Neuroprotective Effects of Diadenosine Polyphosphates in

二腺苷四磷酸(AP4A)是一种内源性二腺苷多磷酸，可减轻心脏的缺血性损伤。在这项研究中，我们报道了AP4A在中风和帕金森病啮齿动物模型中的有效和保护作用。在大脑中动脉(MCA)结扎前脑室注射AP4A，可缩小成年大鼠脑梗塞范围，增强运动能力。在大脑中动脉结扎后早期静脉注射AP4A也能产生保护作用。AP4A可抑制缺氧/再灌注诱导的原代培养大脑皮层细胞末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记(TUNEL)，并减少缺血诱导的线粒体细胞色素c移位和胞浆caspase-3活性的升高。嘌呤能P2/P4拮抗剂五磷酸二肌苷或P1受体拮抗剂磺酰苯茶碱可拮抗AP4A的作用，但不能拮抗P2受体拮抗剂苏拉明，提示AP4A的保护作用是通过抗细胞凋亡机制和激活P1和P4受体来实现的。AP4A对单侧前脑内侧束注射6-羟基多巴胺(6-OHDA)引起的毒性也有保护作用。损毁后一个月，用安非他明治疗的大鼠表现出旋转。在受损的黑质或纹状体中可检测到极少量的酪氨酸羟化酶免疫反应。损毁的纹状体未见KCl2诱导的多巴胺释放。这些多巴胺能变性指标均被AP4A预先处理后减弱。6-OHDA给药后2d，AP4A可使损毁黑质的TUNEL减少。总之，我们的数据表明，AP4A通过抑制细胞凋亡，对缺血或6-OHDA诱导的神经元损伤具有保护作用。我们认为AP4A可能是治疗中风和帕金森病的一个潜在的有用的靶分子。

Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an anti-apoptotic mechanism and the activation of P1- and P4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.