BACKGROUND & AIMS: :Ischemic stroke is one of the leading causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes of ischemic stroke, non-coding RNAs (ncRNAs) have received attention in the past decades. ncRNAs are a class of functional RNAs that regulate gene expression in a post-transcriptional manner, and including microRNAs, long non-coding RNAs, and circular RNAs. Several studies have deciphered that ncRNAs have a key role in the ischemic stroke-induced neuroinflammation and cell death via different molecules and pathways. Thus, ncRNAs show great promise as novel molecular targets in ischemic stroke. In this article, we provide an updated review of the current state of our knowledge about the roles of different types of ncRNAs in neuroinflammation and cell death following ischemic stroke, which may facilitate the translation of ncRNAs research into clinical practice to improve the clinical outcome of stroke therapy.

背景与目标： ：缺血性中风是全球死亡和长期残疾的主要原因之一。作为缺血性中风的许多病理生理过程中涉及的一类重要的普及基因，非编码RNA（ncRNA）在过去的几十年中受到关注。 ncRNA是一类以转录后方式调节基因表达的功能性RNA，包括microRNA，长非编码RNA和环状RNA。几项研究已经证明，ncRNA通过不同的分子和途径在缺血性中风诱发的神经炎症和细胞死亡中具有关键作用。因此，ncRNA作为缺血性卒中的新型分子靶标显示出巨大的希望。在本文中，我们提供了有关不同类型ncRNA在缺血性中风后神经炎症和细胞死亡中作用的知识的最新状态的最新综述，这可能有助于将ncRNAs研究转化为临床实践，以改善ncRNA的临床疗效中风疗法。

BACKGROUND & AIMS: :Cerebrovascular dysfunction contributes to the pathology and progression of Alzheimer's disease (AD), but the mechanisms are not completely understood. Using transgenic mouse models of AD (TgCRND8, PDAPP, and Tg2576), we evaluated blood-brain barrier damage and the role of fibrin and fibrinolysis in the progression of amyloid-beta pathology. These mouse models showed age-dependent fibrin deposition coincident with areas of blood-brain barrier permeability as demonstrated by Evans blue extravasation. Three lines of evidence suggest that fibrin contributes to the pathology. First, AD mice with only one functional plasminogen gene, and therefore with reduced fibrinolysis, have increased neurovascular damage relative to AD mice. Conversely, AD mice with only one functional fibrinogen gene have decreased blood-brain barrier damage. Second, treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, whereas removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology. Third, pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest that fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD.

背景与目标： ：脑血管功能障碍有助于阿尔茨海默氏病（AD）的病理和进展，但其机制尚不完全清楚。使用AD的转基因小鼠模型（TgCRND8，PDAPP和Tg2576），我们评估了血脑屏障损伤以及纤维蛋白和纤维蛋白溶解在淀粉样β病理学进展中的作用。这些小鼠模型显示出年龄依赖性的纤维蛋白沉积与血脑屏障通透性区域一致，如埃文斯蓝外渗所证明。三行证据表明纤维蛋白有助于病理。首先，相对于AD小鼠，仅具有一个功能性纤溶酶原基因的AD小鼠因此具有降低的纤维蛋白溶解作用，其神经血管损伤增加。相反，仅具有一个功能性纤维蛋白原基因的AD小鼠血脑屏障损害减少。第二，用纤溶酶抑制剂氨甲环酸治疗AD小鼠会加剧病理，而用ancrod处理从AD小鼠的循环中去除纤维蛋白原会减弱神经炎症和血管病理的测量。第三，用ancrod预处理减少了因纤溶酶抑制引起的病理增加。这些结果表明纤维蛋白是炎症的介质，并且可能阻碍AD中神经血管损伤的修复过程。纤维蛋白及其参与累积和清除的机制可能会提出新的治疗靶点，以减缓AD的进程。

