Injury of the Blood Brain Barrier and Up-Regulation of ICAM-1 in Polymicrobial Sepsis

Hofer, Stefan; Bopp, Christian; Hoerner, Christian R.; Plaschke, Konstanze; Faden, Rita M.; Martin, Eike; Bardenheuer, Hubert J.; Weigand, Markus A.

doi:10.1016/j.jss.2007.07.021

Cited by 69 publications

(49 citation statements)

References 30 publications

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“…Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser alterations in the volume of distribution but can also develop reduced drug clearances, causing an increase of the AUC in plasma (207). In experimental animals sepsis increased cerebral albumin extravasation as an indicator of the impaired integrity of the blood-brain/ blood-CSF barrier (69,92). Therefore, in the majority of cases, sepsis should lead to a moderate increase in the concentrations of anti-infectives in the CSF and other intracranial compartments.…”

Section: Penetration Of Anti-infectives Into the Csf And Brain Tissuementioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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Section: Penetration Of Anti-infectives Into the Csf And Brain Tissuementioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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“…Increased BBB permeability and altered expression of tight-junctional proteins were reported in three different inflammatory models (Table 3). Similarly, peripheral injection of LPS (the most commonly used model of acute systemic inflammation) induces, at very early stages, a cascade of events leading to BBB disruption, over-expression of adhesion molecules in endothelial cells, recruitment and infiltration of blood-derived leucocytes into brain tissue [61,100,118] (Table 4). Postmortem studies in human brain tissue also show considerable correlation between systemic inflammation and activation of endothelial and perivascular cells [135].…”

Section: Disruption Of Blood-brain Barriermentioning

confidence: 99%

The neuroinflammatory hypothesis of delirium

et al. 2010

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Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short-and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

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“…and plays a role in leukocyte migration in general but notably into the brain through the blood-brain barrier (13,40). Furthermore, upregulation of ICAM-1 expression on CNS vascular endothelial cells occurs during brain inflammation (13,20). P-selectin (CD62P) is an adhesion glycoprotein that is stored in Weibel-Palade bodies of endothelial cells and platelets, which are released upon activation.…”

Section: Therapy Of Cns Aspergillosismentioning

confidence: 99%

Experimental Central Nervous System Aspergillosis Therapy: Efficacy, Drug Levels and Localization, Immunohistopathology, and Toxicity

Clemons

Schwartz

Stevens

2012

Antimicrob Agents Chemother

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ABSTRACTWe have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice givenAspergillus fumigatusconidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.

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Injury of the Blood Brain Barrier and Up-Regulation of ICAM-1 in Polymicrobial Sepsis

Cited by 69 publications

References 30 publications

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

The neuroinflammatory hypothesis of delirium

Experimental Central Nervous System Aspergillosis Therapy: Efficacy, Drug Levels and Localization, Immunohistopathology, and Toxicity

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