Role of Cytokines as Mediators and Regulators of Microglial Activity in Inflammatory Demyelination of the CNS

Merson, Tobias D.; Binder, Michele D.; Kilpatrick, Trevor J.

doi:10.1007/s12017-010-8112-z

Cited by 85 publications

(58 citation statements)

References 449 publications

(457 reference statements)

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“…A number of studies have shown that the expression of iNOS and COX-2, key enzymes for NO, is upregulated in activated glial cells. Pro-inflammatory cytokines such as TNF-a and IL1b are also initiators of the inflammatory response and mediators in the pathogenesis of neurodegenerative disorders [23,24]. Previous evidence has demonstrated the damaging and inflammatory effects of these cytokines in neuropathology [25].…”

Section: Discussionmentioning

confidence: 99%

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

et al. 2015

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Microglia is the resident innate immune cells that sense pathogens and tissue injury in the central nervous system. Microglia becomes activated in response to injury, infection, and other stimuli that threaten neuronal survival. Microglia activation plays an important role in neurodegenerative diseases. Neochlorogenic acid (NCA) is a natural polyphenolic compound found in dried fruits and other plants. Although previous studies have shown that phenolic acids including NCA have outstanding antioxidant, antibacterial, antiviral, and antipyretic activities, there has not yet been investigated for anti-inflammatory effects. Therefore, for the first time we have examined the potential of NCA to inhibit microglial activation and pro-inflammatory responses in the brain. We found that lipopolysaccharide-induced inducible nitric oxide synthase, and cyclooxygenase-2 expression, and nitric oxide formation was suppressed by NCA in a dose-dependent manner in BV2 microglia. NCA also inhibited the production of pro-inflammatory mediators, tumor necrosis factor-α and interleukin-1 beta. Furthermore, phosphorylated nuclear factor-kappa B p65 and p38 mitogen-activated protein kinase activation were blocked by NCA. Taken together, these results suggest that NCA exerts neuroprotective effects through the inhibition of pro-inflammatory pathways in activated microglia.

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Section: Discussionmentioning

confidence: 99%

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

et al. 2015

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“…), there has not been an association found between pain and the site of demyelination 19 though it has been associated with depression, spinal cord involvement at the onset and the presence of spinal cord lesions 3 . The damage to the pain pathways has been theorized to possibly involve glia and cytokines 20 , which has been linked to the possible mechanism of central pain 21 . However, no significant pain relief has been found with any of the disease modifying medications that target the immune system.…”

Section: Discussionmentioning

confidence: 99%

Increased multiple sclerosis relapses related to lower prevalence of pain

Silva

Oliveira

Nascimento

et al. 2015

Arq. Neuro-Psiquiatr.

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While several studies have found a relationship for the development of pain related to one or more multiple sclerosis (MS) factors such as patient's age, duration of disease, disease course, and disability 1,2,3 , virtually an equal number have not 4,5 . Pain clearly has a role in the disease as its prevalence has been reported ranging up to 74% in MS outpatients 6 . While research does implicate factors that may be related to pain, multivariate analyses are lacking, which leaves the issue unclear as to the role of the various risk factors in the development of pain 6 . The development of MS pain and its severity has implications into the general evolution of the disease which itself varies amongst the different clinical forms [relapsing-remitting-(RR), primary progressive-(PP) and secondary progressive-(SP)] as well as its gender-specific presentation. This study investigates the prevalence and severity of pain amongst multiple variables in attempt to further elucidate the role of pain within the evolution of MS. Our goal is to evaluate these results within the context of the recent mechanisms of MS that have addressed not only gender AbstrActObjective: The study aims to investigate the presence of pain amongst multiple sclerosis (MS) patients. Method: One hundred MS patients responded to questionnaires evaluating neuropathic and nociceptive pain, depression and anxiety. Statistical analysis was performed using the Mann-Whitney U, Chi-Square and two-tailed Fisher's exact tests and multivariate logistic regression. Results: Women had a statistically higher prevalence of pain (p = 0.037), and chances of having pain after the age of 50 reduced. Women with pain had a statistically significant lower number of relapses (p = 0.003), restricting analysis to those patients with more than one relapse. After the second relapse, each relapse reduced the chance of having pain by 46%. Presence of pain was independent of Expanded Disability Status Scale (EDSS) anxiety, and depression. Conclusion: Our findings suggest a strong inverse association between relapses and pain indicating a possible protective role of focal inflammation in the control of pain.Keywords: multiple sclerosis, pain, prevalence, relapses, gender. resumoObjetivo: O estudo tem como objetivo investigar a presença de dor entre pacientes com esclerose múltipla (EM). Método: Cem pacientes com EM responderam a questionários avaliando dor neuropática e nociceptiva, depressão e ansiedade. A análise estatística foi realizada através dos testes de Mann-Whitney U, Qui-Quadrado, two tailed Fisher exact test e regressão logística multivariada. Resultados: As mulheres apresentaram estatisticamente uma maior prevalência de dor (p = 0,037), e as chances de ter dor após a idade de 50 reduziram. As mulheres com dor tinham um número com significância estatística reduzido de surtos (p = 0,003), restringindo a análise aos pacientes com mais de um surto. Após o segundo surto, cada surto reduziu a chance de ter dor em 46%. A presença de dor foi independente da Expanded Disabil...

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“…The activation, proliferation, recruitment, and conversion of microglia to a phagocytic amoeboid phenotype is an important cellular response that contributes to clearance of myelin debris in various models of CNS demyelination (Merson et al, 2010). In contrast, DT-challenged MBP-DTR mice exhibited only a modest increase in microglial cell density that retained a ramified morphology with evidence of process thickening reminiscent of "prephagocytic" lesions in early MS cases (Barnett and Prineas, 2004), and "predemyelinating" lesions described by Marik et al (2007).…”

Section: Immune Activity and Myelinationmentioning

confidence: 99%

Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination

Oluich

Stratton

Xing

et al. 2012

Journal of Neuroscience

108

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The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ϳ26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted.

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Role of Cytokines as Mediators and Regulators of Microglial Activity in Inflammatory Demyelination of the CNS

Cited by 85 publications

References 449 publications

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

Increased multiple sclerosis relapses related to lower prevalence of pain

Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination

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