Blood–Brain Barrier Disruption and Complement Activation in the Brain Following Rapid Correction of Chronic Hyponatremia

Baker, Erin A.; Tian, Ying; Adler, Sheldon; Verbalis, Joseph G.

doi:10.1006/exnr.2000.7474

Cited by 72 publications

(52 citation statements)

References 29 publications

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“…The disruption of the BBB as a consequence of the rapid correction of hyponatremia has been thought to be involved in the pathogenesis of ODS. 24,25 However, the extravasation of IgG and EB dye as well as the efficacy of minocycline administration after the disruption of the BBB demonstrate that BBB permeability is not involved in the preventive mechanism of minocycline on ODS. Alternatively, as Kengne et al 26 reported, the increased permeability of BBB after the rapid correction of hyponatremia may not be essential in the pathogenesis of ODS.…”

Section: Discussionmentioning

confidence: 99%

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Suzuki

Sugimura

Iwama

et al. 2010

Journal of the American Society of Nephrology

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Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome (ODS), a severe demyelination disease. The microglia that accumulate in the demyelinative lesions may play a detrimental role in the pathogenesis of ODS by producing proinflammatory cytokines, suggesting that they may be a target for therapeutic intervention. Here, we investigated whether minocycline, a selective and potent inhibitor of microglial activation, could protect against ODS in rats. We induced hyponatremia by liquid diet feeding and dDAVP infusion. Rapid correction of the hyponatremia 7 days later resulted in neurologic impairment with severe demyelinative lesions. Activated microglia accumulated at the site of demyelination. Treatment with minocycline within 24 hours of rapid correction, however, was protective: rats exhibited minimal neurologic impairment, and survival improved. Histologic analysis showed that minocycline inhibited demyelination and suppressed the accumulation of microglia at the site of demyelination. Real-time RT-PCR and immunohistochemical analyses showed that minocycline inhibited the activity of microglia and the expression of inflammatory cytokines (e.g. IL-1␤, inducible nitric-oxide synthase, and TNF-␣), monocyte chemoattractant protein-1, and matrix metalloproteinase-12 in microglia. These results demonstrate that minocycline can protect against ODS by inhibiting the activation and accumulation of microglia at the site of demyelinative lesions, suggesting its possible use in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Suzuki

Sugimura

Iwama

et al. 2010

Journal of the American Society of Nephrology

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“…The fact that significant asymptomatic or pauci-symptomatic demyelination can occur despite minimal opening of the BBB together with our recent study using dexamethasone in ODS 6 challenge the assumption that opening of the BB in ODS plays a crucial role in the development of demyelination. 8,9,23,28 The same process could be applied to the role of microglia in ODS. In accordance with previous studies, [13][14][15]29 we found that minocycline reduced microglia-macrophage activation in CNS.…”

Section: Discussionmentioning

confidence: 99%

“…6 IgG immunohistochemistry was performed as an assessment of BBB reactivity as described previously, using one-step detection with biotinylated anti-rat IgG. 6,9 Myelin, Microglia-Macrophage Activation, and Astrocyte Loss Quantification Image quantification of areas of demyelination and GFAP loss was performed as described previously in animals treated with early minocycline and hypertonic saline. 38,39 Briefly, macro-images of stained sagittal sections of brain were obtained with a Nikon camera fitted with a Nikon macro-objective.…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

“…2,5,6 Previous experiments have suggested that ODS might share key characteristics with other models of central nervous system demyelination in which both opening of the blood-brain barrier (BBB) and microglia-macrophage activation are involved in the genesis of demyelinative changes. [7][8][9][10][11] Minocycline is a second-generation tetracycline that has been well studied in various models of brain pathology including autoimmune or ischemic myelin damage, and others have reported that administration of minocycline in CNS injury was associated with a striking reduction in BBB permeability, inhibition of microglia-macrophage activation, and inflammatory …”