BACKGROUND & AIMS: :The central nervous system (CNS) presents both challenges and opportunities to researchers of redox biochemistry. The CNS is sensitive to oxidative damage during aging or disease; excellent transgenic models of specific neurodegenerative diseases have been created that reproduce oxidative stress components of the corresponding human disorder. Mouse models of familial amyotrophic lateral sclerosis (ALS) based on overexpressed mutant human Cu, Zn-superoxide dismutase (SOD1) are cases in point. These animals experience predictably staged, age-dependent motor neuron degeneration with profound cellular and biochemical damage to nerve fibers and spinal cord tissue. Severe protein and lipid oxidation occurs in these animals, apparently as an indirect consequence of protein aggregation or cytopathic protein-protein interactions, as opposed to aberrant redox catalysis by the mutant enzyme. Recent studies of G93A-SOD1 mice and rats suggest that oxidative damage is part of an unmitigated neuroinflammatory reaction, possibly arising in combination from mitochondrial dysfunction plus pathophysiologic activation of both astrocytes and microglia. Lesions to redox signal-transduction pathways in mutant SOD1+ glial cells may stimulate broad-spectrum upregulation of proinflammatory genes, including arachidonic acid-metabolizing enzymes [e.g., cyclooxygenase-II (COX-II) and 5-lipoxygenase (5LOX)]; nitric oxide synthase (NOS) isoforms; cytokines (particularly tumor necrosis factor alpha, TNF-alpha); chemokines; and immunoglobulin Fc receptors (FcgammaRs). The integration of these processes creates a paracrine milieu inconsistent with healthy neural function. This review summarizes what has been learned to date from studies of mutant SOD1 transgenic animals and demonstrates that the G93A-SOD1 mouse in particular is a robust laboratory for the study of neuroinflammation and redox biochemistry.

背景与目标： ：中枢神经系统（CNS）给氧化还原生物化学研究人员既带来挑战，也带来机遇。中枢神经系统对衰老或疾病期间的氧化损伤敏感；已经建立了特定神经退行性疾病的优秀转基因模型，可以复制相应人类疾病的氧化应激成分。基于过度表达的突变型人铜，锌超氧化物歧化酶（SOD1）的家族性肌萎缩性侧索硬化症（ALS）的小鼠模型就是一个很好的例子。这些动物经历了阶段性的，年龄依赖性的运动神经元变性，并对神经纤维和脊髓组织造成了严重的细胞和生化损伤。与这些突变酶异常的氧化还原催化相反，这些动物中发生严重的蛋白质和脂质氧化，这显然是蛋白质聚集或细胞病变性蛋白质-蛋白质相互作用的间接结果。对G93A-SOD1小鼠和大鼠的最新研究表明，氧化损伤是未减轻的神经炎症反应的一部分，可能是由线粒体功能障碍以及星形胶质细胞和小胶质细胞的病理生理激活共同引起的。突变型SOD1神经胶质细胞中氧化还原信号传导途径的损伤可能会刺激促炎基因的广谱上调，包括花生四烯酸代谢酶[例如，环氧合酶II（COX-II）和5-脂氧合酶（5LOX）]；一氧化氮合酶（NOS）亚型；细胞因子（尤其是肿瘤坏死因子α，TNF-α）；趋化因子和免疫球蛋白Fc受体（FcgammaRs）。这些过程的整合产生了与健康的神经功能不一致的旁分泌环境。这篇综述总结了迄今为止从突变SOD1转基因动物的研究中学到的内容，并证明了G93A-SOD1小鼠特别是用于研究神经炎症和氧化还原生物化学的强大实验室。

BACKGROUND & AIMS: :Inflammation and gut dysbiosis are hallmarks of hypertension (HTN). Hydrogen sulfide (H2S) is an important freely diffusing molecule that modulates the function of neural, cardiovascular and immune systems, and circulating levels of H2S are reduced in animals and humans with HTN. While most research to date has focused on H₂S produced endogenously by the host, H2S is also produced by the gut bacteria and may affect the host homeostasis. Here, we review an association between neuroinflammation and gut dysbiosis in HTN, with special emphasis on a potential role of H2S in this interplay.

背景与目标： ：发炎和肠道营养不良是高血压（HTN）的标志。硫化氢（H2S）是一种重要的自由扩散分子，可调节神经，心血管和免疫系统的功能，在患有HTN的动物和人类中，H2S的循环水平降低。迄今为止，大多数研究都集中在宿主内源性产生的H 2 S上，而H 2 S也是由肠道细菌产生的，并可能影响宿主体内的稳态。在这里，我们审查了HTN中神经炎症与肠道营养不良之间的关联，并特别强调了H2S在这种相互作用中的潜在作用。

BACKGROUND & AIMS: :This study examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with neurodegenerative diseases We also monitored the appearance of a glial cell line-derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) levels, as well as an immune system-associated cells in a selected area of the brain, the olfactory lobe. The studies were based on the hypothesis that LPS treatment stimulates temporal changes within the brain and that these responses include immune cell recruitment, increased tissue levels of immune modulating cytokines and NO, as well as greater glial cell activation resulting in increased production of GDNF. As previously reported by other investigators, our animal model of systemic LPS treatment leads to an increase in the concentrations of circulating cytokines, including TNF-α, IL-Iβ, and IL-6, with a maximum response 6 h post LPS administration. Concomitant with cytokine elevations, circulating NO levels were elevated for several hours post LPS administration. The brain content of the GDNF was also elevated over a similar time frame. Lymphocytes, neutrophils, macrophages, plasma cells, and cytokines were all seen in various areas of LPS-treated brains, often around blood vessels associated with the meninges, with these localizations possibly indicating involvement of both the blood-brain and blood-cerebral spinal fluid barriers in these inflammatory episodes. Our results suggest an involvement of both the peripheral and the central nervous system immune components in response to inflammation and inflammatory episodes. This leads us to propose that inflammation initiates an immune response by activating both microglia and astrocytes and that the presence of continuing and increasing proinflammatory mechanisms results in a situation, where cellular protective mechanisms are overcome and the more susceptible cells enter into cell death pathways, initiating a train of events that is a major part of neurodegeneration.

