Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
复制标题
DOI：
10.1016/j.ejphar.2013.12.039
复制
发表时间：
2014-02-05
影响因子：
5
通讯作者：
Matsumoto, Rae R.
中科院分区：
文献类型：
--
作者：
Kaushal, Nidhi;Robson, Matthew J.;Rosen, Abagail;McCurdy, Christopher R.;Matsumoto, Rae R.
暴露于高剂量或重复剂量的甲基苯丙胺可导致高热和神经毒性，这被认为会增加发展各种神经系统疾病的风险。σ受体拮抗剂可以防止甲基苯丙胺诱导的高热和神经毒性，但通过其传递神经保护的潜在细胞靶点仍然未知。分化的NG 108 -15细胞因此被用作模型系统以开始阐明σ受体拮抗剂靶向的神经保护机制以减轻甲基苯丙胺的作用。在分化的NG 108 -15细胞中，甲基苯丙胺引起活性氧/氮物质的产生，PERK介导的内质网应激的增加和半胱天冬酶-3，8和9的活化，最终导致微摩尔浓度的细胞凋亡，以及更高浓度的坏死细胞死亡。σ受体拮抗剂6-乙酰基-3-（4-（4-（4-氟苯基）哌嗪-1-基）丁基）苯并[d]恶唑-2（3 H）-酮（SN 79）减弱甲基苯丙胺诱导的活性氧/氮物质增加、半胱天冬酶-3、半胱天冬酶-8和半胱天冬酶-9的活化以及伴随的细胞毒性。相比之下，1，3-二（2-甲苯基）-胍（DTG），σ受体激动剂，甲基苯丙胺诱导的细胞死亡的剂量反应曲线向左移动。为了探测温度对神经毒性的影响，与维持在正常细胞培养温度（37 °C）下的细胞相比，维持在升高的温度（40 °C）下的NG 108 -15细胞表现出响应于甲基苯丙胺的细胞死亡的显著和协同增加。SN 79减弱了在40 °C下甲基苯丙胺处理的细胞中观察到的增强的细胞死亡。总之，数据表明，SN 79减少甲基苯丙胺诱导的活性氧/氮物质的产生和半胱天冬酶的活化，从而在常规和升高的温度条件下传递针对甲基苯丙胺的神经保护作用。
Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3,-8 and-9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions.
登录
查看更多内容
影响因子：
4.7
作者：
Kaushal, Nidhi;Seminerio, Michael J.;Shaikh, Jamaluddin;Medina, Mark A.;Mesangeau, Christophe;Wilson, Lisa L.;McCurdy, Christopher R.;Matsumoto, Rae R.
通讯作者：
Matsumoto, Rae R.
影响因子：
3.6
作者：
Kaushal, Nidhi;Elliott, Meenal;Matsumoto, Rae R.
通讯作者：
Matsumoto, Rae R.
影响因子：
5.3
作者：
Kaushal N;Matsumoto RR
通讯作者：
Matsumoto RR
影响因子：
4.7
作者：
Jiang, Yu-Gang;Peng, Yong;Koussougbo, Koku Sossou
通讯作者：
Koussougbo, Koku Sossou
影响因子：
37.3
作者：
Hornick, John R.;Xu, Jinbin;Hawkins, William G.
通讯作者：
Hawkins, William G.