Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
Neuropharmacology. 2010 Jan;58(1):268-76. doi: 10.1016/j.neuropharm.2009.06.029. Epub 2009 Jul 2.
The tachykinin endecapeptide substance P (SP) has been demonstrated to exert a functional role in neurodegenerative disorders, including Alzheimer's disease (AD). Aim of the present study was to evaluate the SP neuroprotective potential against apoptosis induced by the neurotoxic beta-amyloid peptide (A beta) in cultured rat cerebellar granule cells (CGCs). We found that SP protects CGCs against both A beta(25-35)- and A beta(1-42)-induced apoptotic CGCs death as revealed by live/dead cell assay, Hoechst staining and caspase(s)-induced PARP-1 cleavage, through an Akt-dependent mechanism. Since in CGCs the fast inactivating or A-type K(+) current (I(KA)) was potentiated by A beta treatment through up-regulation of Kv4 subunits, we investigated whether I(KA) and the related potassium channel subunits could be involved in the SP anti-apoptotic activity. Patch-clamp experiments showed that the A beta-induced increase of I(KA) current amplitude was reversed by SP treatment. In addition, as revealed by Western blot analysis and immunofluorescence studies, SP prevented the up-regulation of Kv4.2 and Kv4.3 channel subunits expression. These results indicate that SP plays a role in the regulation of voltage-gated potassium channels in A beta-mediated neuronal death and may represent a new approach in the understanding and treatment of AD.
速激肽内十肽 P 物质（SP）已被证明在神经退行性疾病中发挥功能作用，包括阿尔茨海默病（AD）。本研究的目的是评估 SP 对培养的大鼠小脑颗粒细胞（CGC）中由神经毒性β-淀粉样肽（Aβ）诱导的细胞凋亡的神经保护潜力。我们发现 SP 通过 Akt 依赖性机制保护 CGC 免受 Aβ（25-35）和 Aβ（1-42）诱导的凋亡性 CGC 死亡，如活/死细胞检测、Hoechst 染色和 caspase 诱导的 PARP-1 切割所示。由于在 CGC 中，Aβ 通过上调 Kv4 亚基增强快速失活或 A 型 K（+）电流（I（KA）），我们研究了 I（KA）和相关钾通道亚基是否可能参与 SP 的抗凋亡活性。膜片钳实验表明，SP 处理可逆转 Aβ 诱导的 I（KA）电流幅度增加。此外，如 Western blot 分析和免疫荧光研究所示，SP 可防止 Kv4.2 和 Kv4.3 通道亚基表达的上调。这些结果表明 SP 在 Aβ 介导的神经元死亡中调节电压门控钾通道的作用，可能是理解和治疗 AD 的新方法。
