Neuroprotective Effects of Diadenosine Polyphosphates in

多磷酸二腺苷的神经保护作用

• 批准号: 6828425
• 负责人: Yun Wang
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6828425
• 关键词: Parkinson's disease; adenine nucleotides; apoptosis; brain injury; disease /disorder model; ischemia; laboratory rat; nerve injury; neuroprotectants; stroke

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.

二腺苷四磷酸（AP 4A），内源性二腺苷多磷酸，减少心脏缺血性损伤。在这项研究中，我们报告了AP 4A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，侧脑室给予AP 4A，可减少成年大鼠的脑梗死面积并增强其自主活动。在MCA结扎后早期静脉注射AP 4A也可诱导保护作用。AP 4A抑制了缺氧/再灌注诱导的原代皮层培养物中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），并减少了缺血诱导的线粒体细胞色素c易位和细胞质caspase-3活性的增加。嘌呤能P2/P4拮抗剂二肌苷五磷酸盐或P1受体拮抗剂磺酰苯基茶碱，但不是P2受体拮抗剂苏拉明，拮抗AP 4A的作用，这表明所观察到的保护是通过抗凋亡机制和激活P1和P4嘌呤能受体介导的。AP 4A还提供对由单侧内侧前脑束注射6-羟基多巴胺（6-OHDA）诱导的毒性的保护。损伤后1个月，溶剂处理的大鼠表现出安非他明诱导的旋转。在受损的黑质或纹状体中检测到最小的酪氨酸羟化酶免疫反应性。在损伤的纹状体中没有发现KCl诱导的多巴胺释放。所有这些指标的多巴胺能变性减弱预处理与AP 4A。此外，AP 4A减少6-OHDA给药后2天损伤黑质中的TUNEL。总的来说，我们的数据表明，AP 4A是通过抑制细胞凋亡对缺血或6-OHDA诱导的神经元损伤的保护。我们认为，AP 4A可能是一个潜在的有用的靶分子在治疗中风和帕金森病。