Duarte J M N, Oses J P, Rodrigues R J, Cunha R A
Centre for Neurosciences of Coimbra, Faculty of Medicine, Institute of Biochemistry, University of Coimbra, 3004-504 Coimbra, Portugal.
Neuroscience. 2007 Oct 26;149(2):382-91. doi: 10.1016/j.neuroscience.2007.08.005. Epub 2007 Aug 8.
Diabetic encephalopathy is a recognized complication of untreated diabetes resulting in a progressive cognitive impairment accompanied by modification of hippocampal function. The purinergic system is a promising novel target to control diabetic encephalopathy since it might simultaneously control hippocampal synaptic plasticity and glucose handling. We now tested whether streptozotocin-induced diabetes led to a modification of extracellular ATP homeostasis and density of membrane ATP (P2) receptors in the hippocampus, a brain structure involved in learning and memory. The extracellular levels of ATP, evaluated in the cerebrospinal fluid, were reduced by 60.4+/-17.0% in diabetic rats. Likewise, the evoked release of ATP as well as its extracellular catabolism was also decreased in hippocampal nerve terminals of diabetic rats by 52.8+/-10.9% and 38.7+/-6.5%, respectively. Western blot analysis showed that the density of several P2 receptors (P2X(3,5,7) and P2Y(2,6,11)) was decreased in hippocampal nerve terminals. This indicates that the synaptic ATP signaling is globally depressed in diabetic rats, which may contribute for diabetes-associated decrease of synaptic plasticity. In contrast, the density of P2 receptors (P2X(1,2,5,6,7) and P2Y(6) but not P2Y(2)) increased in whole hippocampal membranes, suggesting an adaptation of non-synaptic P2 receptors to sense decreased levels of extracellular ATP in diabetic rats, which might be aimed at preserving the non-synaptic purinergic signaling.
糖尿病性脑病是未经治疗的糖尿病的一种公认并发症，会导致进行性认知障碍，并伴有海马功能改变。嘌呤能系统是控制糖尿病性脑病的一个有前景的新靶点，因为它可能同时控制海马突触可塑性和葡萄糖代谢。我们现在测试了链脲佐菌素诱导的糖尿病是否会导致海马（一个参与学习和记忆的脑结构）细胞外ATP稳态和膜ATP（P2）受体密度的改变。在糖尿病大鼠中，脑脊液中评估的ATP细胞外水平降低了60.4±17.0%。同样，糖尿病大鼠海马神经末梢中ATP的诱发释放及其细胞外分解代谢也分别降低了52.8±10.9%和38.7±6.5%。蛋白质印迹分析表明，海马神经末梢中几种P2受体（P2X(3,5,7)和P2Y(2,6,11)）的密度降低。这表明糖尿病大鼠的突触ATP信号总体上受到抑制，这可能是糖尿病相关突触可塑性降低的原因。相比之下，整个海马膜中P2受体（P2X(1,2,5,6,7)和P2Y(6)，但不包括P2Y(2)）的密度增加，表明非突触P2受体适应了糖尿病大鼠细胞外ATP水平的降低，这可能旨在维持非突触嘌呤能信号。
