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。

BACKGROUND & AIMS: :Activated microglia are an important feature of many neurological diseases and can be imaged in vivo using 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a ligand that binds the peripheral benzodiazepine receptor (PBR). N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide (DAA1106) is a new PBR-specific ligand that has been reported to bind to PBR with higher affinity compared with PK11195. We hypothesized that this high-affinity binding of DAA1106 to PBR will enable better delineation of microglia in vivo using positron emission tomography. [(3)H]DAA1106 showed higher binding affinity compared with [(3)H](R)-PK11195 in brain tissue derived from normal rats and the rats injected intrastriatally with 6-hydroxydopamine or lipopolysaccharide at the site of the lesion. Immunohistochemistry combined with autoradiography in brain tissues as well as correlation analyses showed that increased [(3)H]DAA1106 binding corresponded mainly to activated microglia. Finally, ex vivo autoradiography and positron emission tomography imaging in vivo showed greater retention of [(11)C]DAA1106 compared with [(11)C](R)-PK11195 in animals injected with either lipopolysaccaride or 6-hydroxydopamine at the site of lesion. These results indicate that DAA1106 binds with higher affinity to microglia in rat models of neuroinflammation when compared with PK11195, suggesting that [(11)C]DAA1106 may represent a significant improvement over [(11)C](R)-PK11195 for in vivo imaging of activated microglia in human neuroinflammatory disorders.

背景与目标： ：激活的小胶质细胞是许多神经系统疾病的重要特征，可以使用1-（2-氯苯基）-N-甲基-N-（1-甲基丙基）-3-异喹啉羧酰胺（PK11195）在体内成像，外周苯并二氮杂receptor受体（PBR）。 N-（2,5-二甲氧基苄基）-N-（5-氟-2-苯氧基苯基）乙酰胺（DAA1106）是一种新的PBR特异性配体，据报道与PBR结合的亲和力高于PK11195。我们假设DAA1106与PBR的这种高亲和力结合将使使用正电子发射断层扫描在体内更好地描绘小胶质细胞。 [（3）H] DAA1106在正常大鼠和在病变部位经纹状体注射6-羟基多巴胺或脂多糖的大鼠脑组织中显示出比[（3）H]（R）-PK11195高的结合亲和力。免疫组织化学结合放射自显影在脑组织中以及相关性分析显示，增加的[（3）H] DAA1106结合主要对应于活化的小胶质细胞。最后，在体内注射脂多糖或6-羟基多巴胺的动物体内，离体放射自显影和正电子发射断层显像在体内显示出[（11）C] DAA1106与[（11）C]（R）-PK11195相比保留更大。病变。这些结果表明，与PK11195相比，DAA1106在神经炎症大鼠模型中以更高的亲和力与小胶质细胞结合，这表明[（11）C] DAA1106在体内可能比[（11）C]（R）-PK11195表现出显着改善人类神经炎性疾病中活化小胶质细胞的成像。

BACKGROUND & AIMS: :Chlorpyrifos (CPF) may weaken the immune defenses of children, making them vulnerable to opportunistic bacterial infection. CPF combined with bacterial infection is a potential problem for children during their childhood development. However, there is a lack of studies on the joint effects of these two factors on children. Here, we assessed the effects of CPF combined with lipopolysaccharide (LPS) on the inflammation and development of the nervous system. In this study, the cell toxicity of CPF plus LPS in cultured astrocytes, and the pathogenic effects of CPF plus LPS in neonatal rat models were observed. The hydrogen (H2)-inhalation was used for treatment to explore its therapeutic potential. We found that CPF plus LPS activated the astrocyte, which increased the expressions of HMGB1, TLR4, and p-NF-κB p65, while H2-inhalation reduced the expressions (p < 0.05). We also found that CPF plus LPS induced long-lasting spatial memory deficits throughout brain maturation. However, H2-inhalation improved rat performance in these behavioral experiments (p < 0.05). In conclusion, the sub-toxic concentration of CPF did not cause a significant damage in short term, but induced a severe long-term damage to the brain when combined with LPS. H2-inhalation reduced the neuronal damage and behavioral abnormalities caused by CPF and LPS exposure.

