Modulation of experimental herpes encephalitis-associated neurotoxicity through sulforaphane treatment.
Modulation of experimental herpes encephalitis-associated neurotoxicity through sulforaphane treatment.
复制标题
DOI：
10.1371/journal.pone.0036216
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lokensgard JR
中科院分区：
文献类型：
--
作者：
Schachtele SJ;Hu S;Lokensgard JR
由脑浸润性巨噬细胞和中性粒细胞以及驻留的小胶质细胞产生的活性氧（ROS）对于病毒脑感染期间的病原体清除是关键的。然而，未受抑制的自由基产生也是对原发感染的关键宿主组织旁观者的损伤和细胞毒性的原因。这些不必要的影响，过量的活性氧是打击局部细胞生产的抗氧化酶，包括血红素加氧酶-1（HO-1）和谷胱甘肽过氧化物酶1（Gpx 1）。在这项研究中，我们发现实验性小鼠疱疹脑炎引发了强大的ROS产生，以及抗氧化剂HO-1和Gpx 1的反向上调。这种抗氧化反应不足以防止与病毒性脑感染相关的组织损伤、神经毒性和死亡率。以前的研究证实了我们的数据支持星形胶质细胞作为主要的抗氧化剂生产者在脑细胞培养暴露于HSV-1刺激的小胶质细胞。我们假设，刺激星形胶质细胞以及神经元中的相反抗氧化反应，将减轻体外和体内病毒脑感染期间ROS介导的神经毒性的影响。在这里，我们证明了萝卜硫素，一种有效的抗氧化反应的刺激剂，通过激活核因子E2相关因子2（NRF 2）增强HO-1和Gpx 1在星形胶质细胞中的表达。此外，萝卜硫素治疗被发现有效地减少与HSV刺激的小胶质细胞ROS产生相关的神经毒性。最后，腹腔注射莱菔硫烷到活跃的HSV感染小鼠通过减少脑浸润白细胞，巨噬细胞和嗜中性粒细胞产生的ROS，MHCII阳性，活化的小胶质细胞减少神经炎症。这些数据支持星形胶质细胞产生的抗氧化剂在调节病毒感染引起的氧化应激和神经元损伤中的关键作用。
Reactive oxygen species (ROS) produced by brain-infiltrating macrophages and neutrophils, as well as resident microglia, are pivotal to pathogen clearance during viral brain infection. However, unchecked free radical generation is also responsible for damage to and cytotoxicity of critical host tissue bystander to primary infection. These unwanted effects of excessive ROS are combated by local cellular production of antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutathione peroxidase 1 (Gpx1). In this study, we showed that experimental murine herpes encephalitis triggered robust ROS production, as well as an opposing upregulation of the antioxidants HO-1 and Gpx1. This antioxidant response was insufficient to prevent tissue damage, neurotoxicity, and mortality associated with viral brain infection. Previous studies corroborate our data supporting astrocytes as the major antioxidant producer in brain cell cultures exposed to HSV-1 stimulated microglia. We hypothesized that stimulating opposing antioxidative responses in astrocytes, as well as neurons, would mitigate the effects of ROS-mediated neurotoxicity both in vitro and during viral brain infection in vivo. Here, we demonstrate that the addition of sulforaphane, a potent stimulator of antioxidant responses, enhanced HO-1 and Gpx1 expression in astrocytes through the activation of nuclear factor-E2-related factor 2 (Nrf2). Additionally, sulforaphane treatment was found to be effective in reducing neurotoxicity associated with HSV-stimulated microglial ROS production. Finally, intraperitoneal injections of sulforaphane into mice during active HSV infection reduced neuroinflammation via a decrease in brain-infiltrating leukocytes, macrophage- and neutrophil-produced ROS, and MHCII-positive, activated microglia. These data support a key role for astrocyte-produced antioxidants in modulating oxidative stress and neuronal damage in response to viral infection.
登录
查看更多内容
DOI：
10.3390/molecules15117792
发表时间：
2010-11-03
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Kelsey NA;Wilkins HM;Linseman DA
通讯作者：
Linseman DA
影响因子：
5.1
作者：
Agrawal, L.;Louboutin, J-P;Strayer, D. S.
通讯作者：
Strayer, D. S.
DOI：
10.1073/pnas.0813361106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Chen, Pei-Chun;Vargas, Marcelo R.;Johnson, Jeffrey A.
通讯作者：
Johnson, Jeffrey A.
影响因子：
5.2
作者：
Johnson, Jeffrey A.;Johnson, Delinda A.;Kraft, Andrew D.;Calkins, Marcus J.;Jakel, Rebekah J.;Vargas, Marcelo R.;Chen, Pei-Chun
通讯作者：
Chen, Pei-Chun
影响因子：
6.2
作者：
Hamo, Ludwig;Stohlman, Stephen A.;Bergmann, Cornelia C.
通讯作者：
Bergmann, Cornelia C.