Acute stress induces chronic neuroinflammatory,microglial and behavioral priming: A role for potentiated NLRP3 inflammasome activation

Prior exposure to acute and chronic stressors potentiates the neuroinflammatory and microglial pro-inflammatory response to subsequent immune challenges suggesting that stressors sensitize or prime microglia. Stress-induced priming of the NLRP3 inflammasome has been implicated in this priming phenomenon, however the duration/persistence of these effects has not been investigated. In the present study, we examined whether exposure to a single acute stressor (inescapable tailshock) induced a protracted priming of the NLRP3 inflammasome as well as the neuroinflammatory, behavioral and microglial proinflammatory response to a subsequent immune challenge in hippocampus. In male Sprague-Dawley rats, acute stress potentiated the neuroinflammatory response (IL-1β, IL-6, and NFκBIα) to an immune challenge (lipopolysaccharide; LPS) administered 8 days after stressor exposure. Acute stress also potentiated the proinflammatory cytokine response (IL-1β, IL-6, TNF and NFκBIα) to LPS ex vivo. This stress-induced priming of microglia also was observed 28 days post-stress. Furthermore, challenge with LPS reduced juvenile social exploration, but not sucrose preference, in animals exposed to stress 8 days prior to immune challenge. Exposure to acute stress also increased basal mRNA levels of NLRP3 and potentiated LPS-induction of caspase-1 mRNA and protein activity 8 days after stress.The present findings suggest that acute stress produces a protracted vulnerability to the neuroinflammatory effects of subsequent immune challenges, thereby increasing risk for stress-related psychiatric disorders with an etiological inflammatory component.Further, these findings suggest the unique possibility that acute stress might induce innate immune memory in microglia.     

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson’s disease(PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study,we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with lo...     

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。     

过氧亚硝酸阴离子引起阿片耐受或痛觉过敏的研究进展

背景 吗啡等阿片类药物是临床疼痛治疗的代表性药物,主要用于急、慢性疼痛和癌痛的治疗,但长期应用可产生诸多副作用,如吗啡耐受和痛觉过敏等,从而大大限制了阿片类药物在临床上的使用. 目的 通过对近年过氧亚硝基阴离子在吗啡耐受和痛觉过敏中所起作用的研究进行总结,帮助读者了解国外相关研究的最新趋势和进展. 内容 就过氧亚硝基阴离子的生成途径、消除方式和过氧亚硝基阴离子在阿片耐受或痛觉过敏中的作用方式进行综述.得出如下结论,过氧亚硝基阴离子主要通过硝基化体内蛋白质酪氨酸残基、激活神经炎症和促进细胞凋亡3个方面,引起阿片耐受或痛觉过敏. 趋向 随着越来越多的学者对过氧亚硝基阴离子在吗啡耐受和痛觉过敏中发挥的重要作用达成共识,过氧亚硝基阴离子有望成为临床疼痛治疗的新靶点.     

Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.     

Trans-cinnamaldehyde improves neuroinflammation-mediated NMDA receptor dysfunction and memory deficits through blocking NF-κB pathway in presenilin1/2 conditional double knockout mice