背景与目标： ：毒死rif（CPF）可能会削弱儿童的免疫防御能力，使其容易受到机会性细菌感染。 CPF结合细菌感染是儿童在儿童期发展过程中的潜在问题。但是，关于这两个因素对儿童的联合影响尚缺乏研究。在这里，我们评估了CPF结合脂多糖（LPS）对神经系统炎症和发育的影响。在这项研究中，观察了CPF和LPS在培养的星形胶质细胞中的细胞毒性，以及CPF和LPS在新生大鼠模型中的致病作用。吸入氢气（H2）用于治疗，以探索其治疗潜力。我们发现CPF加LPS激活了星形胶质细胞，增加了HMGB1，TLR4和p-NF-κBp65的表达，而H2吸入则降低了表达（p <0.05）。我们还发现，CPF加LPS会在整个大脑成熟过程中引起长期的空间记忆缺陷。然而，在这些行为实验中，H 2吸入改善了大鼠的表现（p <0.05）。总之，CPF的亚毒性浓度在短期内不会引起明显的损害，但是当与LPS联合使用时，会对脑造成严重的长期损害。吸入H2减少了CPF和LPS暴露引起的神经元损害和行为异常。

BACKGROUND & AIMS: :An overview of current concepts on neuroinflammation and on the dialogue between neurons and non-neuronal cells in three important infections of the central nervous systems (rabies, cerebral malaria, and human African trypanosomiasis or sleeping sickness) is here presented. Large numbers of cases affected by these diseases are currently reported. In the context of an issue dedicated to Camillo Golgi, historical notes on seminal discoveries on these diseases are also presented. Neuroinflammation is currently closely associated with pathogenetic mechanisms of chronic neurodegenerative diseases. Neuroinflammatory signaling in brain infections is instead relatively neglected in the neuroscience community, despite the fact that the above infections provide paradigmatic examples of alterations of the intercellular crosstalk between neurons and non-neuronal cells. In rabies, strategies of immune evasion of the host lead to silencing neuroinflammatory signaling. In the intravascular pathology which characterizes cerebral malaria, leukocytes and Plasmodium do not enter the brain parenchyma. In sleeping sickness, leukocytes and African trypanosomes invade the brain parenchyma at an advanced stage of infection. Both the latter pathologies leave open many questions on the targeting of neuronal functions and on the pathogenetic role of non-neuronal cells, and in particular astrocytes and microglia, in these diseases. All three infections are hallmarked by very severe clinical pictures and relative sparing of neuronal structure. Multidisciplinary approaches and a concerted action of the neuroscience community are needed to shed light on intercellular crosstalk in these dreadful brain diseases. Such effort could also lead to new knowledge on non-neuronal mechanisms which determine neuronal death or survival.

背景与目标： ：这里介绍了有关神经炎症以及中枢神经系统的三种重要感染（狂犬病，脑疟疾和人类非洲锥虫病或昏睡病）中神经元与非神经元细胞之间对话的当前概念的概述。当前报道了受这些疾病影响的大量病例。在有关卡米洛·高尔基（Camillo Golgi）的问题中，还介绍了有关这些疾病的开创性发现的历史记录。目前，神经炎症与慢性神经退行性疾病的致病机制密切相关。尽管上述感染提供了神经元与非神经元细胞之间细胞间串扰改变的范例，但实际上神经感染中的神经炎性信号转导在神经科学界相对被忽略了。在狂犬病中，宿主免疫逃逸的策略导致沉默的神经炎症信号传导。在表征脑疟疾的血管内病理学中，白细胞和疟原虫不会进入脑实质。在昏睡病中，白细胞和非洲锥虫在感染的晚期阶段侵入脑实质。后两种病理在这些疾病中对神经元功能的靶向以及非神经元细胞，尤其是星形胶质细胞和小胶质细胞的致病作用提出了许多问题。这三种感染的特征是非常严重的临床表现和神经元结构的相对稀疏。需要多学科的方法和神经科学界的共同行动来阐明这些可怕的脑部疾病中的细胞间串扰。这种努力也可能导致有关确定神经元死亡或存活的非神经机制的新知识。

