Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist
Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist
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DOI：
10.1016/s0006-8993(98)00540-x
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发表时间：
1998-08-03
期刊：
影响因子：
2.9
通讯作者：
Stone, TW
中科院分区：
文献类型：
--
作者：
Jones, PA;Smith, RA;Stone, TW
我们先前已经证明，外周给予A（2A）受体激动剂2-对-（2-羧乙基）苯乙氨基-5 '-N-乙基羧酰胺腺苷盐酸盐（CGS 21680）可保护海马免受红藻氨酸诱导的兴奋性毒性。本研究利用海马内途径进一步研究CGS 21680介导的保护作用，以及研究腺苷和A（1）和A（2A）受体在红藻氨酸诱导的兴奋性毒性中的作用。将注射液直接注射到麻醉的雄性Wistar大鼠的海马体中。在手术和给予1 μ l溶液中的0.25 nmol红藻氨酸盐后，在灌注和脑切片之前，使动物恢复7天。苏木精和伊红染色显示CA 3区有实质性损伤。在一定剂量范围内，A（2A）受体激动剂CGS 21680的GO给药对该区域没有任何程度的保护作用。同样，A（1）受体激动剂R-苯基异丙基腺苷（R-PIA）和腺苷本身都不能减少红藻氨酸诱导的损伤。然而，海马内注射选择性A（2A）受体拮抗剂4-（2-[7-氨基-2-{2-呋喃基}{1，2，4}三唑并{2，3-a}{1，3，5}三嗪-5-基-氨基]乙基）苯酚（ZM 241385）可显著降低红藻氨酸对CA 3区的损伤。这些结果表明，腺苷A（2A）受体诱导的保护作用最有可能是外周介导的，可能不是由于海马内A（2A）受体的激活。用R-PIA或腺苷观察到的保护作用的缺乏可能是由于A（2A）受体对神经保护性A（1）受体的抑制作用。重要的是，这项研究还质疑内源性释放的腺苷在保护海马免受兴奋性毒性损伤中的作用。(C)1998 Elsevier Science B. V.保留所有权利。
We have previously shown that the peripheral administration of an A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) protected the hippocampus against kainate-induced excitotoxicity. The present study utilises the intrahippocampal route to further investigate CGS 21680-mediated protection as well as examining the role of adenosine and both A(1) and A(2A) receptors in kainate-induced excitotoxicity. Injections were made directly into the hippocampus of anaesthetised male Wistar rats. Following surgery and the administration of 0.25 nmol kainate in 1 mu l of solution, the animals were left to recover for seven days before perfusion and brain slicing. Haematoxylin and eosin staining revealed substantial damage to the CA3 region. Go-administration of the A(2A) receptor agonist CGS 21680 over a range of doses did not protect the region to any degree. Similarly neither the A(1) receptor agonist R-phenylisopropyladenosine (R-PIA), nor adenosine itself reduced kainate-induced damage. The intrahippocampal injection of the selective A(2A) receptor antagonist, 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385) however, significantly decreased kainate damage to the CA3 region. These results show that adenosine A(2A) receptor-induced protection is most likely to be mediated peripherally and is probably not due to activation of A(2A) receptors within the hippocampus. The lack of protection observed with either R-PIA or adenosine may be due to an inhibitory action of the A(2A) receptor on the neuroprotective A(1) receptor. Importantly, this study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage. (C) 1998 Elsevier Science B.V. All rights reserved.