背景与目标： ：这项研究检查了脂多糖（LPS）处理的大鼠模型在脑组织中炎性细胞和细胞因子的产生，该模型模拟了许多与神经退行性疾病相关的神经病理变化。我们还监测了神经胶质细胞系衍生的神经营养因子（GDNF）的出现和循环的一氧化氮（NO）水平，以及大脑的选定区域（嗅觉叶）中与免疫系统相关的细胞。这些研究基于以下假设：LPS治疗会刺激大脑内的时间变化，并且这些反应包括免疫细胞募集，免疫调节细胞因子和NO的组织水平增加以及神经胶质细胞活化增加，从而导致GDNF产生增加。正如其他研究人员先前报道的那样，我们的系统性LPS治疗动物模型导致循环细胞因子（包括TNF-α，IL-Iβ和IL-6）的浓度增加，在LPS给药后6小时达到最大反应。 LPS给药后数小时，伴随细胞因子升高，循环NO水平升高。 GDNF的大脑含量在相似的时间范围内也有所升高。在接受LPS治疗的大脑的各个区域（通常是与脑膜相关的血管周围）都可以看到淋巴细胞，嗜中性粒细胞，巨噬细胞，浆细胞和细胞因子，这些定位可能表明血脑和脑脊髓液都参与了这些炎症发作的障碍。我们的结果表明，外周和中枢神经系统免疫成分都参与了对炎症和炎症发作的反应。这导致我们提出炎症通过激活小胶质细胞和星形胶质细胞来启动免疫反应，并且持续不断增加的促炎机制的存在导致细胞保护机制被克服，更易感的细胞进入细胞死亡途径的情况开始。一连串的事件，是神经退行性疾病的主要部分。

BACKGROUND & AIMS: :Although, current medications for Parkinson's disease can control and relief symptoms of the disease efficiently, they are unable to either prevent progression of the disease or maintain their controlling ability as a long-term medication. To find suitable adjuvant and/or alternative treatments, researchers have investigated antioxidative and anti-inflammatory approaches, since emerging evidence consider oxidative stress and neuroinflammation as leading causes of the development of Parkinson's disease. Here, how oxidative stress and neuroinflammation take part in Parkinson's disease pathogenesis was discussed based on featured studies in this context. Then, preclinical and clinical trial studies, which evaluated antioxidative and anti-inflammatory compounds' ability to treat Parkinson's disease, were reviewed.

背景与目标： ：尽管目前用于帕金森氏病的药物可以有效控制和缓解疾病的症状，但它们不能预防疾病的进展或不能作为长期药物来维持其控制能力。为了找到合适的佐剂和/或替代疗法，研究人员研究了抗氧化和抗炎的方法，因为越来越多的证据认为氧化应激和神经炎症是帕金森氏病发展的主要原因。在此，基于此背景下的特色研究，讨论了氧化应激和神经炎症如何参与帕金森氏病的发病机理。然后，回顾了临床前和临床试验研究，评估了抗氧化和抗炎化合物治疗帕金森氏病的能力。

BACKGROUND & AIMS: :High dietary salt intake increases risk of stress-related neuropsychiatric disorders. Here, we explored the contribution of high dietary salt intake-induced neuroinflammation in key stress-responsive brain regions, the hypothalamic paraventricular nucleus and basolateral amygdala, in promoting exaggerated neuronal activation and coping behaviors in response to acute psychogenic stress. Mice that underwent high dietary salt intake exhibited increased active stress coping behaviors during and after an acute swim stress, and these were reduced by concurrent administration of minocycline, an inhibitor of microglial activation, without affecting body fluid hyperosmolality caused by high dietary salt intake. Moreover, minocycline attenuated high dietary salt intake-induced increases of paraventricular nucleus tumor necrosis factor-α, activated microglia (ionized calcium-binding adaptor molecule 1), and acute swim stress-induced neuronal activation (c-Fos). In the basolateral amygdala, similar effects were observed on ionized calcium-binding adaptor molecule 1+ and c-Fos+ counts, but not tumor necrosis factor-α levels. These data indicate that high dietary salt intake promotes neuroinflammation, increasing recruitment of neurons in key stress-associated brain regions and augmenting behavioral hyper-responsivity to acute psychological stress.