BACKGROUND & AIMS: BACKGROUND:Obstructive sleep apnea (OSA) in humans chronically promotes the neuronal damage in the hippocampus. Toll-like receptor 2 (TLR2) is pivotal for the development of numerous hippocampal diseases. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA. Here in our study, the effects of TLR2 antagonism on the neural damage elicited by CIH were examined. METHODS:Ortho-vanillin (O-vanillin) is an inhibitor of TLR2. Adult male mice were subjected to 8 h of intermittent hypoxia per day with or without O-vanillin for 28 days. Neuronal damage, the number of microglia, the interaction of TLR2 with its adapter protein myeloid differentiation factor 88 (MYD88), the expressions of inflammatory cytokines, and the oxidative stress were observed. RESULTS:O-vanillin inhibited the increased interaction of TLR2 and MyD88, the activation of NFκB, the aggregation of microglia, the overexpression of proinflammatory agents, the elevation of oxidative stress, and hippocampal neuron cell apoptosis induced by CIH. CONCLUSIONS:Our experiments indicate that TLR2 antagonism may alleviate the hippocampal neuronal damage caused by CIH via inhibiting neuroinflammation and oxidative stress.

背景与目标： 背景：人类阻塞性睡眠呼吸暂停（OSA）长期促进海马神经元的损害。 Toll样受体2（TLR2）对于许多海马疾病的发展至关重要。慢性间歇性缺氧（CIH）是OSA的突出特征。在我们的研究中，研究了TLR2拮抗作用对CIH引起的神经损伤的影响。
方法：邻香兰素（O-香兰素）是TLR2的抑制剂。成年雄性小鼠每天进行8小时间歇性缺氧，有或没有O-香兰素，持续28天。观察神经元损伤，小胶质细胞数量，TLR2与其衔接蛋白髓样分化因子88（MYD88）的相互作用，炎性细胞因子的表达和氧化应激。
结果：O-香兰素可抑制CIH诱导的TLR2和MyD88的相互作用增强，NFκB的活化，小胶质细胞的聚集，促炎剂的过度表达，氧化应激的升高以及海马神经元细胞凋亡。
结论：我们的实验表明，TLR2拮抗作用可通过抑制神经炎症和氧化应激减轻CIH引起的海马神经元损伤。

BACKGROUND & AIMS: :Stroke is one of the most frequent causes of death and disability worldwide. Cerebral ischemia is the major insult of stroke and induces acute inflammation by triggering excessive production of proinflammatory cytokines, leading to the exacerbation of primary brain damage. Toll-like receptor (TLR)- and nitric oxide-mediated signaling pathways have been identified under ischemic stress. However, the interaction between these two pathways in controlling proinflammatory cytokines has not been well addressed during cerebral ischemia. Adult male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) for stroke induction. The MCAO procedure resulted in a significant infarct in the brain after 24h. The infarcted side of the brain had marked elevation of TNF-α gene and protein expression, compared to the sham brain. The expression of CD14, a co-receptor of TLR4, was induced by MCAO, while the expression of TLR4 remained unchanged. The levels of inducible nitric oxide synthase (iNOS) and nitrotyrosine were also upregulated in the infracted side of the brain. Correspondingly, exposing murine microglial BV2 cells to hypoxia (1% O2) for 20h resulted in an increased expression of TNF-α, CD14, iNOS, and nitrotyrosine. When BV2 cells were treated with l-canavanine, an iNOS selective inhibitor, the elevation of TNF-α and CD14 induced by hypoxia was inhibited. This inhibition was associated with an increase of IκB. These results suggest that the upregulation of TNF-α production in ischemic stroke is partially through increasing iNOS, and then CD14 expression leading to the activation of the NF-κB pathway in microglia.

