Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists
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.
A
Conclusion
These results show the benefits of A2A adenosine receptor agonists in an excitotoxic model. The results also provide evidence for a neuroprotective action of an A2A antagonist, which may be due to interaction between A1 and A2A 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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