背景与目标： ：高饮食盐摄入量会增加与压力有​​关的神经精神疾病的风险。在这里，我们探讨了高饮食盐摄入引起的神经炎症在关键的应激反应脑区域，下丘脑室旁核和基底外侧杏仁核中的作用，以促进过度的神经元活化和应对急性精神压力的应对行为。高饮食饮食盐摄入量的小鼠在急性游泳应激期间和之后表现出增加的主动应激应对行为，并且通过同时施用小胶质细胞活化抑制剂米诺环素而减少了这些行为，而不会影响高饮食饮食盐摄入引起的体液高渗。此外，米诺环素减弱高饮食盐摄入量引起的脑室旁核肿瘤坏死因子-α，活化的小胶质细胞（离子化钙结合衔接分子1）和急性游泳应激诱导的神经元活化（c-Fos）的增加。在基底外侧杏仁核中，对电离的钙结合衔接子分子1和c-Fos计数观察到相似的作用，但未观察到肿瘤坏死因子-α水平。这些数据表明，高盐饮食摄入会促进神经炎症，增加关键应激相关脑区神经元的募集，并增强对急性心理应激的行为高反应性。

BACKGROUND & AIMS: :Geniposidic acid (GPA) is an extract from Eucommia ulmoides Oliv. Bark (Eucommiaceae). Accumulating evidences have reported GPA has anti-aging, anti-oxidative stress, anti-inflammatory and neurotrophic effects on neurons. However, whether GPA could alleviate memory deficits in Alzheimer's disease animal models is not clear. We aimed to investigate the effect of GPA treatment on cognitive performance, Aβ deposition and glial cells activation in the transgenic mouse model of AD. 6-7 months APP/PS1 mice were given GPA for 90 days; behavioral experiments were executed to estimate the memory and spatial learning abilities of mice, and the mechanism of neuroprotective effect of GPA was investigated with a focus on amyloid-β deposition, astrocytes and microglia activation and neuroinflammation. GPA treatment significantly improved the spatial learning and memory abilities and also decreased cerebral amyloid-β deposition in APP/PS1 mice. Via HE staining, we found that GPA could ameliorate histopathological changes in cerebrum. We also found that GPA treatment inhibited the activation of astrocytes and microglia, down-regulated the expression of pro-inflammatory cytokines and iNOS, and up-regulated the expression of anti-inflammatory cytokines and Arg-1. In addition, GPA down-regulated the gene expression of HMGB-1 receptors (TLR2, TLR4 and RAGE) then mediated MyD88, TRAF6 and phospho-ERK1/2, subsequently modulated the expression of key AP-1 and NF-κB family members (c-Fos, c-Jun and p65). The reversal of the pro-inflammatory state suggested GPA can serves as a multi-target candidate by alleviating Aβ deposition and neuroinflammation for the auxiliary therapy of Alzheimer's disease.

背景与目标： ：Geniposidicic acid（GPA）是杜仲杜仲的提取物。树皮（杜仲科）。越来越多的证据表明，GPA对神经元具有抗衰老，抗氧化应激，抗炎和神经营养作用。但是，GPA是否可以减轻阿尔茨海默氏病动物模型中的记忆缺陷尚不清楚。我们旨在研究GPA处理对AD转基因小鼠模型中认知能力，Aβ沉积和神经胶质细胞活化的影响。 6-7个月对APP / PS1小鼠给予GPA 90天；进行行为实验以估计小鼠的记忆和空间学习能力，并研究了GPA的神经保护作用机理，重点是淀粉样β沉积，星形胶质细胞和小胶质细胞活化以及神经炎症。 GPA处理显着改善了空间学习和记忆能力，还减少了APP / PS1小鼠的脑淀粉样β沉积。通过HE染色，我们发现GPA可以改善大脑的组织病理学变化。我们还发现，GPA治疗可抑制星形胶质细胞和小胶质细胞的活化，下调促炎性细胞因子和iNOS的表达，并上调抗炎性细胞因子和Arg-1的表达。此外，GPA下调HMGB-1受体（TLR2，TLR4和RAGE）的基因表达，然后介导MyD88，TRAF6和磷酸化ERK1 / 2，随后调节关键AP-1和NF-κB家族成员的表达（ c-Fos，c-Jun和p65）。促炎状态的逆转提示，GPA可以通过减轻Aβ沉积和神经炎症来作为阿尔茨海默氏病的辅助疗法，从而成为多靶点候选药物。

