D-Ribose-LCysteine attenuates manganese-induced cognitive and motor deficit,oxidative damage,and reactive microglia activation

Due to overexposure, manganese (Mn) accumulation in the brain can trigger the inhibition of glutathione synthesis and lead to increased generation of reactive oxygen species (ROS) and oxidative stress. D-Ribose-L-Cysteine (RibCys) has been demonstrated to effectively support glutathione synthesis to scavenge ROS and protect cells from oxidative damage. In the present study, we examined the effects of RibCys on weight changes, cognitive and motor associated activities, oxidative stress markers, striatal and cortical histology, and microglia activation following Mn exposure. Rats were exposed to either saline, Mn or/and RibCys for two weeks. The Mn exposed rats received RibCys either as pre-, co-, or post-treatments. Mn caused a significant decrease in weight, memory and motor activities, increased lactate dehydrogenase level, overexpression of IBA1 reflecting microglia activation, and distortion of the neuronal cytoarchitecture of the striatum and motor cortex, respectively. Interventions with RibCys mitigated Mn-induced neurotoxic events. Our novel study demonstrates that RibCys effectively ameliorates the neurotoxicity following Mn treatment and maybe a therapeutic strategy against the neurological consequences of Mn overexposurec     

神经胶质细胞参与吗啡耐受机制及治疗的研究进展

 吗啡是临床上常用的强效镇痛药，然而长期应用会导致其镇痛效能降低，发生吗啡耐受。以往对吗啡耐受机制的研究主要集中在脊髓神经元敏化等中枢神经元机制，近年来越来越多的学者开始关注神经胶质细胞，特别是小胶质细胞和星形胶质细胞，在吗啡耐受形成中的作用。本文简要综述了神经胶质细胞参与吗啡耐受的作用机制及其治疗的研究进展，为解决临床上中重度疼痛治疗中的难点问题提供新的解决思路与依据。     

Colony stimulating factors in the nervous system

Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.     

白藜芦醇对蛛网膜下腔出血后神经炎症的作用和机制研究

目的研究白藜芦醇对蛛网膜下腔出血(subarachnoid hemorrhage,SAH)后血肿区脑组织神经炎症的作用和机制。方法将48只成年雄性SD大鼠随机分为三组:假手术组,SAH组和SAH+白藜芦醇处理组,每组16只。采用枕大池两次注血法构建SAH模型。SAH组和SAH+白藜芦醇组在构建模型前15 min和构建模型后5min分别给予生理盐水或白藜芦醇各一次。于构建模型后72小时利用NSS评分评估大鼠的神经功能,然后处死大鼠并获取保存脑组织。利用ELISA检测脑组织内促炎因子IL-1,IL-6、TNF-α和抗炎因子IL-4,IL-10、TGF-β的表达水平,利用RT-PCR检测小胶质细胞M1型特征性基因IL-1β、CD32和M2型特征性基因CD206、Arginase-1的表达水平。结果与假手术组相比,SAH组大鼠神经功能下降(P0.05),脑组织中促炎因子IL-1,IL-6、TNF-α和抗炎因子IL-4,IL-10、TGF-β的表达水平升高(P0.05),小胶质细胞M1型特征性基因IL-1β、CD32和M2型特征性基因CD206、Arginase-1的表达水平也升高(P 0.05)。与生理盐水处理组相比,白藜芦醇处理组神经功能损伤程度下降(P 0.05),脑组织中促炎因子IL-1,IL-6、TNF-α表达水平降低、抗炎因子IL-4,IL-10、TGF-β的表达水平升高(P 0.05),小胶质细胞M1型特征性基因IL-1β、CD32表达水平降低、M2型特征性基因CD206、Arginase-1的表达水平升高(P0.05)。结论白藜芦醇通过促进SAH后小胶质细胞由M1型向M2型转换,从而减轻了神经炎症和神经功能损伤。     

Corticosterone-mediated microglia activation affects dendritic spine plasticity and motor learning functions in minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is characterized as cognitive deficits including memory and learning dysfunctions after liver injuries or hepatic diseases. Our understandings of neurological mechanisms of MHE-associated cognitive syndromes, however, are far from complete. In the current study we generated a mouse MHE model by repetitive administrations of thioacetamide (TAA), which induced hyperammonemia plus elevated proinflammatory cytokines in both the general circulation and motor cortex. MHE mice presented prominent motor learning deficits, which were associated with excess dendritic spine pruning in the motor cortex under 2-photon in vivo microscopy. The pharmaceutical blockade of glucocorticoid receptor or suppression of its biosynthesis further rescued motor learning deficits and synaptic protein loss. Moreover, MHE mice presented microglial activation, which can be alleviated after glucocorticoid pathway inhibition. In sum, our data demonstrates corticosterone-induced microglial activation, synaptic over-pruning and motor learning impairments in MHE, providing new insights for MHE pathogenesis and potential targets of clinical interventions.     