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confidence: 99%

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Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia

Gankam-Kengne

Soupart

Pochet

et al. 2010

Journal of the American Society of Nephrology

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Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the bloodbrain barrier, inhibited microglial activation, decreased both the expression of IL1␣ and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans. Osmotic demyelination syndrome (ODS) is a severe neurologic condition that is characterized by severe demyelination in the central nervous system (CNS) secondary to osmotic imbalance. In a clinical setting, this syndrome often occurs after too rapid correction of chronic hyponatremia. [1][2][3][4][5] In ODS, demyelination is widespread in the brain, with predominance in hippocampus, basal ganglia, and subcortical regions. The physiopathology of this disorder is not yet fully understood, and an experimental murine model has been developed to better understand the mechanisms leading to myelin damage after an osmotic injury. 2,5,6 Previous experiments have suggested that ODS might share key characteristics with other models of central nervous system demyelination in which both opening of the blood-brain barrier (BBB) and microglia-macrophage activation are involved in the genesis of demyelinative changes. [7][8][9][10][11] Minocycline is a second-generation tetracycline that has been well studied in various models of brain pathology including autoimmune or ischemic myelin damage, and others have reported that administration of minocycline in CNS injury was associated with a striking reduction in BBB permeability, inhibition of microglia-macrophage activation, and inflammatory

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“…17 In essence, the fluctuations in osmolality that are associated with CPM have been shown to cause significant dehydration of brain endothelial cells. 18 This leads to disruption of the blood brain barrier and allows the entry of a variety of circulating immune factors to the central nervous system, where they can subsequently contribute to the demyelination process. Support for this theory comes from rodent studies in which dexamethasone exerted a protective effect against the development of myelinolysis, and human case reports in which patients with significant CPM responded to therapy with dexamethasone or intravenous immunoglobulin.…”

Section: Discussionmentioning

confidence: 99%

Central pontine myelinolysis secondary to hypokalaemic nephrogenic diabetes insipidus

Davenport¹,

Liew²,

Lau

et al. 2009

Ann Clin Biochem

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Central pontine myelinolysis (CPM) has been described in alcoholic patients and in the aftermath of rapid correction of chronic hyponatraemia. We describe a case of CPM occurring secondary to nephrogenic diabetes insipidus (DI), which developed as a consequence of severe hypokalaemia. A 63-year-old man with alcohol dependence was admitted to hospital with severe pulmonary sepsis and type 1 respiratory failure. On admission, he had euvolaemic hyponatraemia of 127 mmol/L, consistent with a syndrome of inappropriate antidiuretic hormone secondary to his pneumonia. Following admission, his plasma potassium dropped from 3.2 to a nadir of 2.3 mmol/L. Mineralocorticoid excess, ectopic adrenocorticotrophic hormone production and other causes of hypokalaemia were excluded. The hypokalaemia provoked significant hypotonic polyuria and a slow rise in plasma sodium to 161 mmol/L over several days. Plasma glucose, calcium and creatinine were normal. The polyuria did not respond to desmopressin, and subsequent correction of his polyuria and hypernatraemia after normalization of plasma potassium confirmed the diagnosis of nephrogenic DI due to hypokalaemia. The patient remained obtunded, and the clinical suspicion of osmotic demyelination was confirmed on magnetic resonance imaging. The patient remained comatose and passed away 10 days later. This is the first reported case of nephrogenic DI resulting in the development of CPM, despite a relatively slow rise in plasma sodium of less than 12 mmol/L/24 h. Coexisting alcohol abuse, hypoxaemia and hypokalaemia may have contributed significantly to the development of CPM in this patient.

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Blood–Brain Barrier Disruption and Complement Activation in the Brain Following Rapid Correction of Chronic Hyponatremia

Cited by 72 publications

References 29 publications

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia

Central pontine myelinolysis secondary to hypokalaemic nephrogenic diabetes insipidus

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