A chronic neuroinflammatory response has been considered as a critical pathogenesis promoting neurodegenerative progression in Alzheimer’s disease (AD). During neuroinflammatory process, microglia are excessively activated and simultaneously release numerous pro-inflammatory mediators that cause synaptic dysfunction in the forebrain prior to neuronal degeneration and memory deficits in AD. Thus, prevention of neuroinflammation-mediated synaptic dysfunction may be a potential therapeutic approach against neurodegenerative disorders. Trans-cinnamaldehyde (TCA) is a primary bioactive component derived from the stem bark of Cinnamomum cassia, and it possesses potent anti-inflammatory and neuroprotective activities in in vivo and in vitro experiments. However, the in-depth molecular mechanisms of TCA underlying anti-neuroinflammatory and neuroprotective effects on memory deficits in AD are still unclear. The presenilin 1 and 2 conditional double knockout (PS cDKO) mice exhibit AD-like phenotypes including obvious neuroinflammatory responses and synaptic dysfunction and memory deficits. Here, PS cDKO were used to evaluate the potential neuroprotective effects of TCA against neuroinflammation-mediated dementia by performing behavioral tests, electrophysiological recordings and molecular biology analyses. We observed that TCA treatment reversed abnormal expression of synaptic proteins and tau hyperphosphorylation in the hippocampus and prefrontal cortex of PS cDKO mice. TCA treatment also ameliorated NMDA receptor (NMDAR) dysfunction including impaired NMDAR-mediated responses and long-term potentiation (LTP) induction in the hippocampus of PS cDKO mice. Moreover, TCA possesses an ability to suppress neuroinflammatory responses by diminishing microglial activation and levels of pro-inflammatory mediators in the hippocampus and prefrontal cortex of PS cDKO mice. Importantly, improving NMDAR dysfunction and memory deficits of PS cDKO mice was due to the inhibition of neuroinflammatory responses through TCA’s interruptive effect on the nuclear factor kappa B (NF-κB) signaling pathway. Therefore, TCA may be a potential anti-neuroinflammatory agent for deterring neurodegenerative progression of AD.     

酸枣仁汤通过抑制神经炎症和改善神经营养水平促进APP/PS1痴呆小鼠海马神经发生＊

目的 观察酸枣仁汤对APP/PS1痴呆小鼠海马促炎性因子和神经营养因子的影响，并探讨其改善神经发生的可能机制。方法 32只APP/PS1小鼠随机分为模型组（Model，20 mL·kg^-1）、多奈哌齐组（Donepezil，0.92 mg·kg^-1）、酸枣仁汤低剂量组（L-SZRD，12.96 g·kg^-1）和酸枣仁汤高剂量组（H-SZRD， 25.92 g·kg^-1），8只相同月龄和相同品系的C57BL/6JNju小鼠设为空白组（Control，20 mL·kg^-1）。灌胃30天后，采用HE染色观察小鼠海马病理形态变化，采用免疫荧光（IF）对小鼠海马中5-溴脱氧尿苷（BrdU）、肾上腺皮质激素（DCX）、神经元核抗原（NeuN）进行标记，采用免疫印迹（Western blot）检测各组小鼠海马中肿瘤坏死因子α（Tumor necrosis factor-α，TNF-α）、白细胞介素1β（Interleukin-1β，IL-1β）、白细胞介素6（Interleukin-6，IL-6）、c-fos、表皮细胞生长因子（Epidermal growth factor，EGF）、血管内皮生长因子（Vascular endothelial growth factor，VEGF）、脑源性神经营养因子（Brain derived neurotrophic factor，BDNF）的蛋白表达水平。结果 Control组小鼠海马CA3区和DG区细胞排列整齐，细胞染色均匀，细胞数量较多且细胞连接紧密。Model组小鼠海马CA3区和DG区细胞排列欠整齐，细胞核固缩明显，细胞数量明显减少。Donepezil组、L-SZRD组和H-SZRD组小鼠海马CA3区和DG区细胞排列稍整齐，细胞核固缩减少，细胞数量有所增加。与Control组比较，Model组小鼠海马DG区BrdU、DCX、NeuN标记的阳性细胞数明显减少（P < 0.01），与Model组比较，Donepezil组、L-SZRD组和H-SZRD组小鼠海马DG区BrdU、DCX、NeuN标记的阳性细胞数增加（P < 0.01，P < 0.05）。与Control组比较，Model组小鼠海马中TNF-α、IL-1β、IL-6、c-fos的蛋白表达水平明显升高（P < 0.01），而EGF、VEGF、BDNF的蛋白表达水平明显下降（P < 0.01），与Model组比较，Donepezil组、L-SZRD组和H-SZRD组小鼠海马中TNF-α、IL-1β、IL-6、c-fos的蛋白表达水平降低（P < 0.01，P < 0.05），而EGF、VEGF、BDNF的蛋白表达水平升高（P < 0.01，P < 0.05）。结论 酸枣仁汤可通过抑制神经炎症和改善神经营养促进APP/PS1痴呆小鼠海马神经发生。     

Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury

The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning.Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.