Adenosine receptors and hypoglycemic responses

描述（由申请人提供）： 由于大脑高度依赖于葡萄糖，低血糖症具有神经毒性，而且如果低血糖症不产生强大的神经保护和反调节反应，这种毒性甚至会更大。介导这些低血糖保护作用的机制尚不清楚。然而，DNA微阵列数据表明，低血糖诱导腺苷，腺苷受体是已知的介导许多神经保护反应的代谢应激，如缺血和缺氧。另一方面，阻断A1和A2 a腺苷受体的药物增强了人类（包括糖尿病患者）的反调节反应。由于A1腺苷受体介导对缺血和缺氧的细胞保护反应，A1受体也可介导对低血糖的神经保护反应。相反，A2 a受体实际上可以增强神经毒性，可能是通过拮抗A1受体。此外，A2 a受体介导低血糖诱导的血管舒张，可能是咖啡因和茶碱增强反调节的作用。因此，特异性阻断A2 a受体和/或激活A1受体可能改善糖尿病患者对低血糖的神经保护和反调节反应。为了评估这种方法的可行性，拟议的研究将评估A1和A2 a受体对低血糖反应的影响，这还没有在体内进行过检查。由于A1和A2 a受体的药理学拮抗剂具有有限的特异性和通过血脑屏障的渗透性，因此拟定的研究将评估A1和/或A2 a基因缺失的小鼠（A1和A2 a基因敲除小鼠）对低血糖的反应。这些研究可能导致A2 a受体拮抗剂的开发，以改善糖尿病患者低血糖的结局。

DESCRIPTION (provided by applicant): Because the brain is highly dependent on glucose, hypoglycemia is neurotoxic, and would be even more so except that hypoglycemia produces robust neuroprotective and counterregulatory responses. The mechanisms mediating these protective effects to hypoglycemia are unclear. However, DNA microarray data indicate that hypoglycemia induces adenosine, and adenosine receptors are known to mediate many neuroprotective responses to metabolic stresses such as ischemia and hypoxia. On the other hand, drugs that block the both the A1 and A2a adenosine receptors enhance counterregulatory responses in humans, including in diabetic patients. Since A1 adenosine receptors mediate cytoprotective responses to ischemia and hypoxia, A1 receptors may also mediate neuroprotective responses to hypoglycemia. In contrast, A2a receptors can actually potentiate neurotoxicity, possibly by antagonizing A1 receptors. Furthermore, A2a receptors mediate hypoglycemia-induced vasodilation, possibly accounting for the effects of caffeine and theophylline to enhance counterregulation. Therefore specific blockade of A2a receptors and/or activation of A1 receptors might improve neuroprotective and counterregulatory responses to hypoglycemia in patients with diabetes. To assess the feasibility of this approach, the proposed study will assess the influence of A1 and A2a receptors on responses to hypoglycemia, which has not been examined in vivo. Since pharmacological antagonists of the A1 and A2a receptors are of limited specificity and permeability through the blood-brain barrier, the proposed studies will assess responses to hypoglycemia in mice in which the A1 and/or A2a genes are genetically deleted (A1 and A2a knockout mice). These studies could lead to the development of A2a receptor antagonists to improve outcome of hypoglycemia in patients with diabetes.