BACKGROUND & AIMS: :Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer's Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

背景与目标： ：醛脱氢酶2缺乏症（ALDH2 * 2）约5.6亿东亚人因饮酒而面部潮红。最近的荟萃分析表明，ALDH2 * 2突变与阿尔茨海默氏病（AD）之间存在潜在的联系。其他研究将长期饮酒与AD的危险因素联系起来。在本研究中，我们显示，AD患者的成纤维细胞在具有ApoEε4等位基因的AD患者的成纤维细胞中也具有ALDH2 * 2突变或ALDH2 * 2的过表达，表现出乙醛负荷增加，氧化应激和线粒体功能障碍相对性增加对健康受试者的治疗和暴露于乙醇会加剧这些功能障碍。在体内模型中，野生型小鼠每天暴露于乙醇达11周后会导致线粒体功能障碍，大脑中的氧化应激和醛水平升高，并且这些疾病在ALDH2 * 2 / * 2（纯合子）小鼠中更大。慢性乙醇暴露后，相对于野生型，ALDH2 * 2 / * 2小鼠的大脑中AD相关蛋白，淀粉样β-淀粉样蛋白和神经炎症的水平更高。相对于野生型WT小鼠的神经元或星形胶质细胞的反应，培养的ALDH2 * 2 / * 2小鼠的初级皮层神经元对乙醇的敏感性增加，并且其初级星形胶质细胞的活化更大。重要的是，ALDH2和ALDH2 * 2的激活剂Alda-1抑制了乙醇诱导的Aβ升高以及体内外的神经炎症。这些数据表明醛，特别是乙醇衍生的乙醛的代谢障碍是AD相关病理的一个原因，并突显了普通人群，尤其是携带ALDH2 * 2突变的东亚人的饮酒风险。

BACKGROUND & AIMS: :Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS.

背景与目标： 模式识别受体（PRRs）对于感染和组织损伤的反应至关重要。然而，它们在自身免疫中的作用尚不清楚。本文中，我们证明2 C型凝集素受体（CLR）Mcl和Mincle在实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症（MS）的动物模型）的发病机理中起重要作用。在骨髓细胞上表达较低水平的Mcl和Mincle的同类大鼠表现出EAE发生率的大幅降低。 Mcl和Mincle的体内沉默或它们的内源性配体SAP130的沉默表明，这些受体在中枢神经系统中的表达对于T细胞募集和重新活化成致病性Th17 / GM-CSF表型至关重要。与此相一致，我们在MS患者的脑部病变中发现了表达MCL和MINCLE的细胞，我们还发现MCL / MINCLE信号通路的上调和MCL / MINCLE刺激后MS患者外周血单核细胞中的应答增加。总之，这些数据支持CLR在自身免疫中的作用，并暗示MCL / MINCLE途径是MS中潜在的治疗靶点。

BACKGROUND & AIMS: :It has been hypothesized that neuroinflammation triggered during brain development can alter brain functions later in life. We investigated the contribution of inflammation to the alteration of normal brain circuitries in the context of neuroexcitotoxicity following neonatal ventral hippocampal lesions in rats with ibotenic acid, an NMDA glutamate receptor agonist. Excitotoxic ibotenic acid lesions led to a significant and persistent astrogliosis and microglial activation, associated with the production of inflammatory mediators. This response was accompanied by a significant increase in metabotropic glutamate receptor type 5 (mGluR5) expression within two distinct neuroinflammatory cell types; astrocytes and microglia. The participation of inflammation to the neurotoxin-induced lesion was further supported by the prevention of hippocampal neuronal loss, glial mGluR5 expression and some of the behavioral perturbations associated to the excitotoxic lesion by concurrent anti-inflammatory treatment with minocycline. These results indicate that neuroinflammation significantly contributes to long-lasting excitotoxic effects of the neurotoxin and to some behavioral phenotypes associated with this model. Thus, the control of the inflammatory response may prevent the deleterious effects of excitotoxic processes that are triggered during brain development, limiting the risk to develop some of the behavioral manifestations related to these processes in adulthood.

