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 A 1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A 2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A 2 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′-Nethylcarboxoamidoadenosine (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 A 2A 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 A 2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A 2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…But the first report by Phillis' group that a non-selective A 2A R antagonist (CGS 15943) attenuated cerebral ischemic injury [225], in contrast to A 1 R antagonists [226], appeared as a serendipitous observation. Similar observations were made by von Lubitz in a similar gerbil model of brain ischemia [227]. However, this concept of A 2A R blockade as a neuroprotective strategy was difficult to understand at the time and consequently was not widely accepted until the group of Ongini and the group of Chen demonstrated that both the pharmacological blockade of A 2A Rs with a selective antagonist (SCH 582610) [228] as well as the genetic inactivation of A 2A Rs (using A 2A R knockout mice) [229] conferred a robust neuroprotection in animal models of focal ischemia.…”

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

“…The striking pattern of the dependence of physiological and therapeutic effects of adenosine receptor stimulation on the dose (Ceruti et al, 1996) and/or duration of exposure to the stimulating agent (present study; Von Lubitz et al, 1994aLubitz et al, , 1995b may be related to desensitiza-tion of receptor-coupled G proteins. Chronic exposure of rat adipocytes to a selective adenosine A: agonist R-phenylisopropyladenosine (R-PIA) results in a profound loss of immunoreactivity for G proteins, particularly G iα1 and G iα3 , both in vitro and in vivo (Longabaugh et al, 1989).…”

Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction

“…It is likely therefore, that the release of ATP and adenosine under ischemic conditions is mechanistically and temporally separated [49] , suggesting that the initial elevations in ATP can activate neurodegenerative mechanisms that may be followed, after conversion of ATP to adenosine by neuroprotective and neurodegenerative roles for the purines. However, this appears to be strongly dependent upon CNS region, animal model and the type of insult, and requires more investigation to elucidate these complex mechanisms [80,[84][85][86][87][88][89][90][91][92][93][94][95][96] .…”