Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis.
Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis.
复制标题
DOI：
10.1186/1742-2094-7-33
复制
发表时间：
2010-06-09
影响因子：
9.3
通讯作者：
Barbeito L
中科院分区：
文献类型：
--
作者：
Gandelman M;Peluffo H;Beckman JS;Cassina P;Barbeito L
在神经系统的病理过程中，细胞外增加的三磷酸腺苷通过P2X7受体作为细胞毒性因子和促炎介质发挥作用。在肌萎缩侧索硬化症(ALS)的动物模型中，表达超氧化物歧化酶1(SOD1G93A)突变的星形胶质细胞表现为神经炎性表型，有助于疾病的进展和运动神经元的死亡。在这里，我们研究了通过P2X7受体作用的细胞外ATP作为神经毒性表型的启动者的作用，这种表型导致非转基因和SOD1G93A星形胶质细胞中星形胶质细胞介导的运动神经元死亡。我们评估了运动神经元与SOD1G93A或非转基因星形胶质细胞共培养后的存活情况，这些非转基因星形胶质细胞经过已知的调节ATP释放或P2X7受体的药物处理。我们还研究了星形胶质细胞的增殖和细胞外ATP的降解。重复受到ATP或P2X7选择性激动剂BzATP的刺激，会导致星形胶质细胞产生神经毒性，导致运动神经元死亡。亮蓝G对ATP和BzATP效应的抑制进一步证实了P2X7受体的参与。在SOD1G93A星形胶质细胞培养中，药物抑制P2X7受体或用apyrase促进细胞外ATP降解足以完全消除它们对运动神经元的毒性。SOD1G93A星形胶质细胞也表现出依赖于ATP的增殖增加和细胞外ATP降解的基础增加。在这里，我们发现，脊髓星形胶质细胞中的P2X7受体激活启动了一种神经毒性表型，导致运动神经元死亡。值得注意的是，SOD1G93A星形胶质细胞的神经毒性表型依赖于基础激活的P2X7受体。因此，药物抑制P2X7受体可能通过星形胶质细胞减轻ALS的神经炎症。
During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X7 receptors. In animal models of amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1G93A) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. Here we studied the role of extracellular ATP acting through P2X7 receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non-transgenic and SOD1G93A astrocytes. We evaluated motor neuron survival after co-culture with SOD1G93A or non-transgenic astrocytes pretreated with agents known to modulate ATP release or P2X7 receptor. We also characterized astrocyte proliferation and extracellular ATP degradation. Repeated stimulation by ATP or the P2X7-selective agonist BzATP caused astrocytes to become neurotoxic, inducing death of motor neurons. Involvement of P2X7 receptor was further confirmed by Brilliant blue G inhibition of ATP and BzATP effects. In SOD1G93A astrocyte cultures, pharmacological inhibition of P2X7 receptor or increased extracellular ATP degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. SOD1G93A astrocytes also displayed increased ATP-dependent proliferation and a basal increase in extracellular ATP degradation. Here we found that P2X7 receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. Remarkably, the neurotoxic phenotype of SOD1G93A astrocytes depended upon basal activation the P2X7 receptor. Thus, pharmacological inhibition of P2X7 receptor might reduce neuroinflammation in ALS through astrocytes.
登录
查看更多内容
影响因子：
5.3
作者：
Cassina, Patricia;Cassina, Adriana;Radi, Rafael
通讯作者：
Radi, Rafael
DOI：
10.1093/jnen/63.7.686
发表时间：
2004-07-01
影响因子：
3.2
作者：
Franke, H;Günther, A;Illes, P
通讯作者：
Illes, P
影响因子：
4.2
作者：
Cassina, P;Peluffo, H;Barbeito, L
通讯作者：
Barbeito, L
影响因子：
5.3
作者：
Matute, Carlos;Torre, Iratxe;Domercq, Maria
通讯作者：
Domercq, Maria
影响因子：
23.9
作者：
Marchetto, Maria C. N.;Muotri, Alysson R.;Gage, Fred H.
通讯作者：
Gage, Fred H.