Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering

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Abstract. It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myoinositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 mol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.Organic osmolytes play a key role in cell volume homeostasis. Several organs, most notably the kidney and brain, are particularly dependent on adaptive mechanisms that regulate their volume during osmotic perturbations (1-3). The brain adapts to chronic (1-to 2-d) hyponatremia by extruding electrolytes and organic osmolytes, thus limiting brain cell swelling. Conversely, during correction of chronic hyponatremia, the restoration of brain osmolyte contents counters brain dehydration; however, this process normally requires several days for completion (4,5). Depletion of brain osmolytes during adaptation to chronic hyponatremia makes the brain vulnerable to injury when the hyponatremia is corrected. Brain myelinolysis is a well recognized consequence of excessive correction of chronic hyponatremia (6 -8). Among human subjects, additional risk factors, such as hypokalemia, chronic liver disease, diuretics (thiazides), or malnutrition, could also be implicated in the pathogenesis of this demyelinating disease (6). Areas of more severe injury are topographically correlated with sites that are more depleted of organic osmolytes after correction of hyponatremia (9).Urea has been successfully used to treat hyponatremia (10 -12). In previous studies, we demonstrated that exogenous urea protected animals against myelinolysis in a rat model of hyponatremia (6,13,14). Similarly, clinical observations suggest that uremic patients can tolerate large fluctuations in serum sodium levels without developing myelinolysis (15). We recently confirmed this hypothesi...

Section: Discussionmentioning

confidence: 99%

Rapid (24-Hour) Reaccumulation of Brain Organic Osmolytes (Particularly myo-Inositol) in Azotemic Rats after Correction of Chronic Hyponatremia

Soupart¹,

Silver²,

Schroöeder³

et al. 2002

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“…26,27 Other interventions that reduced mortality after the rapid correction of hyponatremia include the administration of myoinositol 28 or urea, 29 which affect the brain's organic osmolyte content. However, it is sometimes difficult to control the serum sodium levels or administer compounds such as myoinositol and urea in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Suzuki

Sugimura

Iwama

et al. 2010

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.

“…Thus far, re-lowering serum sodium is the most beneficial treatment when the initial osmotic injury has already occurred. 6,[33][34][35] Our results suggest that, in clinical practice, early administration of minocycline might have a role in preventing neurologic damage in hyponatremic patients who underwent rapid correction of their sodium deficit. Nevertheless, re-lowering of serum sodium should remain the treatment of choice when a toxic gradient is achieved until further work is done to fully explore the possibilities of minocycline in management of rapid correction of chronic hyponatremia in terms of the minimal effective dose and possible combination with re-lowering of serum sodium.…”

Section: Discussionmentioning

confidence: 84%

“…36,37 Pelleted chow was given to the animal on day 5 of the experiment, after the blood sampling for the determination of final 24-hour SNa; to avoid incidental re-lowering occurring at the day 5, water was given only at day 6 of the experiment. 6,33 Blood Measurements Blood samples (0.3 ml) were collected via tail transection at days 4 and 5 after light halothane anesthesia for serum sodium analysis. In animals of group 2, blood samples were taken after the first injection of minocycline.…”

Section: Drug Treatmentmentioning

confidence: 99%

Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia

Gankam-Kengne

Soupart

Pochet

et al. 2010

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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