preconditioning allows CA1 hippocampal neurons to become resistant to prolonged exposure to ischemia. Adenosine, by stimulating A 1 receptors, plays a crucial role in eliciting the cell mechanisms underlying preconditioning; A 2A receptors are not involved in this phenomenon, whereas A 3 receptor activation is harmful to ischemic preconditioning.British Journal of Pharmacology (2003) 140 , 305–314. doi: 10.1038/sj.bjp.0705442