Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation.
Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation.
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抗炎化合物在人类免疫缺陷病毒 1 糖蛋白 120 介导的脑炎症中的作用。
DOI：
10.1186/1742-2094-11-91
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发表时间：
2014-05-16
影响因子：
9.3
通讯作者：
Bendayan R
中科院分区：
文献类型：
--
作者：
Ashraf T;Jiang W;Hoque MT;Henderson J;Wu C;Bendayan R
神经炎症是与脑人类免疫缺陷病毒-1（HIV-1）感染相关的常见免疫反应。鉴定具有更好的脑渗透性并可以靶向炎症相关信号通路的治疗化合物可能有助于治疗HIV相关的神经系统并发症。本研究的目的是通过大鼠脑室内注射HIV-1病毒外壳蛋白gp 120来建立脑炎症的体内模型，并研究HIV辅助治疗（如米诺环素、氯喹和辛伐他汀）的抗炎特性。雄性Wistar大鼠连续7天，脑室内每天给予单剂量的gp 120 ADA（500 ng），预先腹腔内给予或不给予米诺环素、氯喹或辛伐他汀。在gp 120给药之前，将CCR 5拮抗剂马拉韦罗脑室内给药7天作为对照。使用实时qPCR评估额叶皮质、海马和纹状体中炎症标志物的基因表达。采用酶联免疫吸附法（ELISA）检测脑脊液（CSF）中白细胞介素1β（IL 1β）和肿瘤坏死因子α（TNF α）的分泌。用免疫印迹法检测丝裂原活化蛋白激酶（MAPK）（细胞外信号相关激酶1/2（ERK 1/2）、c-Jun N末端激酶（JNKs）和P38激酶（P38 Ks））的蛋白表达。学生t检验和方差分析用于确定统计学显著性。在注射gp 120 ADA的大鼠中，与注射生理盐水或热灭活gp 120的对照组相比，额叶皮质、纹状体和海马中白细胞介素-1 β（IL-1β）和诱导型一氧化氮合酶（iNOS）的mRNA转录显著升高。在CSF中，检测到TNF-α和IL-1β显著升高。马拉韦罗降低了这些标志物的上调，表明R5-嗜性gp 120与CCR 5趋化因子受体的相互作用对于诱导炎症反应至关重要。米诺环素、氯喹或辛伐他汀可减弱不同脑区IL-1β和iNOS转录本的上调。在CSF中，米诺环素抑制TNF-α和IL-1β的分泌，而氯喹减弱IL-1β的分泌。在注射gp 120的动物中，在海马中观察到ERK 1/2和JNKs的活化，并且ERK 1/2活化被抗炎剂显著降低。我们的数据表明，抗炎化合物可以通过与MAPK信号通路的相互作用完全或部分逆转gp 120相关的脑炎症，并表明它们在预防和治疗HIV相关神经系统并发症方面的潜在作用。
Neuroinflammation is a common immune response associated with brain human immunodeficiency virus-1 (HIV-1) infection. Identifying therapeutic compounds that exhibit better brain permeability and can target signaling pathways involved in inflammation may benefit treatment of HIV-associated neurological complications. The objective of this study was to implement an in vivo model of brain inflammation by intracerebroventricular administration of the HIV-1 viral coat protein gp120 in rats and to examine anti-inflammatory properties of HIV adjuvant therapies such as minocycline, chloroquine and simvastatin. Male Wistar rats were administered a single dose of gp120ADA (500 ng) daily for seven consecutive days, intracerebroventricularly, with or without prior intraperitoneal administration of minocycline, chloroquine or simvastatin. Maraviroc, a CCR5 antagonist, was administered intracerebroventricularly prior to gp120 administration for seven days as control. Real-time qPCR was used to assess gene expression of inflammatory markers in the frontal cortex, hippocampus and striatum. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) secretion in cerebrospinal fluid (CSF) was measured applying ELISA. Protein expression of mitogen-activated protein kinases (MAPKs) (extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs) and P38 kinases (P38Ks)) was detected using immunoblot analysis. Student’s t-test and ANOVA were applied to determine statistical significance. In gp120ADA-injected rats, mRNA transcripts of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) were significantly elevated in the frontal cortex, striatum and hippocampus compared to saline or heat-inactivated gp120-injected controls. In CSF, a significant increase in TNF-α and IL-1β was detected. Maraviroc reduced upregulation of these markers suggesting that the interaction of R5-tropic gp120 to CCR5 chemokine receptor is critical for induction of an inflammatory response. Minocycline, chloroquine or simvastatin attenuated upregulation of IL-1β and iNOS transcripts in different brain regions. In CSF, minocycline suppressed TNF-α and IL-1β secretion, whereas chloroquine attenuated IL-1β secretion. In gp120-injected animals, activation of ERK1/2 and JNKs was observed in the hippocampus and ERK1/2 activation was significantly reduced by the anti-inflammatory agents. Our data demonstrate that anti-inflammatory compounds can completely or partially reverse gp120-associated brain inflammation through an interaction with MAPK signaling pathways and suggest their potential role in contributing towards the prevention and treatment of HIV-associated neurological complications.
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影响因子：
9.3
作者：
Dohgu S;Fleegal-DeMotta MA;Banks WA
通讯作者：
Banks WA
DOI：
10.1016/j.bbapap.2005.08.017
发表时间：
2005-12-30
影响因子：
3.2
作者：
Kaminska, B
通讯作者：
Kaminska, B
DOI：
10.1007/s11481-011-9332-1
发表时间：
2012-06
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Meulendyke KA;Pletnikov MV;Engle EL;Tarwater PM;Graham DR;Zink MC
通讯作者：
Zink MC
影响因子：
3.2
作者：
Heaton, Robert K.;Franklin, Donald R.;Ellis, Ronald J.;McCutchan, J. Allen;Letendre, Scott L.;LeBlanc, Shannon;Corkran, Stephanie H.;Duarte, Nichole A.;Clifford, David B.;Woods, Steven P.;Collier, Ann C.;Marra, Christina M.;Morgello, Susan;Mindt, Monica Rivera;Taylor, Michael J.;Marcotte, Thomas D.;Atkinson, J. Hampton;Wolfson, Tanya;Gelman, Benjamin B.;McArthur, Justin C.;Simpson, David M.;Abramson, Ian;Gamst, Anthony;Fennema-Notestine, Christine;Jernigan, Terry L.;Wong, Joseph;Grant, Igor
通讯作者：
Grant, Igor
DOI：
10.1093/jnen/63.10.1038
发表时间：
2004-10-01
影响因子：
3.2
作者：
Langford, D;Grigorian, A;Masliah, E
通讯作者：
Masliah, E