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，可减少心脏缺血性损伤。在这项研究中，我们报告了 AP4A 在中风和帕金森病啮齿动物模型中的有效保护作用。 AP4A 在大脑中动脉 (MCA) 结扎前脑室内给予，可减少成年大鼠的脑梗塞面积并增强运动活动。 MCA 结扎后早期静脉注射 AP4A 也能产生保护作用。 AP4A 抑制原代皮质培养物中缺氧/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)，并减少缺血诱导的线粒体细胞色素 c 易位和体内细胞质 caspase-3 活性的增加。嘌呤能 P2/P4 拮抗剂二肌苷五磷酸或 P1 受体拮抗剂磺酰苯基茶碱（而非 P2 受体拮抗剂苏拉明）拮抗 AP4A 的作用，表明观察到的保护作用是通过抗凋亡机制以及 P1 和 P4 嘌呤能受体的激活介导的。 AP4A 还可以防止单侧内侧前脑束注射 6-羟基多巴胺 (6-OHDA) 引起的毒性。损伤后一个月，媒介物治疗的大鼠表现出安非他明诱导的旋转。在病变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。在受损纹状体中没有发现氯化钾诱导的多巴胺释放。所有这些多巴胺能变性指标均通过 AP4A 预处理而减弱。此外，施用 6-OHDA 后第 2 天，AP4A 降低了病变黑质中的 TUNEL。总的来说，我们的数据表明 AP4A 通过抑制细胞凋亡来保护缺血或 6-OHDA 引起的神经元损伤。我们认为 AP4A 可能是治疗中风和帕金森病的潜在有用靶分子。