The selective A2 adenosine receptor agonist CGS 21680 enhances excitatory transmitter amino acid release from the ischemic rat cerebral cortex

O’Regan, Michael H.; Simpson, Richard E.; Perkins, L.M.; Phillis, John W.

doi:10.1016/0304-3940(92)90498-v

Cited by 120 publications

(35 citation statements)

References 18 publications

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“…Apart from regulating cerebral blood flow, adenosine A 2A receptors appear to be involved in the excitatory phenomena in the hippocampus (Sebastião and Ribeiro, 1992;Sebastião et al, 1995) and in the intraischemic release of glutamate and aspartate (O'Regan et al, 1992). Facilitation of neurotransmitter release appears to result from the interaction of adenosine A 2 receptors and P-type calcium channels (Umemiya and Berger, 1994).…”

Section: Discussionmentioning

confidence: 99%

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

Lubitz¹,

Lin

Jacobson³

1995

European Journal of Pharmacology

132

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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.

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Section: Discussionmentioning

confidence: 99%

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

Lubitz¹,

Lin

Jacobson³

1995

European Journal of Pharmacology

132

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“…130 Similarly, A 2A agonists increase glutamate release in the brain during ischemia. 131,132 These results, of course, are the opposite of what would be predicted if adenosine had a neuroprotective action through its actions on the A 2A receptor. Because A 2A antagonists can be used with minimal effects on the cardiovascular physiology, A 2A antagonists may be considered as neurotherapeutic agents in stroke.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 92%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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“…This is particularly intriguing given that cortical and hippocampal A 2A Rs have a low abundance (in the range of 20 fmol/mg of protein compared to a 50-times greater density of A 1 Rs; [7]) and the amplitude of the effect resulting from A 2A R activation is discrete, especially when [238,258]. Indeed, some studies reported that A 2A R activation was involved in enhancing the extracellular levels of glutamate triggered by noxious stimuli [231,238,249,251]. However, in more simplified models of neuronal dysfunction, it was not possible to confirm that the presynaptic modulation of glutamate release by A 2A Rs was related to their control of neuronal damage.…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

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

Cunha

2005

Purinergic Signalling

482

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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The selective A2 adenosine receptor agonist CGS 21680 enhances excitatory transmitter amino acid release from the ischemic rat cerebral cortex

Cited by 120 publications

References 18 publications

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

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

Targeting Astrocytes for Stroke Therapy

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

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