背景与目标： ：已经假设在大脑发育过程中触发的神经炎症会在以后的生活中改变大脑的功能。我们调查了NMDA谷氨酸受体激动剂ibotenic acid大鼠新生腹侧海马区损伤后神经兴奋性中神经兴奋毒性对炎症对正常脑回路改变的影响。兴奋性的阿波替尼酸损害导致明显的持续性星形胶质细胞增生和小胶质细胞活化，并伴有炎性介质的产生。这种反应伴随着两种不同的神经炎性细胞类型中代谢型谷氨酸受体5（mGluR5）表达的显着增加。星形胶质细胞和小胶质细胞。通过同时给予米诺环素抗炎治疗，预防海马神经元丢失，神经胶质mGluR5表达以及与兴奋性毒性病变相关的一些行为扰动，进一步支持了炎症参与神经毒素诱导的病变。这些结果表明，神经炎症极大地促进了神经毒素的持久兴奋性毒性作用以及与该模型有关的某些行为表型。因此，炎症反应的控制可以防止在大脑发育过程中触发的兴奋性毒性过程的有害影响，从而限制了在成年期发展出与这些过程有关的某些行为表现的风险。

BACKGROUND & AIMS: :Multiple system atrophy (MSA) is a fatal disorder with no effective treatment. MSA pathology is characterized by α-synuclein (aSyn) accumulation in oligodendrocytes, the myelinating glial cells of the central nervous system (CNS). aSyn accumulation in oligodendrocytes forms the pathognomonic glial cytoplasmic inclusions (GCIs) of MSA. MSA aSyn pathology is also associated with motor and autonomic dysfunction, including an impaired ability to sweat. MSA patients have abnormal CNS expression of glial-cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Our prior studies using the parent compound FTY720, a food and drug administration (FDA) approved immunosuppressive for multiple sclerosis, reveal that FTY720 protects parkinsonian mice by increasing BDNF. Our FTY720-derivative, FTY720-Mitoxy, is known to increase expression of oligodendrocyte BDNF, GDNF, and nerve growth factor (NGF) but does not reduce levels of circulating lymphocytes as it is not phosphorylated so cannot modulate sphingosine 1 phosphate receptors (S1PRs). To preclinically assess FTY720-Mitoxy for MSA, we used mice expressing human aSyn in oligodendrocytes under a 2,' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter. CNP-aSyn transgenic (Tg) mice develop motor dysfunction between 7 and 9 mo, and progressive GCI pathology. Using liquid chromatography-mass spectrometry (LC-MS/MS) and enzymatic assays, we confirmed that FTY720-Mitoxy was stable and active. Vehicle or FTY720-Mitoxy (1.1 mg/kg/day) was delivered to wild type (WT) or Tg littermates from 8.5-11.5 mo by osmotic pump. We behaviorally assessed their movement by rotarod and sweat production by starch‑iodine test. Postmortem tissues were evaluated by qPCR for BDNF, GDNF, NGF and GDNF-receptor RET mRNA and for aSyn, BDNF, GDNF, and Iba1 protein by immunoblot. MicroRNAs (miRNAs) were also assessed by qPCR. FTY720-Mitoxy normalized movement, sweat function and soleus muscle mass in 11.5 mo Tg MSA mice. FTY720-Mitoxy also increased levels of brain GDNF and reduced brain miR-96-5p, a miRNA that acts to decrease GDNF expression. Moreover, FTY720-Mitoxy blocked aSyn pathology measured by sequential protein extraction and immunoblot, and microglial activation assessed by immunohistochemistry and immunoblot. In the 3-nitropropionic acid (3NP) toxin model of MSA, FTY720-Mitoxy protected movement and mitochondria in WT and CNP-aSyn Tg littermates. Our data confirm potent in vivo protection by FTY720-Mitoxy, supporting its further evaluation as a potential therapy for MSA and related synucleinopathies.

