Hippocampal injury and neurobehavioral deficits are improved by PD 81,723 following hyperglycemic cerebral ischemia

Abstract

We investigated the effects of PD 81,723, an allosteric enhancer for the adenosine A1 receptor subtype, on hippocampal injury and Morris water maze (MWM) performance following hyperglycemic cerebral ischemia and reperfusion (4-VO, 10 min) in the rat. PD 81,723 (3 or 10 mg/kg) or the equivalent volume of saline was administered intraperitoneally 30 min prior to ischemia. Moderate hyperglycemia was achieved by administration of d-glucose (3g/kg, ip) 15 min prior to induction of ischemia. Morris water maze trials were performed on the 6th, 7th, and 8th days after the ischemic insult. The rat brains were sectioned (8 μm), stained with cresyl violet/acid fuchsin, and evaluated for hippocampal ischemic injury by an experimenter blinded to the treatment conditions. At the higher dose, PD 81,723 (10 mg/kg) had no effect on hippocampal injury or MWM performance following hyperglycemic ischemia compared to corresponding saline-treated animals. In contrast, a lower dose of PD 81,723 (3 mg/kg) resulted in significant (P < 0.05, n = 8) reduction of hippocampal injury following hyperglycemic ischemia. Furthermore, corresponding Morris water maze performance (latency, learning index, and cumulative distance swum) was significantly improved by PD 81,723 (P < 0.05, n = 8). The results of the present study suggest that, in the presence of PD 81,723, an A1 allosteric enhancer, endogenously produced adenosine is sufficient to exert significant neuroprotection during hyperglycemic ischemia. Moreover, the present study provides further evidence for a neuromodulatory role of adenosine during hyperglycemic ischemia.