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Purines and Neuroprotection

  • Trevor W. Stone
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 513)

Abstract

The activation of adenosine Al, A2 and A3 receptors can protect neurones against damage generated by mechanical or hypoxic/ischaemic insults as well as excitotoxins. Al receptors are probably effective by suppressing transmitter release and producing neuronal hyperpolarisation. They are less likely to be of therapeutic importance due to the plethora of side effects resulting from Al agonism, although the existence of receptor subtypes and recent synthetic chemistry efforts to increase ligand selectivity, may yet yield clinically viable compounds.

Activation of A2A receptors can protect neurons, although there is much uncertainty as to whether agonists are acting centrally or via a peripheral mechanism such as altering blood flow or immune cell function. Selective antagonists at the A2A receptor, such as 4-(2-[7-amino-2- {2-furyl} {1,2,4} triazolo {2,3-a} {1,3,5} triazin5-yl-amino]ethyl)phenol (ZM 241385) and 7-(2-phenylethyl)-5-amino-2-(2-furyl)pyrazolo-[4,3e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), can also protect against neuronal death produced by ischaemia or excitotoxicity. In addition, A2A receptor antagonists can reduce damage produced by combinations of subthreshold doses of the endogenous excitotoxin quinolinic acid and free radicals. Since the A2A receptors do not seem to be activated by normal endogenous levels of adenosine, their blockade should not generate significant side effects, so that Am receptor antagonists appear to be promising candidates as new drugs for the prevention of neuronal damage. Adenosine A3 receptors have received less attention to date, but agonists are clearly able to afford protection against damage when administered chronically.

Given the disappointing lack of success of NMDA receptor antagonists in human stroke patients, despite their early promise in animal models, it is possible that A2A receptor antagonists could have a far greater clinical utility.

Keywords

Adenosine Receptor Kainic Acid Quinolinic Acid Ischaemic Damage CA3a Region 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Trevor W. Stone
    • 1
  1. 1.Division ofNeuroscience and Biomedical SystemsWest Medical Bldg, University of GlasgowGlasgowUK

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