Qin Z H, Wang Y, Chen R W, Wang X, Ren M, Chuang D M, Chase T N
Experimental Therapeutics Branch, National Institute of Neurodegenerative Disorders and Stroke, National Institutes of Health, Bldg. 10, 10 Center Drive, Bethesda, MD 20892-1406, USA.
J Pharmacol Exp Ther. 2001 Apr;297(1):78-87.
Prostaglandin A(1) (PGA1) reportedly inhibits NF-kappaB activation and induces expression of heat shock proteins. Since both these effects could be neuroprotective, the therapeutic potential of PGA1 in neurodegenerative disorders, where excitotoxicity may contribute to pathogenesis, was evaluated in rat striatal neurons exposed to the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA). Intrastriatal administration of PGA1 (5-80 nmol) attenuated QA (60 nmol)-induced internucleosomal DNA fragmentation. The inhibitory effects of a single dose of PGA1 (80 nmol) on QA (60 nmol)-induced DNA fragmentation were observed 12 to 48 h after treatment. PGA1 (80 nmol) also attenuated QA-induced DNA fragmentation when administered up to 4 h after QA exposure. PGA1 significantly decreased the loss of D1 dopamine receptors and GAD(67) mRNA in QA-injected striatum as measured by quantitative receptor autoradiography and in situ hybridization histochemistry, suggesting that it reduced the neuronal loss induced by QA. Protection of striatal neurons against QA-induced death by PGA1 was further indicated by Nissl staining 10 days after QA administration. PGA1 (5-80 nmol) significantly inhibited QA-induced NF-kappaB activation by blocking inhibitory kappaB-alpha degradation but had no effect on activator protein-1 binding activity. PGA1 (80 nmol) treatment substantially increased 70- and 72-kDa heat shock protein levels in striatum. These results indicate that PGA1 blunts NMDA receptor-mediated neuronal apoptosis by a mechanism possibly involving the up-regulation of neuroprotective heat shock proteins and inhibition of NF-kappaB activation. In view of its potent neuroprotective activity, PGA1 could prove useful in the treatment of certain neurodegenerative disorders related to excitotoxicity.
据报道，前列腺素A(1)(PGA1)可抑制核因子κB的激活并诱导热休克蛋白的表达。由于这两种效应都可能具有神经保护作用，因此在暴露于N-甲基-D-天冬氨酸(NMDA)受体激动剂喹啉酸(QA)的大鼠纹状体神经元中评估了PGA1在神经退行性疾病中的治疗潜力，在这些疾病中，兴奋性毒性可能参与发病机制。纹状体内注射PGA1(5-80 nmol)可减轻QA(60 nmol)诱导的核小体间DNA片段化。在治疗后12至48小时观察到单剂量PGA1(80 nmol)对QA(60 nmol)诱导的DNA片段化的抑制作用。当在QA暴露后长达4小时给予PGA1(80 nmol)时，也可减轻QA诱导的DNA片段化。通过定量受体放射自显影和原位杂交组织化学测量，PGA1显著降低了QA注射纹状体中D1多巴胺受体和GAD(67)mRNA的损失，表明它减少了QA诱导的神经元损失。QA给药10天后的尼氏染色进一步表明PGA1对纹状体神经元具有抗QA诱导死亡的保护作用。PGA1(5-80 nmol)通过阻断抑制性κB-α降解显著抑制QA诱导的核因子κB激活，但对激活蛋白-1结合活性没有影响。PGA1(80 nmol)处理显著增加了纹状体中70 kDa和72 kDa热休克蛋白水平。这些结果表明，PGA1通过一种可能涉及上调神经保护热休克蛋白和抑制核因子κB激活的机制减弱NMDA受体介导的神经元凋亡。鉴于其强大的神经保护活性，PGA1可能被证明对治疗某些与兴奋性毒性相关的神经退行性疾病有用。
