Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía - S.S.A., Mexico City, Mexico.
Toxicology. 2013 Feb 8;304:109-19. doi: 10.1016/j.tox.2012.12.011. Epub 2012 Dec 26.
6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage.
6-羟多巴胺(6-OHDA)是一种神经毒素,可在啮齿动物中产生帕金森病的实验模型,常用于诱导多巴胺能通路损伤。需要对与 6-OHDA 诱导的早期毒性相关的那些分子机制进行特征描述,以便更好地了解进一步导致神经退行性变的细胞事件。本研究探讨了 6-OHDA 如何触发早期下游信号通路,从而在大鼠纹状体中引发神经毒性。在损伤后早期评估了线粒体功能、半胱天冬酶依赖性细胞凋亡、激酶信号(Akt、ERK1/2、SAP/JNK 和 p38)以及核因子 kappa B(NF-κB)和核因子-红细胞 2 相关因子 2(Nrf2)之间的串扰。我们发现,6-OHDA 通过抑制线粒体复合物 I、细胞色素 c 和凋亡诱导因子(AIF)的释放,以及激活半胱天冬酶 9 和 3 来诱导细胞凋亡,从而引发细胞损伤,调节激酶信号和 NF-κB 介导的炎症反应,同时抑制由 Nrf2 通路调节的抗氧化系统。我们的结果表明,SAP/JNK 和 p38 的上调可能在 6-OHDA 毒性的早期阶段发挥作用,以触发细胞凋亡的内在途径并增强 NF-κB 的激活。反过来,这些细胞事件抑制了细胞保护机制的激活,从而导致普遍损伤的状态。