背景与目标： ：多系统萎缩症（MSA）是一种致命疾病，没有有效的治疗方法。 MSA病理学的特征是α-突触核蛋白（aSyn）在少突胶质细胞（中枢神经系统（CNS）的髓质胶质细胞）中积累。 aSyn在少突胶质细胞中的积累形成了MSA的病原性胶质细胞质包涵体（GCI）。 MSA aSyn病理还与运动和自主神经功能障碍有关，包括出汗能力受损。 MSA患者的神经胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的CNS表达异常。我们先前使用的母体化合物FTY720（食品和药物管理局（FDA）批准用于多发性硬化症的免疫抑制剂）进行的研究表明，FTY720通过增加BDNF来保护帕金森氏症小鼠。我们的FTY720衍生物FTY720-Mitoxy可增加少突胶质细胞BDNF，GDNF和神经生长因子（NGF）的表达，但不会降低循环淋巴细胞的水平，因为它没有被磷酸化，因此无法调节鞘氨醇1磷酸受体（S1PRs） 。为了临床前评估FTY720-Mitoxy的MSA，我们使用了在2''3'-环核苷酸3'-磷酸二酯酶（CNP）启动子下在少突胶质细胞中表达人aSyn的小鼠。 CNP-aSyn转基因（Tg）小鼠在7到9个月之间发展运动功能障碍，并出现进行性GCI病理。使用液相色谱-质谱（LC-MS / MS）和酶促测定，我们确认FTY720-Mitoxy是稳定和活跃的。通过渗透泵将媒介物或FTY720-三甲氧基（1.1mg / kg /天）从8.5-11.5mo递送至野生型（WT）或Tg同窝幼仔。我们通过淀粉碘试验通过轮转仪和汗液产生行为评估了它们的运动。通过qPCR评估死后组织的BDNF，GDNF，NGF和GDNF受体RET mRNA，并通过免疫印迹评估aSyn，BDNF，GDNF和Iba1蛋白。还通过qPCR评估了MicroRNA（miRNA）。 FTY720-Mitoxy使11.5 mo Tg MSA小鼠的运动，汗液功能和比目鱼肌质量正常化。 FTY720-Mitoxy还增加了大脑GDNF的水平，并减少了大脑miR-96-5p（一种可降低GDNF表达的miRNA）。此外，FTY720-Mitoxy阻断了通过顺序蛋白质提取和免疫印迹测定的aSyn病理，并通过免疫组织化学和免疫印迹评估了小胶质细胞的活化。在MSA的3-硝基丙酸（3NP）毒素模型中，FTY720-Mitoxy保护了WT和CNP-aSyn Tg同窝仔的运动和线粒体。我们的数据证实了FTY720-Mitoxy在体内具有有效的保护作用，支持其进一步评估为MSA和相关突触核蛋白病的潜在疗法。

BACKGROUND & AIMS: BACKGROUND:Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Previous studies demonstrate that miR-429 is up-regulated in the brain lesions of TBI mice, while its role in regulating neuroinflammation and brain injury remains largely unknown. METHOD:The expression of miR-429 in LPS-activated microglia and microglia in TBI model was detected by RT-PCR. The effects of miR-429 inhibitors on LPS-activated microglia in vitro as well as neurological recovery and post-traumatic neuroinflammatory response in TBI model mice were detected in vivo. RESULTS:LPS and TBI significantly induce the up-expression of miR-429, inflammatory cytokines, MAPK-p38 and phosphorylated NF-κB in microglia, which were all inhibited by miR-429 inhibitors. Meanwhile, miR-429 inhibitors also attenuated the neurological impairment in TBI mice. Bioinformatics analysis showed that miR-429 could target and inhibit the expression of dual specificity protein phosphatase 1 (DUSP1), thus inhibiting the expression of MAPK-p38 and phosphorylated NF-κB. CONCLUSION:miR-429 plays a pro-inflammatory role in activated microglia by targeting DUSP1 signaling pathway. Inhibiting miR-429 can attenuate the inflammatory response of microglia and TBI-mediated brain damage.

背景与目标： 背景：神经炎症是创伤性脑损伤（TBI）的常见治疗靶点，因为它可导致延迟的继发性细胞死亡，并且有可能在最初的伤害后数年内发生。先前的研究表明，miR-429在TBI小鼠的脑损伤中被上调，而其在调节神经炎症和脑损伤中的作用仍然未知。
方法：采用RT-PCR技术检测miR-429在LPS激活的小胶质细胞和TBI模型小胶质细胞中的表达。体内检测到miR-429抑制剂对LPS激活的小胶质细胞的作用以及TBI模型小鼠的神经功能恢复和创伤后神经炎症反应。
结果：LPS和TBI显着诱导小胶质细胞中miR-429，炎性细胞因子，MAPK-p38和磷酸化NF-κB的表达，均被miR-429抑制剂抑制。同时，miR-429抑制剂也减轻了TBI小鼠的神经功能损害。生物信息学分析表明，miR-429可以靶向并抑制双重特异性蛋白磷酸酶1（DUSP1）的表达，从而抑制MAPK-p38和磷酸化的NF-κB的表达。
结论：miR-429通过靶向DUSP1信号通路在活化的小胶质细胞中起促炎作用。抑制miR-429可以减弱小胶质细胞的炎症反应和TBI介导的脑损伤。

