Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist

Abstract

Despite significant progress in understanding of the potential of adenosine A1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A2 receptors in the regulation of cerebral blood flow, we have investigated the effect of both acute and chronic administration of the selective adenosine receptor agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N- ethylcarboxoamidoadenosine (APEC) and antagonist 8-(3-chlorostyryl)caffeine (CSC) on the outcome of 10 min ischemia in gerbils. Acute treatment with APEC improved recovery of postischemic blood flow and survival without affecting neuronal preservation in the hippocampus. Acute treatment with CSC had no effect on the cerebral blood flow but resulted in a very significant protection of hippocampal neurons. Significant improvement of survival was present during the initial 10 days postischemia. Due to subsequent deaths of animals treated acutely with CSC, the end-point mortality (14 days postischemia) in this group did not differ statistically from that seen in the controls. It is, however, possible that the late mortality in the acute CSC group was caused by the systemic effects of brain ischemia that are not subject to the treatment with this drug. Chronic treatment with APEC resulted in a statistically significant improvement in all studied measures. Although chronic treatment with CSC improved postischemic blood flow, its effect on neuronal preservation was minimal and statistically insignificant. Mortality remained unaffected. The results indicate that the acute treatment with adenosine A2A receptor antagonists may have a limited value in treatment of global ischemia. However, since administered CSC has no effect on the reestablishment of postischemic blood flow, treatment of stroke with adenosine A2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.

Fig. 1

Postischemic cortical blood flow in controls (black circles) and in animals treated acutely with either APEC (open circles) or CSC (open squares). Time measured from the moment of the occlusion which ends 10 min later. Note the swift increase of flow in the APEC group and virtually identical pattern of recovery in control and CSC groups.

Fig. 2

Postischemic cortical blood flow in animals treated chronically with either APEC (open circles) or CSC. The recovery of flow in both groups is significantly better (P < 0.05, Student-Newman-Keuls) than in the controls (black circles). For most of its course, recovery in the CSC group is also much better (P < 0.05, Student-Newman-Keuls) than in the APEC group.

Fig. 3

Postischemic survival in controls (black circles) and animals treated acutely with either APEC (open circles) or CSC (open squares). Between day 5 and 10, survival in both APEC and CSC groups is statistically better than in the control group (P < 0.05, Fisher’s test). However, at the end-point, the significance is lost in the CSC group (see text for details).

Fig. 4

Survival in animals treated chronically with either APEC (open circles) or CSC (open squares). While survival in the APEC group is significantly better than in the controls (black circles (P < 0.05)) beginning with day 4 postischemia, the difference between CSC and control groups has no statistical significance.

Fig. 5

Survival of the hippocampal neurons following vehicle (black bar), and either acute CSC (shaded bar) or acute APEC (open bar). Acute treatment with CSC results in a significant (P <0.01, Student-Newman-Keuls test) improvement of hippocampal morphology.

Fig. 6

Neuronal survival in the hippocampus following chronic treatment with either CSC (shaded bar) or APEC (open bar). While treatment with CSC results in a numerical improvement vs. controls (black bar), there is no statistical significance. The number of morphologically intact neurons in the APEC group is, however, significantly better (P < 0.03, Student-Newman-Keuls test). Note that neuronal preservation following chronic treatment with APEC is statistically indistinguishable from that seen after acute exposure to CSC (Fig. 5).