Potential mechanisms underlying the accelerated cognitive decline in people with chronic low back pain: A scoping review

A growing body of evidence has shown that people with chronic low back pain (CLBP) demonstrate significantly greater declines in multiple cognitive domains than people who do not have CLBP. Given the high prevalence of CLBP in the ever-growing aging population that may be more vulnerable to cognitive decline, it is important to understand the mechanisms underlying the accelerated cognitive decline observed in this population, so that proper preventive or treatment approaches can be developed and implemented. The current scoping review summarizes what is known regarding the potential mechanisms underlying suboptimal cognitive performance and cognitive decline in people with CLBP and discusses future research directions. Five potential mechanisms were identified based on the findings from 34 included studies: (1) altered activity in the cortex and neural networks; (2) grey matter atrophy; (3) microglial activation and neuroinflammation; (4) comorbidities associated with CLBP; and (5) gut microbiota dysbiosis. Future studies should deepen the understanding of mechanisms underlying this association so that proper prevention and treatment strategies can be developed.     

三七皂苷R1对大鼠脊髓损伤后线粒体功能和神经炎症的作用及相关机制研究

【摘要】 目的：探究三七皂苷R1（notoginsenoside R1,NGR1）对大鼠脊髓损伤（spinal cord injury,SCI）后线粒体功能和神经炎症的作用及相关机制。方法：SPF级2月龄SD雄性大鼠80只,体质量为250～280g,按随机数字表法分为A1组、B1组、C1组和D1组,每组各20只。A1组仅暴露脊髓,B1组、C1组和D1组大鼠采用改良的Allen′s打击法建立急性SCI模型。A1组和B1组腹腔注射生理盐水,C1组、D1组腹腔注射对应剂量的NGR1和ML385[核因子E2 相关因子2（nuclear factor E2 related factor2,Nrf2）抑制剂]。给药1d、2d、3d采用BBB评分法评估大鼠后肢运动功能恢复情况;给药结束后,各取3只大鼠脊髓样本,铬化青染色与TUNEL染色观察大鼠脱髓鞘及细胞凋亡;利用试剂盒评估脊髓组织线粒体功能;ELISA检测脊髓组织炎症因子的表达;免疫荧光双染色检测脊髓组织离子钙结合衔接分子1（ionized calcium binding adapter molecule 1,Iba1）+诱导型一氧化氮合酶（inducible nitric oxide synthase,iNOS）+细胞数;RT-qPCR检测脊髓组织Nrf2、血红素加氧酶-1（heme oxygenase-1,HO-1）mRNA的表达;Western-blot检测脊髓组织Nrf2、HO-1、Bcl2 相关X（BCL2-associated X,Bax）蛋白、细胞淋巴瘤-2（B cell lymphoma-2,Bcl-2）蛋白表达。将购买的PC12细胞分为A2组、B2组、C2组和D2组。A2组正常培养,B2组、C2组和D2组细胞在含H2O2的培养基中培养,C2组和D2组分别加入的NGR1和ML385。各组细胞培养24h后采用CCK8法检测PC12细胞活性;Annexin V-FITC/PI染色检测PC12细胞凋亡;ELISA检测PC12细胞中炎症因子的表达;RT-qPCR检测PC12细胞Nrf2、HO-1 mRNA的表达;Western-blot检测PC12细胞Nrf2、HO-1、Bax蛋白、Bcl-2蛋白表达。结果：与A1组相比,B1组大鼠BBB评分降低,脱髓鞘加重,细胞凋亡增加,超氧化物歧化酶（superoxide dismutase,SOD）活性、Ca2+-Mg2+-ATP酶活性下降,丙二醛（malondialdehyde,MDA）浓度、磷脂酶A2（phospholipase A2,PLA2）活性升高,肿瘤坏死因子-α（tumor necrosis factor-α,TNF-α）、白介素-8 （interleukin-8,IL-8）、白介素-6（interleukin-6,IL-6）水平升高,Iba1+iNOS+细胞数增加,Bax蛋白、Nrf2、HO-1 mRNA和蛋白表达增加,Bcl-2蛋白表达减少（P＜0.05）;与B1组和D1组相比,C1组大鼠BBB评分升高（P＜0.05）,脱髓鞘减轻,细胞凋亡减少,SOD活性、Ca2+-Mg2+-ATP酶活性升高,MDA浓度、PLA2活性降低,TNF-α、IL-8和IL-6水平降低,Iba1+iNOS+细胞数减少,Bax蛋白表达减少,Nrf2、HO-1 mRNA和蛋白、Bcl-2蛋白表达增加（P＜0.05）。与A2组相比,B2组细胞活性降低,细胞凋亡增加,TNF-α、IL-8和IL-6水平升高,Bax蛋白、Nrf2、HO-1 mRNA和蛋白表达增加,Bcl-2蛋白表达减少（P＜0.05）;与B2组和D2组相比,C2组细胞活性升高,细胞凋亡减少,TNF-α、IL-8和IL-6水平降低,Bax蛋白表达减少,Nrf2、HO-1 mRNA和蛋白、Bcl-2蛋白表达增加（P＜0.05）。结论：NGR1能够减轻SCI大鼠脊髓细胞凋亡及氧化应激,促进大鼠运动功能恢复,改善大鼠SCI后线粒体功能和神经炎症;NGR1能够提高PC12细胞活性,抑制其凋亡和炎症水平,其通过激活Nrf2/HO-1信号通路发挥作用。     

