adenosine-5--(n-ethylcarboxamide) and Brain-Ischemia

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Brain Ischemia; Dose-Response Relationship, Drug; Female; Injections, Intraventricular; Male; Mice; Receptors, Purinergic P1; Vasodilator Agents

The potential usefulness of adenosine receptor stimulation in the therapy for ischemic brain disease is dependent upon retention of adenosine receptors and their transduction mechanisms after ischemia. The receptors most clearly associated with adenosine-dependent cerebral inhibition are the A1-type (A1-AR), which work via a Gi protein to inhibit adenylate cyclase. In brain membranes from rats recovering at various times after 15 min of complete cardiac arrest-induced ischemia, the levels of A1-AR decreased temporarily to 60% of the control values. However, agonist affinities for A1-AR, as well as guanine nucleotide-sensitive high-affinity binding, remain unchanged. The significant decrease of agonist affinities to A1-AR produced by calcium depletion in control membranes was markedly attenuated after ischemia. Moreover, the A1-AR agonist-induced inhibition of cAMP production parallels the decrease in these receptor numbers. It was blocked in the postischemic membranes but reverts to control levels upon extending the recovery period to one week after the insult. It is concluded that in addition to the lowering of the number of A1-AR binding sites, the coupling of A1 receptor activation to adenylate cyclase response is inhibited after ischemia, but not at the level of receptor-Gi protein interaction.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Binding, Competitive; Brain Ischemia; Calcium; Colforsin; Cyclic AMP; Down-Regulation; Edetic Acid; Egtazic Acid; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Heart Arrest; Male; Models, Biological; Rats; Rats, Wistar; Receptors, Purinergic; Signal Transduction

The effects of selective adenosine receptor agonists [N6-cyclopentyladenosine (CPA) and N-ethylcarboxamidoadenosine (NECA)] and antagonists [8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazoline-5-im ine (CGS-15943A)] on aspartate and glutamate release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (for 20 min) was elicited by four-vessel occlusion. Excitatory amino acid releases were compared from control ischemic rats and drug-treated rats. Basal levels of aspartate and glutamate release were not greatly affected by pretreatment with the adenosine receptor agonists or antagonists. However, CPA (10(-10) M) and NECA (10(-9) M) significantly inhibited the ischemia-evoked release of aspartate and glutamate into cortical superfusates. The ability to block ischemia-evoked release of excitatory amino acids was not evident at higher concentrations of CPA (10(-6) M) or NECA (10(-5) M). The selective A1 receptor antagonist DPCPX also had no effect on release when administered at a low dosage (0.01 mg/kg, i.p.) but blocked the ischemia-evoked release of aspartate and glutamate at a higher dosage (0.1 mg/kg). Evoked release was inhibited by the selective A2 receptor antagonist CGS-15943A (0.1 mg/kg, i.p.). Thus, adenosine and its analogs may suppress ischemia-evoked release of excitatory neurotransmitter amino acids via high-affinity A1 receptors, whereas coactivation of lower-affinity A2 receptors may block (or reverse) the A1-mediated response.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Aspartic Acid; Brain Ischemia; Cerebral Cortex; Glutamates; Glutamic Acid; Male; Neurotransmitter Agents; Purinergic Antagonists; Quinazolines; Rats; Rats, Inbred Strains; Receptors, Purinergic; Triazoles; Xanthines

The effects of adenosine (A) receptor agonists on ischemia-induced impairment of 2-deoxyglucose (2-DG) uptake by rat hippocampal slices was evaluated. Hippocampal slices were exposed to 20-min hypoxia + hypoglycemia (ischemia) and then returned to oxygenated and glucose-containing Krebs-Ringer solution for 6 h. Ischemia reduced 2-DG uptake in the hippocampal slices. The ischemia-induced reduction in 2-DG uptake was attenuated by pretreatment with A1 receptor agonists but not with A2 receptor agonists. 8-Phenyltheophylline, an A1 receptor antagonist, exacerbated the ischemia-induced decrease. The A1 receptor agonist-induced neuroprotective effect was blocked by co-treatment with 8-phenyltheophylline. The present study suggests that the A1 receptor-mediated function has a protective role in ischemia-induced decreases in glucose metabolism in hippocampal slices.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Brain Ischemia; Deoxyglucose; Hippocampus; In Vitro Techniques; Male; Nervous System Diseases; Phenylisopropyladenosine; Purinergic Antagonists; Rats; Rats, Wistar; Receptors, Purinergic; Theophylline; Vasodilator Agents