The inflammatory event of birth: How oxytocin signaling may guide the development of the brain and gastrointestinal system

The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed, but beyond these functions, OT’s adaptive functions at birth are quite numerous, as OT coordinates many physiological processes in the mother and fetus to ensure a successful delivery. In this review we explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system based on evidence that birth is a potent inflammatory/immune event. We discuss data with relevance for a number of neurodevelopmental disorders, as well as the emerging role of the gut-brain axis for health and disease. Finally, we discuss the potential relevance of sex differences in OT signaling present at birth in the increased male vulnerability to neurodevelopmental disabilities.     

Reducing age-dependent monocyte-derived macrophage activation contributes to the therapeutic efficacy of NADPH oxidase inhibition in spinal cord injury

ObjectiveThe average age at the time of spinal cord injury (SCI) has increased to 43 years old. Middle-aged mice (14 months old, MO) exhibit impaired recovery after SCI with age-dependent increases in reactive oxygen species (ROS) production through NADPH oxidase (NOX) along with pro-inflammatory macrophage activation. Despite these aging differences, clinical therapies are being examined in individuals regardless of age based upon preclinical data generated primarily using young animals (∼4 MO). Our objective is to test the extent to which age affects SCI treatment efficacy. Specifically, we hypothesize that the effectiveness of apocynin, a NOX inhibitor, is age-dependent in SCI.MethodsApocynin treatment (5 mg/kg) or vehicle was administered 1 and 6 h after moderate T9 contusion SCI (50kdyn IH) and then daily for 1 week to 4 and 14 MO mice. Locomotor and anatomical recovery was evaluated for 28 days. Monocyte-derived macrophage (MDM) and microglial activation and ROS production were evaluated at 3 and 28 days post-injury.ResultsApocynin improved functional and anatomical recovery in 14 but not 4 MO SCI mice. Apocynin-mediated recovery was coincident with significant reductions in MDM infiltration and MDM-ROS production in 14 MO SCI mice. Importantly, microglial activation was unaffected by treatment.ConclusionThese results indicate that apocynin exhibits age-dependent neuroprotective effects by blocking excessive neuroinflammation through NOX-mediated ROS production in MDMs. Further, these data identify age as a critical regulator for SCI treatment efficacy and indicate that pharmacologically reduced macrophage, but not microglia, activation and ROS production reverses age-associated neurological impairments.     

银椴苷对激活的原代小胶质细胞极化及神经炎症的影响＊

目的 银椴苷（Tiliroside，Tle）是一种天然产物，存在于结香花（Edgeworthia chrysantha Lindl.）、金英（Galphimia gracilis）、和Phlomoides spectabilis等生物体中。本文主要探讨Tle对脂多糖（lipopolysaccharide，LPS）激活的原代小胶质细胞的M1/M2极化的转化作用及其抑制神经炎症反应的影响。方法 MTT检测各浓度Tle对LPS激活的原代小胶质细胞活性的影响；Griess试剂检测LPS激活的原代小胶质细胞的一氧化氮（Nitric oxide，NO）产物生成量的影响；ELISA法检测Tle对LPS激活的原代小胶质细胞的肿瘤坏死因子-α（Tumor necrosis factor-α，TNF-α）、白细胞介素-6（Interleukin-6，IL-6）蛋白水平的影响；qRT-PCR检测Tle对LPS激活的原代小胶质细胞的精氨酸酶-1（Arginase-1，Arg-1）和胰岛素生长因子-1（Insulin growth factor-1，IGF-1）的mRNA表达水平。结果 Tle（0-80 μmol·L^-1）对LPS激活的原代小胶质细胞活性没有明显影响；Tle显著降低LPS激活的原代小胶质细胞亚硝酸盐的含量，并对炎症因子IL-6、TNF-α蛋白水平有显著抑制作用，同时显著提高抗炎因子Arg-1和IGF-1的mRNA水平。结论 Tle能够通过促进LPS激活的原代小胶质细胞M1型向M2型转化从而抑制神经炎症反应，因此Tle具有一定的神经保护作用。     

Excess salt intake promotes M1 microglia polarization via a p38/MAPK/AR-dependent pathway after cerebral ischemia in mice

A high salt diet (HSD) is among the most important risk factors for many diseases. One mechanism by which HSD aggravates cerebral ischemic injury is independent of blood pressure changes. The direct role of HSD in inflammation after cerebral ischemia is unclear. In this research, after twenty-one days of being fed a high salt diet, permanent focal ischemia was induced in mice via operation. At 12 h and 1, 3 and 5 days postischemia, the effects of HSD on the lesion volume, microglia polarization, aldose reductase (AR) expression, and inflammatory processes were analyzed. We report that in mice, surplus dietary salt promotes inflammation and increases the activation of classical lipopolysaccharide (LPS)-induced microglia/macrophages (M1). This effect depends on the expression of the AR protein in activated microglia after permanent middle cerebral artery ligation (pMCAL) in HSD mice. The administration of either the AR inhibitor Epalrestat or a p38-neutralizing antibody blocked the polarization of microglia and alleviated stroke injury.In conclusion, HSD promotes polarization in pro-inflammatory M1 microglia by upregulating the expression of the AR protein via p38/MAPK, thereby exacerbating the development of ischemia stroke.     

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.