Botanical Phenolics and Brain Health

The high demand for molecular oxygen, the enrichment of polyunsaturated fatty acids in membrane phospholipids, and the relatively low abundance of antioxidant defense enzymes are factors rendering cells in the central nervous system (CNS) particularly vulnerable to oxidative stress. Excess production of reactive oxygen species (ROS) in the brain has been implicated as a common underlying factor for the etiology of a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. While ROS are generated by enzymatic and nonenzymatic reactions in the mitochondria and cytoplasm under normal conditions, excessive production under pathological conditions is associated with activation of Ca²⁺-dependent enzymes including proteases, phospholipases, nucleases, and alterations of signaling pathways which subsequently lead to mitochondrial dysfunction, release of inflammatory factors, and apoptosis. In recent years, there is considerable interest to investigate antioxidative and anti-inflammatory effects of phenolic compounds from different botanical sources. In this review, we describe oxidative mechanisms associated with AD, PD, and stroke, and evaluate neuroprotective effects of phenolic compounds, such as resveratrol from grape and red wine, curcumin from turmeric, apocynin from Picrorhiza kurroa, and epi-gallocatechin from green tea. The main goal is to provide a better understanding of the mode of action of these compounds and assess their use as therapeutics to ameliorate age-related neurodegenerative diseases.     

MPTP-induced dopaminergic degeneration and deficits in object recognition in rats are accompanied by neuroinflammation in the hippocampus

Emotional changes, impairment of object recognition, and neuroinflammation are seen in Parkinson's disease with dementia (PDD). Here, we show that bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the rat substantia nigra pars compacta (SNc) of Wistar rats caused degeneration of nigrostriatal dopaminergic neurons, microglial activation in the SNc and hippocampus, and cell loss in the hippocampal CA1 area. With regard to behavior, an increase in anxiety-like behavior and impairment of object recognition were observed during the fourth week after MPTP lesioning. The behavioral changes were not caused by motor impairment, since the rats had already recovered from MPTP-induced catalepsy before the tests were performed. These findings show that MPTP-induced neuroinflammation and its consequences, for example, microglial activation and cell loss in the hippocampus, may be involved in dopaminergic degeneration-related behavioral deficits and suggest that, in addition to the dopaminergic system, the limbic system may also participate in the pathophysiology of PDD. MPTP-lesioned rats are therefore proposed as a useful tool for assessing the ability of pharmacological agents to prevent recognition deficits in PDD.     

Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada?

IntroductionSARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection.DevelopmentWe systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system.ConclusionsSARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.     

阿尔茨海默病中小胶质细胞的作用及针刺干预研究概况

阿尔茨海默病是最常见的神经退行性疾病,该病病因病机尚不明确,目前仍缺乏有效的治疗药物和治疗方法。小胶质细胞作为中枢神经系统固有的先天免疫细胞,其介导的神经炎症在阿尔茨海默病发病机制中起着核心作用,而自噬的激活可以减少神经细胞凋亡,抑制神经炎症。针刺对于治疗阿尔茨海默病疗效显著,且对小胶质细胞具有调控作用,能抑制中枢性炎症、激活自噬功能、调节突触可塑性。     

The fetal inflammatory response syndrome: the origins of a concept,pathophysiology, diagnosis,and obstetrical implications