BACKGROUND & AIMS: :Glucagon-like peptide-1 (GLP-1) is a hormone mainly secreted from enteroendocrine L cells. GLP-1 and its receptor are also expressed in the brain. GLP-1 signaling has pivotal roles in regulating neuroinflammation and memory function, but it is unclear how GLP-1 improves memory function by regulating neuroinflammation. Here, we demonstrated that GLP-1 enhances neural structure by inhibiting lipopolysaccharide (LPS)-induced inflammation in microglia with the effects of GLP-1 itself on neurons. Inflammatory secretions of BV-2 microglia by LPS aggravated mitochondrial function and cell survival, as well as neural structure in Neuro-2a neurons. In inflammatory condition, GLP-1 suppressed the secretion of tumor necrosis factor-alpha (TNF-α)-associated cytokines and chemokines in BV-2 microglia and ultimately enhanced neurite complexity (neurite length, number of neurites from soma, and secondary branches) in Neuro-2a neurons. We confirmed that GLP-1 improves neurite complexity, dendritic spine morphogenesis, and spine development in TNF-α-treated primary cortical neurons based on altered expression levels of the factors related to neurite growth and spine morphology. Given that our data that GLP-1 itself enhances neurite complexity and spine morphology in neurons, we suggest that GLP-1 has a therapeutic potential in central nervous system diseases.

背景与目标： ：胰高血糖素样肽1（GLP-1）是一种主要从肠内分泌L细胞分泌的激素。 GLP-1及其受体也在大脑中表达。 GLP-1信号在调节神经炎症和记忆功能中起着关键作用，但目前尚不清楚GLP-1如何通过调节神经炎症来改善记忆功能。在这里，我们证明了GLP-1通过抑制脂多糖（LPS）诱导的小胶质细胞炎症增强了神经结构，其中GLP-1本身对神经元有影响。 LPS引起的BV-2小胶质细胞的炎性分泌物加剧了线粒体功能和细胞存活，以及Neuro-2a神经元的神经结构。在炎症状态下，GLP-1抑制了BV-2小胶质细胞中与肿瘤坏死因子-α（TNF-α）相关的细胞因子和趋化因子的分泌，并最终增强了神经突的复杂性（神经突的长度，来自体细胞的神经突的数量以及次级分支）。在Neuro-2a神经元中。我们证实，基于与神经突生长和脊柱形态有关的因子的表达水平改变，GLP-1可改善TNF-α治疗的原代皮层神经元的神经突复杂性，树突状棘形态和脊柱发育。鉴于我们的数据表明GLP-1本身会增强神经元的神经突复杂性和脊柱形态，因此我们建议GLP-1在中枢神经系统疾病中具有治疗潜力。

BACKGROUND & AIMS: :Alzheimer's disease is a chronic neurological ailment that seriously threatens human health and imposes a huge burden on families and the society at large. Emerging evidence suggests that neuroinflammation is an important pathological manifestation of neurodegenerative diseases, and currently considered a new research target. We previously found that artemisinin B from Artemisia annua Linn. has strong anti-inflammatory and immunological activities. In the present study, we assessed the anti-neuroinflammatory effects of artemisinin B in vitro and in vivo, exploring the underlying mechanisms. The results demonstrated that artemisinin B inhibited NO secretion from LPS-induced BV2 cells and significantly reduced the expression levels of the inflammatory cytokines IL-1β, IL-6 and TNF-α. This was accompanied by reduced gene expression levels of MyD88 and NF-κB as well as TLR4 and MyD88 protein levels. These inhibitory effects were further confirmed in AD model mice. This study also showed that artemisinin B improved spatial memory in dementia mice in the water maze and step-through tests, and altered the pathological features and the levels of inflammatory cytokines in the hippocampus and the cortex. These results suggested that artemisinin B might inhibit neuroinflammation and exert neuroprotective effects on cognitive functions by modulating the TLR4-MyD88-NF-κB signaling pathway. This study provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases.

背景与目标： ：阿尔茨海默氏病是一种慢性神经系统疾病，严重威胁着人类健康，并给家庭和整个社会带来沉重负担。新兴证据表明，神经炎症是神经退行性疾病的重要病理表现，目前被认为是新的研究目标。我们先前发现来自青蒿的青蒿素B。具有很强的抗炎和免疫活性。在本研究中，我们评估了青蒿素B在体外和体内的抗神经炎作用，探索其潜在机制。结果表明，青蒿素B抑制了LPS诱导的BV2细胞的NO分泌，并显着降低了炎性细胞因子IL-1β，IL-6和TNF-α的表达水平。这伴随着MyD88和NF-κB的基因表达水平以及TLR4和MyD88蛋白水平的降低。在AD模型小鼠中进一步证实了这些抑制作用。这项研究还表明，青蒿素B改善了痴呆小鼠在水迷宫和逐步测试中的空间记忆，并改变了海马和皮层的病理特征以及炎性细胞因子的水平。这些结果表明青蒿素B可能通过调节TLR4-MyD88-NF-κB信号通路抑制神经炎症并对认知功能发挥神经保护作用。这项研究为青蒿素B在神经炎性疾病治疗中的潜在应用提供了直接的证据。