Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology

Both oxidative damage and inflammation have been implicated in age-related neurodegenerative diseases including Alzheimer’s Disease (AD). The yellow curry spice, curcumin, has both antioxidant and anti-inflammatory activities which confer significant protection against neurotoxic and genotoxic agents. We used 22 month Sprague-Dawley (SD) rats to compare the effects of the conventional NSAID, ibuprofen, and curcumin for their ability to protect against amyloid β-protein (Aβ)-induced damage. Lipoprotein carrier-mediated, intracerebroventricular infusion of Aβ peptides induced oxidative damage, synaptophysin loss, a microglial response and widespread Aβ deposits. Dietary curcumin (2000 ppm), but not ibuprofen, suppressed oxidative damage (isoprostane levels) and synaptophysin loss. Both ibuprofen and curcumin reduced microgliosis in cortical layers, but curcumin increased microglial labeling within and adjacent to Aβ-ir deposits. In a second group of middle-aged female SD rats, 500 ppm dietary curcumin prevented Aβ-infusion induced spatial memory deficits in the Morris Water Maze and post-synaptic density (PSD)-95 loss and reduced Aβ deposits. Because of its low side-effect profile and long history of safe use, curcumin may find clinical application for AD prevention.     

The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging

Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using positron emission tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR (recently renamed as Translocator protein (18 kDa)). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.     

Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge

Acute and chronic stressors sensitize or prime the neuroinflammatory response to a subsequent peripheral or central immunologic challenge. However, the neuroimmune process(es) by which stressors prime or sensitize subsequent neuroinflammatory responses remains unclear. Prior evidence suggested that toll-like receptors (TLRs) might be involved in the mediation of primed neuroinflammatory responses, but the role of TLRs during a stressor has never been directly tested. Here, a novel TLR2 and TLR4 antagonist, OxPAPC, was used to probe the contribution of TLRs in the stress sensitization phenomenon. OxPAPC has not previously been administered to the brain, and so its action in blocking TLR2 and TLR4 action in brain was first verified. Administration of OxPAPC into the CNS prior to stress prevented the stress-induced potentiation of hippocampal pro-inflammatory response to a subsequent peripheral LPS challenge occurring 24 h later. In addition, in vivo administration of OxPAPC prior to stress prevented the sensitized pro-inflammatory response from isolated microglia following administration of LPS ex vivo, further implicating microglia as a key neuroimmune substrate that mediates stress-induced sensitized neuroinflammation.     

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n = 30) and ASD (n = 27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p = 0.018) as well as downstream elements SHANK3 (p = 0.005) and PLCB1 (p = 0.009) but that the pro-inflammatory marker NOS2 was increased (p = 0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p = 0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p = 0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.     

Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming

High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism’s innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges.     

Sickness: From the focus on cytokines,prostaglandins, and complement factors to the perspectives of neurons

Systemic inflammation leads to a variety of physiological (e.g. fever) and behavioral (e.g. anorexia, immobility, social withdrawal, depressed mood, disturbed sleep) responses that are collectively known as sickness. While these phenomena have been studied for the past few decades, the neurobiological mechanisms by which sickness occurs remain unclear. In this review, we first revisit how the body senses and responds to infections and injuries by eliciting systemic inflammation. Next, we focus on how peripheral inflammatory molecules such as cytokines, prostaglandins, and activated complement factors communicate with the brain to trigger neuroinflammation and sickness. Since depression also involves inflammation, we further elaborate on the interrelationship between sickness and depression. Finally, we discuss how immune activation can modulate neurons in the brain, and suggest future perspectives to help unravel how changes in neuronal functions relate to sickness responses.     

Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats

Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-α), which can trigger neuronal death cascades and exacerbate edema after CNS insults. Minocycline is neuroprotective in some brain ischemia models in part by blunting the microglial response. We tested the hypothesis that minocycline would attenuate neuroinflammation as reflected by brain tissue levels of TNF-α after hypothermic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6 min normothermic CA. Hypothermia (30 °C) was then induced by an aortic saline flush. After a total of 20 min CA, resuscitation was achieved via cardiopulmonary bypass (CPB). After 5 min reperfusion, minocycline (90 mg kg⁻¹; n = 6) or vehicle (PBS; n = 6) was given. Hypothermia (34 °C) was maintained for 6 h. Rats were sacrificed at 6 or 24 h. TNF-α was quantified (ELISA) in four brain regions (cerebellum, CEREB; cortex, CTX; hippocampus, HIP; striatum, STRI). Naïve rats (n = 6) and rats subjected to the same anesthesia and CPB but no CA served as controls (n = 6). Immunocytochemistry was used to localize TNF-α. Naïve rats and CPB controls had no detectable TNF-α in any brain region. CA markedly increased brain TNF-α. Regional differences were seen, with the highest TNF-α levels in striatum in CA groups (10-fold higher, P < 0.05 vs. all other brain regions). TNF-α was undetectable at 24 h. Minocycline attenuated TNF-α levels in CTX, HIP and STRI (P < 0.05). TNF-α showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-α levels after prolonged hypothermic CA, with maximal increases in striatum. Surprisingly, TNF-α co-localized in neurons and not microglia. Minocycline attenuated TNF-α by approximately 50% but did not totally ablate its production. That minocycline decreased brain TNF-α levels suggests that it may represent a therapeutic adjunct to hypothermia in CA neuroprotection.     

miR-122-5p调节创伤性脑外伤后小胶质细胞极化减弱炎症反应北大核心CSCD

目的探讨miR-122-5p对创伤性脑外伤后小胶质细胞凋亡、极化和炎症反应的影响。方法建立创伤性脑外伤(traumatic brain injury,TBI)小鼠模型和细胞模型。使用TBI小鼠脑匀浆刺激星型胶质细胞产生外泌体,microRNA微阵列分析外泌体中显著改变的microRNA。实时荧光定量PCR检测TBI小鼠模型和TBI细胞模型中miR-122-5p表达。使用TUNEL凋亡染色、免疫荧光共聚焦、蛋白质印迹研究miR-122-5p抑制剂在TBI神经炎症中对小胶质细胞凋亡、小胶质细胞M1/M2表型转化、NLRP3通路及NFκB磷酸化的作用。结果通过microRNA微阵列分析发现有83个下调miRNA(改变2倍以上,P<0.05),其中miR-122-5p显著下调(P<0.01),miR-122-5p在TBI小鼠及细胞模型中表达显著下降[(1.0±0.00)vs.(0.41±0.15),P<0.001];[(1.0±0.00)vs.(0.34±0.07),P<0.001]。TUNEL凋亡检测、免疫荧光染色结果表明抑制miR-122-5p表达,可以显著减轻LPS诱导的小胶质细胞凋亡[(8.03±1.30)vs.(3.17±0.34),P<0.001],促进小胶质细胞M1向M2表型转化,即M1表型极化减少[(56.96±13.70)vs.(34.70±3.47),P=0.002],M2表型极化增加[(30.46±3.67)vs.(40.74±2.49),P=0.005]。蛋白质印迹结果表明miR-122-5p抑制剂降低NLRP3炎症小体活化[(0.77±0.10)vs.(0.51±0.11),P=0.02],降低NFκB的磷酸化[(0.73±0.08)vs.(0.50±0.07),P=0.003]。结论miR-122-5p在TBI星形胶质细胞分泌的外泌体及小胶质细胞中表达下调,miR-122-5p抑制剂可以通过抑制TBI后NLRP3炎症小体通路的活化及NFκB的磷酸化,促进小胶质细胞M1向M2表型转化,减少小胶质细胞凋亡,从而减轻TBI后小胶质细胞炎症损伤。     

慢性牙周炎与帕金森病相关性的研究进展

慢性牙周炎属于慢性感染性疾病,与多种全身疾病存在双向关系。帕金森病是一种常见的神经退行性变性疾病,炎症反应在其进展中起到一定作用。近年来,大量研究提示慢性牙周炎与帕金森病等神经退行性变性疾病之间存在潜在联系,帕金森病患者牙周状况较差,其口腔菌群组成与健康人群存在差异;与此同时,慢性牙周炎患者罹患帕金森病的风险更高,定期牙周治疗可能在一定程度上降低该风险。慢性牙周炎与帕金森病的相互作用机制尚未明确,部分研究认为帕金森病患者可能由于运动及非运动症状,无法有效维护口腔卫生,增加牙周炎患病风险;小胶质细胞介导的神经炎症则可能是慢性牙周炎影响帕金森病的关键,牙周致病菌及炎症介质或可通过多种途径进入大脑并激活小胶质细胞,最终影响帕金森病的发生发展。本文就慢性牙周炎与帕金森病相关性及可能的交互作用机制的最新研究进展作一综述,以期为进一步探讨两者相互影响的研究提供思路。