Von Lubitz D K, Lin R C, Jacobson K A
Laboratory of Bioorganic Chemistry, NIH/NIDDK, Bethesda, MD 20892, USA.
Eur J Pharmacol. 1995 Dec 20;287(3):295-302. doi: 10.1016/0014-2999(95)00498-x.
Despite significant progress in understanding of the potential of adenosine A1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A2 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'-N- ethylcarboxoamidoadenosine (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 A2A 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 A2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.
尽管在理解基于腺苷A1受体的疗法治疗脑缺血和中风的潜力方面取得了重大进展，但对于选择性刺激腺苷A2A受体对脑血管骤停结局的影响却知之甚少。鉴于腺苷A2受体在调节脑血流中发挥的主要作用，我们研究了选择性腺苷受体激动剂2-[(2-氨基乙氨基)-羰基乙基苯乙氨基]-5'-N-乙基羧酰胺腺苷（APEC）和拮抗剂8-(3-氯苯乙烯基)咖啡因（CSC）急性和慢性给药对沙土鼠10分钟缺血结局的影响。APEC急性治疗可改善缺血后血流恢复和存活率，而不影响海马神经元的保存。CSC急性治疗对脑血流无影响，但对海马神经元有非常显著的保护作用。缺血后最初10天内存活率有显著改善。由于急性接受CSC治疗的动物随后死亡，该组的终点死亡率（缺血后14天）与对照组相比无统计学差异。然而，急性CSC组的晚期死亡率可能是由脑缺血的全身效应引起的，而这种药物对此无治疗作用。APEC慢性治疗在所有研究指标上均有统计学意义的改善。虽然CSC慢性治疗可改善缺血后血流，但其对神经元保存的影响很小且无统计学意义。死亡率不受影响。结果表明，腺苷A2A受体拮抗剂急性治疗在全脑缺血治疗中的价值可能有限。然而，由于给予的CSC对缺血后血流的重建无影响，用腺苷A2A受体拮抗剂治疗中风可能不可取。需要进一步研究以阐明长期使用作用于腺苷A2受体的药物是否可用于治疗中风和其他神经退行性疾病。