背景与目标： ：中风是世界范围内最常见的死亡和残疾原因之一。脑缺血是中风的主要损害，并通过触发促炎性细胞因子的过量产生而诱发急性炎症，从而导致原发性脑损伤的加剧。在缺血性应激下已经确定了Toll样受体（TLR）和一氧化氮介导的信号通路。然而，在脑缺血期间，这两种途径之间在控制促炎性细胞因子中的相互作用尚未得到很好的解决。对成年雄性C57BL / 6小鼠进行大脑中动脉闭塞（MCAO）诱导中风。 24小时后，MCAO程序导致大脑严重梗塞。与假脑相比，脑梗死一侧的TNF-α基因和蛋白质表达明显升高。 MCAO诱导TLR4的共受体CD14的表达，而TLR4的表达保持不变。诱导型一氧化氮合酶（iNOS）和硝基酪氨酸的水平在大脑的患侧也被上调。相应地，将鼠小神经胶质BV2细胞暴露于低氧（1％O2）条件下20小时会导致TNF-α，CD14，iNOS和硝基酪氨酸的表达增加。当用iNOS选择性抑制剂l-canavanine处理BV2细胞时，缺氧诱导的TNF-α和CD14升高被抑制。这种抑制与IκB的增加有关。这些结果表明缺血性中风中TNF-α产生的上调部分是通过增加iNOS，然后是CD14表达导致小胶质细胞中NF-κB途径的激活。

BACKGROUND & AIMS: :Neuroinflammation is closely associated with the pathogenesis of neurological disorders. The hallmark of neuroinflammation is considered to be microglial activation. Therefore, inhibition of microglial activation might hold a promising therapy for neurological disorders. Resveratrol, a natural non-flavonoid polyphenol found in grapes and red wine, has been recognized as a bioactive agent with potential benefit for health. Several lines of evidence show that resveratrol could exert neuroprotection against ischemia, seizure, and neurodegenerative diseases. However, the mechanisms underlying its beneficial neuroprotective effects are poorly defined. Here, by using rat primary cortical neuron-glia cultures, results showed that resveratrol attenuated lipopolysaccharide (LPS)-induced cortical neurotoxicity. Further studies revealed that microglia were responsible for resveratrol-mediated neuroprotection. Resveratrol significantly inhibited LPS-induced microglial activation and subsequent production of multiple pro-inflammatory and cytotoxic factors such as tumor necrosis factor-α, nitric oxide, and interleukin-1β. Collectively, resveratrol produced neuroprotection against microglia-induced neurotoxicity. Thus, resveratrol might represent a potential benefit for the treatment of inflammation-related neurological disorders.

背景与目标： ：神经炎症与神经系统疾病的发病机制密切相关。神经炎症的标志被认为是小胶质细胞激活。因此，抑制小胶质细胞活化可能对神经系统疾病具有广阔的前景。白藜芦醇是一种在葡萄和红酒中发现的天然非类黄酮多酚，被认为是一种对健康具有潜在益处的生物活性剂。几条证据表明白藜芦醇可以对缺血，癫痫和神经退行性疾病发挥神经保护作用。但是，其有益的神经保护作用的机制尚不清楚。在这里，通过使用大鼠原代皮层神经元神经胶质细胞培养物，结果表明白藜芦醇减弱了脂多糖（LPS）诱导的皮层神经毒性。进一步的研究表明，小胶质细胞负责白藜芦醇介导的神经保护作用。白藜芦醇显着抑制LPS诱导的小胶质细胞活化，并随后抑制多种促炎和细胞毒性因子的产生，例如肿瘤坏死因子-α，一氧化氮和白介素-1β。总的来说，白藜芦醇产生了针对小胶质细胞诱导的神经毒性的神经保护作用。因此，白藜芦醇可能代表着治疗炎症相关神经系统疾病的潜在益处。

