PACAP38 protects rat cortical neurons against the neurotoxicity evoked by sodium nitroprusside and thrombin.
PACAP38 protects rat cortical neurons against the neurotoxicity evoked by sodium nitroprusside and thrombin.
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DOI：
10.1016/j.regpep.2008.07.004
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发表时间：
2009-01-08
影响因子：
--
通讯作者：
Grammas, Paula
中科院分区：
文献类型：
--
作者：
Sanchez, Alma;Rao, Haripriya Vittal;Grammas, Paula
垂体腺苷环化酶激活多肽(PACAP)38是一种广泛分布于神经系统的多功能抗炎抗凋亡神经肽。本研究的目的是确定PACAP38对硝普钠(SNP)和凝血酶这两种不同机制的神经毒性药物是否具有神经保护作用。用1 mM SNP处理原代培养的皮质神经元4小时后，神经细胞死亡显著减少100 NM PACAP38。PACAP38下调SNP诱导的细胞周期蛋白(Cyclin E)的表达，上调细胞周期蛋白依赖性激酶抑制因子p57Kip2和抗凋亡蛋白Bcl2的表达。同样，100 NM凝血酶或凝血酶受体激活肽(TRAP 6)诱导的神经元死亡可通过PACAP38治疗而减少。凝血酶刺激的细胞周期蛋白(CDK4)的表达被PACAP38抑制，而PACAP38则抑制凝血酶介导的p57Kip2的减少。然而，PACAP38不影响凝血酶诱导的Bc l-2的降低。最后，SNP和凝血酶(或TRAP)都能增加caspase3的活性，这种作用被PACAP38降低。这些数据表明，PACAP38支持神经元在体外存活，抑制细胞周期进程，增强抗凋亡蛋白。我们的结果支持PACAP可能是一种有用的治疗药物，用于减少神经退行性疾病中的神经细胞死亡。
Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 is a multifunctional anti-inflammatory and anti-apoptotic neuropeptide widely distributed in the nervous system. The objective of this study is to determine whether PACAP38 is neuroprotective against sodium nitroprusside (SNP) and thrombin, two mechanistically distinct neurotoxic agents. Treatment of primary cortical neuronal cultures with 1 mM SNP for 4 h causes neuronal cell death that is significantly reduced by 100 nM PACAP38. PACAP38 down-regulates SNP-induced cell cycle protein (cyclin E) expression and up-regulates p57KIP2, a cyclin-dependent kinase inhibitor as well as the anti-apoptotic protein Bcl-2. Similarly, neuronal death induced by 100 nM thrombin or the thrombin receptor activating peptide (TRAP 6) is reduced by PACAP38 treatment. Thrombin-stimulated cell cycle protein (cdk4) expression is decreased by PACAP38 while PACAP38 inhibits thrombin-mediated reduction of p57KIP2. However, the decrease in Bcl-2 evoked by thrombin is not affected by PACAP38. Finally, both SNP and thrombin (or TRAP) increase caspase 3 activity, an effect that is decreased by PACAP38. These data show that PACAP38 supports neuronal survival in vitro suppressing cell cycle progression and enhancing anti-apoptotic proteins. Our results support the possibility that PACAP could be a useful therapeutic agent for reducing neuronal cell death in neurodegenerative diseases.
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