Neuroprotective Effects--Diadenosine Polyphosphates CNS

神经保护作用--二腺苷多磷酸 CNS

• 批准号: 7149317
• 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/7149317
• 关键词: Parkinson' s disease; adenosine; apoptosis; brain disorder chemotherapy; central nervous system; cerebral ischemia /hypoxia; cysteine endopeptidases; cytochrome c; disease /disorder model; dopamine; drug screening /evaluation; enzyme activity; laboratory rat; neuropharmacology; neuroprotectants; nonhuman therapy evaluation; polyphosphates; stroke therapy; terminal nick end labeling; tyrosine 3 monooxygenase

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.

四磷酸二腺苷（AP4A）是一种内源性多磷酸二腺苷，可减轻心脏缺血性损伤。在这项研究中，我们报道了AP4A在脑卒中和帕金森病啮齿动物模型中的有效保护作用。在结扎大脑中动脉（MCA）前给予AP4A脑室内注射，可减少成年大鼠脑梗死面积，增强运动活性。在MCA结扎后早期静脉给药AP4A也能产生保护作用。AP4A抑制原代皮质培养物缺氧/再灌注诱导的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），并在体内减少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拮抗剂二磷酸肌苷或P1受体拮抗剂磺酰基苯基茶碱，而不是P2受体拮抗剂苏拉明，可以拮抗AP4A的作用，表明所观察到的保护作用是通过抗凋亡机制和P1-和P4嘌呤能受体的激活介导的。AP4A对单侧内侧前脑束注射6-羟基多巴胺（6-OHDA）诱导的毒性也有保护作用。损伤后一个月，给药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低的酪氨酸羟化酶免疫反应性。损伤纹状体中未见kcl诱导的多巴胺释放。经AP4A预处理后，各组大鼠多巴胺能变性指标均有所减弱。此外，AP4A在6-OHDA给药后2 d降低了受损黑皮肤的TUNEL。综上所述，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可能是脑卒中和帕金森病治疗中潜在有用的靶标分子。