The fetus can deploy a local or systemic inflammatory response when exposed to microorganisms or, alternatively, to non-infection-related stimuli (e.g., danger signals or alarmins). The term “Fetal Inflammatory Response Syndrome” (FIRS) was coined to describe a condition characterized by evidence of a systemic inflammatory response, frequently a result of the activation of the innate limb of the immune response. FIRS can be diagnosed by an increased concentration of umbilical cord plasma or serum acute phase reactants such as C-reactive protein or cytokines (e.g., interleukin-6). Pathologic evidence of a systemic fetal inflammatory response indicates the presence of funisitis or chorionic vasculitis. FIRS was first described in patients at risk for intraamniotic infection who presented preterm labor with intact membranes or preterm prelabor rupture of the membranes. However, FIRS can also be observed in patients with sterile intra-amniotic inflammation, alloimmunization (e.g., Rh disease), and active autoimmune disorders. Neonates born with FIRS have a higher rate of complications, such as early-onset neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and death, than those born without FIRS. Survivors are at risk for long-term sequelae that may include bronchopulmonary dysplasia, neurodevelopmental disorders, such as cerebral palsy, retinopathy of prematurity, and sensorineuronal hearing loss. Experimental FIRS can be induced by intra-amniotic administration of bacteria, microbial products (such as endotoxin), or inflammatory cytokines (such as interleukin-1), and animal models have provided important insights about the mechanisms responsible for multiple organ involvement and dysfunction. A systemic fetal inflammatory response is thought to be adaptive, but, on occasion, may become dysregulated whereby a fetal cytokine storm ensues and can lead to multiple organ dysfunction and even fetal death if delivery does not occur (“rescued by birth”). Thus, the onset of preterm labor in this context can be considered to have survival value. The evidence so far suggests that FIRS may compound the effects of immaturity and neonatal inflammation, thus increasing the risk of neonatal complications and long-term morbidity. Modulation of a dysregulated fetal inflammatory response by the administration of antimicrobial agents, anti-inflammatory agents, or cell-based therapy holds promise to reduce infant morbidity and mortality.     

U99194A对睡眠剥夺小鼠认知功能及海马肥大细胞活化的影响

目的:研究多巴胺受体3（dopamine receptor three, D3R）拮抗剂U99194A对睡眠剥夺（sleep deprivation, SD）小鼠认知功能及海马肥大细胞活化的影响。方法:将42只雄性C57BL/6小鼠采用随机数字表法分为3组（每组14只）：对照组（Ctrl组）、睡眠剥夺组（SD组）及睡眠...     

Reactive astrocytes and α1-antichymotrypsin in Alzheimer’s disease

There is ample genetic, biochemical, cellular and molecular evidence to show that the amyloid β peptide (Aβ), a proteolytic fragment of the amyloid precursor protein (APP), plays an important, if not causative role in Alzheimer’s disease (AD). An additional hallmark of AD is the neuroinflammatory response that is associated with the amyloid deposition. We discovered that the acute phase protein α1-antichymotrypsin (ACT) is overexpressed by reactive astrocytes, and is tightly associated with virtually all amyloid plaques in the AD brain. It has also been shown that Aβ and ACT bind in vitro. Recently, we have reported that astrocytic expression of ACT in APP transgenic mice leads to an increased plaque deposition in ACT/APP doubly transgenic mice compared to the APP mice alone, suggesting that ACT interferes with Aβ clearance. The main objective of this review is to summarize the role of astrocytosis and ACT in the pathogenesis of AD.     

Synergism in the repression of COX-2- and TNFα-induction in platelet activating factor-stressed human neural cells

Platelet activating factor (PAF; β-acetyl-γ-O-hexadecyl-l-α-phosphatidylcholine) triggers a rapid pro-inflammatory gene expression program in primary cultures of human neural (HN) cells. Two genes and gene products consistently induced after PAF treatment are the cytosoluble prostaglandin synthase cycloooxygenase-2 (COX-2) and the pro-apoptotic tumor necrosis factor alpha (TNFα). Both of these mediators are associated with the activation of inflammatory signaling, neural cell dysfunction, apoptosis and brain cell death, and both have been found to be up-regulated after brain injury in vivo. In this study we investigated the effects of the non-halogenated synthetic glucocorticoid budesonide epimer R (BUDeR), the novel PAF antagonist LAU-0901, and the electron spin trap and free radical scavenger phenyl butyl nitrone (PBN), upon early COX-2 and TNFα gene activation and prostaglandin E₂ (PGE₂) release in PAF-stressed primary HN cells. The data indicate that these three biochemically unrelated classes of inflammatory repressors act synergistically in modulating PAF-induced up-regulation of COX-2, TNFα, and PGE₂ by quenching oxidative stress or inflammatory signaling, resulting in increased HN cell survival. These, or analogous classes of compounds, may be useful in the design of more effective combinatorial pharmacotherapeutic strategies in the treatment of complex neuro-inflammatory disorders.