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

Abstract

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 B7 min from OGD start, n ¼ 20) and were invariably followed by irreversible loss of electrically evoked field epsps (fepsps, n ¼ 42). 3 When tested on OGD episodes of longer duration (8-10 min, n ¼ 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.

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

“…Both drugs in fact block the occurrence of AD and significantly protect from the irreversible disruption of excitatory neurotransmission caused by prolonged, severe (7-min) OGD episodes. These results are consistent with those obtained in the same brain region when different A 3 antagonists were used [14]. LJ1251 and MRS 1523 possess high affinity for the rat A 3 receptors (K i = 3.89 nM [33] and 113 nM [31], respectively).…”

“…Alterations in AD characteristics caused by A 3 antagonists may be attributable to their actions on glutamate-mediated cellular responses. The time window of A 3 receptor-mediated effects found in the present work and reported by Pugliese et al [14] overlaps with the delay that can be obtained by treating the slices with glutamate receptor antagonists [25,40,41]. NMDA receptors are essential to AD initiation and propagation [26].…”

“…Similarly, during 7-min OGD no AD appearance was recorded in the presence of MRS1523 (100 nM, n=5, Fig.1A, right panel). These results are in agreement with our previous results showing that MRS1523 and several chemically diverse A 3 receptor antagonists prevented the irreversible failure of neurotransmission induced by 7-min OGD and induced a complete abolishment or delay of AD [14]. The protective effect of LJ1251 against OGD-evoked irreversible depression of fEPSPs was concentration dependent (Fig.…”

“…A harmful role of A 3 receptors during in vitro oxygen glucose deprivation (OGD) was confirmed by the observation that blocking the A 3 adenosine receptor consistently abolishes or delays the occurrence of anoxic depolarization (AD) and significantly protects from the irreversible disruption of excitatory neurotransmission caused by a severe ischemic episode [14]. These results agree with the observation that acute administration of a selective adenosine A 3 agonist exacerbates the damage elicited by global ischemia in the gerbil [15].…”

“…Prolonged, severe episodes of OGD bring about the irreversible depression of neurotransmission and the appearance of AD [14,25], a phenomenon strictly correlated with the extent of brain damage during ischemia both in vivo and in vitro [26]. Brief periods of ischemia are followed by complete recovery of neurotransmission and imply shorter times of A 3 receptor stimulation by endogenous adenosine released during the ischemic episode [10,13,27,28].…”