BACKGROUND & AIMS: :Neurodegenerative diseases encompass complex cell signaling disturbances that initially damage neuronal circuits and synapses. Due to multiple protective mechanisms enacted to counteract the onset of neurodegenerative diseases, there is often a prolonged period without noticeable impairments during their initiation. Since severe cognitive deficit or vision loss takes place after that period there is an opportunity to harness endogenous protective mechanisms as potential therapeutic approaches. The activation of the biosynthesis of the docosanoid mediator neuroprotectin D1 (NPD1) is an early response to the upsurge of protein misfolding and other neuroinflammatory events. This overview discusses the potent neuroprotective and inflammation-modulating bioactivity of NPD1. This lipid mediator represents an early response to neurodegenerations, aiming to restore homeostasis.

背景与目标： 神经退行性疾病包括复杂的细胞信号传导障碍，最初会破坏神经元回路和突触。由于采取了多种保护机制来抵消神经退行性疾病的发作，因此通常有一段较长的时期，而在其启动过程中却没有明显的损害。由于在此期间之后发生严重的认知缺陷或视力丧失，因此有机会利用内源性保护机制作为潜在的治疗方法。 docosanoid介质神经保护素D1（NPD1）的生物合成的激活是对蛋白质错误折叠和其他神经炎性事件激增的早期反应。此概述讨论了NPD1的强大的神经保护和炎症调节生物活性。这种脂质介体代表对神经变性的早期反应，旨在恢复体内平衡。

BACKGROUND & AIMS: :There are many animal models for studying different aspects of neurodegeneration. Lipopolysaccharide (LPS) injected in rats intracerebroventricularly induces neuroinflammation quite similar to the inflammatory component of chronic neurodegenerative conditions such as Alzheimer's disease. We used this model to examine the effect of estradiol on neuroinflammation. LPS or pyrogen-free saline were injected intracerebroventricularly (i.c.v.) into the lateral ventricle of male Wistar rats and estradiol was administered (200 micrograms/kg s.c.) 48 h before or 24 h after LPS injection. LPS-induced body weight loss was partially postponed by the treatment, especially in the rats pretreated with estradiol. When analyzing GFAP glial cell morphology in the CA3c area of the hippocampus and corpus callosum, as well as the number of astroglial cells in CA3c and CA1, GFAP expression was found to be reduced. This was true especially in the animals pretreated with estradiol and to a much lesser extent in the posttreated ones. The data support the possible existence of a neuroimmunomodulatory effect of estradiol administration in neurodegenerative conditions, which influences the inflammatory component.

背景与目标： ：有许多动物模型可用于研究神经退行性变的不同方面。大鼠脑室内注射的脂多糖（LPS）诱导的神经炎症与慢性神经退行性疾病（例如阿尔茨海默氏病）的炎症成分非常相似。我们使用该模型检查了雌二醇对神经炎症的作用。将LPS或不含热原的盐水经脑室内（i.c.v.）注射入雄性Wistar大鼠的侧脑室，并在LPS注射前48小时或注射后24小时给予雌二醇（200微克/ kg s.c.）。 LPS诱导的体重减轻部分被治疗推迟，尤其是在雌二醇预处理的大鼠中。分析海马和call体CA3c区的GFAP胶质细胞形态，以及CA3c和CA1中星形胶质细胞的数量时，发现GFAP表达降低。尤其是在用雌二醇预处理的动物中，尤其是在后处理动物中，这种情况尤为严重。数据支持在神经退行性疾病中雌二醇给药的神经免疫调节作用的可能存在，这会影响炎症成分。