Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists

doi:10.1016/S0306-4522(97)00613-1

Neuroscience

Volume 85, Issue 1, 26 March 1998, Pages 229-237

https://doi.org/10.1016/S0306-4522(97)00613-1 Get rights and content

Abstract

The neuroprotective role of adenosine receptor agonists in various models of ischaemia and neuronal excitotoxicity has been attributed to adenosine A₁ receptor activation. In this study we examine the role of the A_2A receptor in the kainate model of excitotoxicity. Kainate (10 mg/kg) was administered systemically 10 min after the intraperitoneal injection of adenosine analogues. The A_2A agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS21680) protected the hippocampus at concentrations of 0.1 and 0.01 mg/kg, but not at 2 μg/kg. The addition of the centrally acting adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine partially reduced protection only in the CA3a region, suggesting that only a small proportion of the protection was attributable to the A₁ receptor. A less potent A_2A agonist, N⁶-[2-(3,5-dimethyoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (1 mg/kg), provided only partial protection against kainate. 4-(2-[7-Amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol, a selective A_2A antagonist, also showed protection against kainate-induced neuronal death, when administered alone or in combination with CGS21680.

These results show that adenosine A_2A receptor activation is protective against excitotoxicity. The protection is largely independent of A₁ receptor activation or blockade.

Section snippets

Experimental procedures

Male Wistar rats (Harlan Dlac) of weight 240–310 g, housed under standard conditions, were used in all experiments. All injections were made by the intraperitoneal route in a volume no greater than 3 ml/kg. Kainate and CGS21680 were dissolved in saline, DPMA in methanol, 8-(p-sulphophenyltheophylline) (8-PST) in distilled water, 8-cyclopentyl-1,3-dipropylxanthine (CPX) in ethanol and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385) in polyethylene

Results

Kainate (10 mg/kg) caused damage in the CA1, CA2 and CA3a areas of the hippocampus (Fig. 1, Fig. 2), with no evidence of neuron mortality in the CA3b and CA4 regions. The damage associated with the excitotoxin was similar to other reports, with the largest extent of neuronal death observed in the CA1 (48.4±7.4% damage) and CA3a (38.1±7.0%) regions, while the CA2 region suffered more moderate (22.2±6.4%) damage. Saline controls induced no significant hippocampal neuronal death in any region (Fig.

Discussion

Kainate has been used extensively in neurobiological research as it preferentially damages neurons in the limbic system, particularly the hippocampus.[28]It is considered a good experimental model for temporal lobe epilepsy and global ischaemia.18, 46Adenosine or its analogues have been shown previously to mitigate against kainate-induced excitotoxicity and ischaemic damage, via interaction with the A₁ receptor,13, 19, 30, 33, 40, 51, 52while little attention has been given to the A₂ receptor.

Conclusion

These results show the benefits of A_2A adenosine receptor agonists in an excitotoxic model. The results also provide evidence for a neuroprotective action of an A_2A antagonist, which may be due to interaction between A₁ and A_2A receptors. While suggesting that the effects of CGS21680 are specific and do not substantially involve A₁ receptors, this study suggests that the action is at least partly peripherally mediated. Further work to distinguish between centrally and peripherally mediated

Acknowledgements

P.A.J. was funded by a University of Glasgow Postgraduate Scholarship. The authors would like to thank Zeneca for the gift of ZM241385.

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Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists

Abstract

Section snippets

Experimental procedures

Results

Discussion

Conclusion

Acknowledgements

Eur. J. Pharmac.

Eur. J. Pharmac.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

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N6-[2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists and antagonists with both high affinity and high selectivity for the adenosine A2 receptor

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Anoxic ischaemic cell change in the rat brain. Light microscope and fine structural observations

J. neurol. Sci.

Characterisation of the A2 adenosine receptor labelled by [3H]NECA in rat striatal membranes

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Protection against kainate-induced excitotoxicity by adenosine A_2A receptor agonists and antagonists

N⁶-[2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists and antagonists with both high affinity and high selectivity for the adenosine A₂ receptor

Characterisation of the A₂ adenosine receptor labelled by [³H]NECA in rat striatal membranes