Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Brain Res. 2011 Apr 22;1386:1-14. doi: 10.1016/j.brainres.2011.01.059. Epub 2011 Jan 26.
It is well recognized that exposure of neurons to excessive levels of the excitatory neurotransmitter glutamate, termed glutamate excitotoxicity, contributes to the damage and degeneration seen in many acute and chronic neurological diseases. However, it is becoming increasingly evident that inflammation also can play a role in certain neurodegenerative diseases and inflammatory mediators, such as tumor necrosis factor-α (TNF-α), may directly interact with excitotoxic processes. In a postnatal rat cerebellar slice model, we found that TNF-α exacerbated AMPA-induced excitotoxicity in Purkinje neurons in a dose-dependent manner beyond the toxicity caused by AMPA alone. It also was shown that combinations of TNF-α and AMPA increased the mean intracellular activity of calpains, calcium-activated cysteine proteases that are known to contribute to cell death in Purkinje neurons. Additionally, these combinations augmented colbalt influx, a marker for calcium entry that selectively occurs through calcium permeable AMPA receptors only. Pharmacologic blockade of calcium permeable AMPA receptors with a specific antagonist, 1-naphthyl acetyl spermine (NASPM), reversed the apparent increase in AMPA receptor calcium permeability caused by TNF-α as measured by cobalt influx; caused a reduction in the Purkinje neuron calpain activity; and reversed the enhanced neurodegeneration induced by the combination of TNF-α and AMPA. From these studies we concluded that TNF-α augmented AMPA-induced toxicity in Purkinje neurons by increasing intracellular calcium flux through calcium permeable AMPA receptors, and this increase in calcium was directly involved in enhanced activation of calpains and a greater percentage of Purkinje neuron loss.
众所周知，神经元暴露于过量的兴奋性神经递质谷氨酸（称为谷氨酸兴奋性毒性）会导致许多急性和慢性神经疾病中观察到的损伤和变性。然而，炎症也可能在某些神经退行性疾病中起作用，这一点变得越来越明显，并且炎症介质，如肿瘤坏死因子-α（TNF-α），可能直接与兴奋性毒性过程相互作用。在产后大鼠小脑切片模型中，我们发现 TNF-α以剂量依赖的方式加剧了 AMPA 诱导的浦肯野神经元兴奋性毒性，超过了 AMPA 单独引起的毒性。还表明，TNF-α和 AMPA 的组合增加了钙激活半胱氨酸蛋白酶 calpain 的细胞内平均活性，已知 calpain 在浦肯野神经元中导致细胞死亡。此外，这些组合增强了钴内流，这是钙进入的标志物，仅通过钙渗透性 AMPA 受体选择性发生。用特定的拮抗剂 1-萘基乙酰基 spermine（NASPM）对钙渗透性 AMPA 受体进行药理学阻断，逆转了 TNF-α引起的 AMPA 受体钙通透性的明显增加，如钴内流所测量的；降低了浦肯野神经元 calpain 活性；并逆转了 TNF-α和 AMPA 组合诱导的增强的神经变性。从这些研究中我们得出结论，TNF-α通过增加钙渗透性 AMPA 受体的细胞内钙通量来增强 AMPA 诱导的浦肯野神经元毒性，并且这种钙增加直接参与了 calpain 的增强激活和更大比例的浦肯野神经元丧失。
