Microglial activation and increased synthesis of complement component C1q precedes blood–brain barrier dysfunction in rats

Lynch, Nicholas J.; Willis, Colin L.; Nolan, Christopher C.; Roscher, Silke; Fowler, Maxine J; Weihe, Eberhard; Ray, David; Schwaeble, Wilhelm

doi:10.1016/j.molimm.2003.08.009

Cited by 86 publications

(75 citation statements)

References 37 publications

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“…Neither fibrinogen nor mouse IgG could be detected in brains of either NGFQb-or Qb-immunized mice (n = 4 per group). In line with these results, brains of immunized mice did not show elevated CD68 immunoreactivity confirming the absence of elevated microglial activation, an early marker of BBB dysfunction (45). To validate our experiments, we included diseased mice with a known defect in the BBB and analyzed their brains.…”

Section: Influence Of Ngfqb Vaccination On Bbb and Basal Forebrain Chsupporting

confidence: 66%

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

Röhn¹,

Ralvenius

Paul

et al. 2011

The Journal of Immunology

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Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. For a substantial proportion of patients, conventional drug treatments do not provide adequate pain relief. Consequently, novel approaches to pain management, involving alternative targets and new therapeutic modalities compatible with chronic use, are being sought. Nerve growth factor (NGF) is a major mediator of chronic pain. Clinical testing of NGF antagonists is ongoing, and clinical proof of concept has been established with a neutralizing mAb. Active immunization, with the goal of inducing therapeutically effective neutralizing autoreactive Abs, is recognized as a potential treatment option for chronic diseases. We have sought to determine if such a strategy could be applied to chronic pain by targeting NGF with a virus-like particle (VLP)-based vaccine. A vaccine comprising recombinant murine NGF conjugated to VLPs from the bacteriophage Qβ (NGFQβ) was produced. Immunization of mice with NGFQβ induced anti-NGF–specific IgG Abs capable of neutralizing NGF. Titers could be sustained over 1 y by periodic immunization but declined in the absence of boosting. Vaccination with NGFQβ substantially reduced hyperalgesia in collagen-induced arthritis or postinjection of zymosan A, two models of inflammatory pain. Long-term NGFQβ immunization did not change sensory or sympathetic innervation patterns or induce cholinergic deficits in the forebrain, nor did it interfere with blood-brain barrier integrity. Thus, autovaccination targeting NGF using a VLP-based approach may represent a novel modality for the treatment of chronic pain.

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Section: Influence Of Ngfqb Vaccination On Bbb and Basal Forebrain Chsupporting

confidence: 66%

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

Röhn¹,

Ralvenius

Paul

et al. 2011

The Journal of Immunology

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“…Microglia can generate similar substances under ischemia-like 3,29 and ischemic 30 conditions. Lynch et al 31 correlated microglial activation to BBB disruption in a model of 3-chlorpropanediol toxicity. Although they showed increased complement and inflammatory cytokine expression in microglia where BBB disruption occurred, their study did not prove a direct detrimental role.…”

Section: Discussionmentioning

confidence: 99%

Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Yenari

Tang

et al. 2006

Stroke

322

264

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Background-Blood-brain barrier (BBB) disruption after stroke can worsen ischemic injury by increasing edema and causing hemorrhage. We determined the effect of microglia on the BBB and its primary constituents, endothelial cells (ECs) and astrocytes, after ischemia using in vivo and in vitro models. Methods and Results-Primary astrocytes, ECs, or cocultures were prepared with or without added microglia. Primary ECs were more resistant to oxygen-glucose deprivation/reperfusion than astrocytes. ECs plus astrocytes showed intermediate vulnerability. Microglia added to cocultures nearly doubled cell death. This increase was prevented by minocycline and apocynin. In vivo, minocycline reduced infarct volume and neurological deficits and markedly reduced BBB disruption and hemorrhage in mice after experimental stroke. Conclusions-Inhibition of microglial activation may protect the brain after ischemic stroke by improving BBB viability and integrity. Microglial inhibitors may prove to be an important treatment adjunct to fibrinolysis.

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“…C3 was also found to be produced by astrocytes and neurons in response to HIV or proinflammatory cytokines (74,314,457). Cultured human brain pericytes from a patient with Alzheimer's disease have been shown to produce C1q (512), and activated astroglial cells can produce C1q, which has been associated with increased blood-brain barrier damage in a rat model of neurotoxicity (306). Microglial cells have been shown to upregulate C1q, C3, C4, and C5a production in response to injury (183).…”

Section: The Complement Systemmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

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Microglial activation and increased synthesis of complement component C1q precedes blood–brain barrier dysfunction in rats

Cited by 86 publications

References 37 publications

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

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