Role of organic osmolytes in myelinolysis. A topographic study in rats after rapid correction of hyponatremia.

Abstract

IntroductionOrganic osmolytes have been implicated in the pathogenesis of myelinolysis because some of them are accumulated slowly during correction of chronic hyponatremia. I investigated whether there was a topographic correlation between demyelinative lesions and the regional changes of organic osmolytes after rapid correction of chronic hyponatremia.In normal female Sprague-Dawley rats, concentrations of glutamate, glutamine, taurine, and betaine were highest in the cerebral cortex and decreased toward the brain stem. Conversely, glycine level was highest in the brainstem, and decreased toward the cortex. Myoinositol, glycerophosphorylcholine, glycerophosphorylethanolamine, and creatine were distributed more evenly. In chronic hyponatremic rats (plasma Na 110±4 meq/liter), organic osmolytes decreased globally with the total loss ranging from 13 (medulla) to 24 (cerebellum) mmol/kg H20. After rapid correction with intraperitoneal injection of hypertonic saline, the recovery of the loss of organic osmolytes was 48% in the cerebral cortex, cerebellum, and medulla oblongata, 44% in pons, but only 17% in midbrain and 36% in striatum. Histopathology of the brain was examined in nine rats 2-7 d after correction of hyponatremia. Large demyelinative lesions were seen persistently in the midbrain and striatum, and smaller lesions in cerebrum, cerebellum, and pons were found less frequently. This is the first report of regional distribution of brain organic osmolytes. (9), rapid correction of hyponatremia has been shown persistently resulting in demyelinative lesions. However, not all investigators agree on the association of rapid correction of hyponatremia with CPM. In a large autopsy series of CPM, it was found that hyponatremic patients only accounted for a small fraction (10). It is clear that rapid correction of hyponatremia is not the sole cause of CPM. Other factors such as alcoholism, malnutrition, chronic liver diseases, malignancy, severe burns, and potassium depletion are also important (1,(11)(12)(13).In this study, I investigated the role of organic osmolytes in the pathogenesis of myelinolysis in rats after rapid correction of hyponatremia. Organic osmolytes are important solutes which are accumulated in, or released from, cells during the adaptation process to the increase or decrease in surrounding osmolality. The major organic osmolytes in the brain are glutamate, glutamine, taurine, creatine/phosphocreatine, and myonositol (14-17). We have previously shown that after rapid correction of chronic hyponatremia, the reaccumulation of brain organic osmolytes in rats is outpaced by the reaccumulation of brain Na and Cl, and speculated that the delayed increase of organic osmolytes may be relevant to the development of myelinolysis (18). CPM and extrapontine myelinolysis in humans are anatomical site-specific lesions as described earlier (1, 2). The topographic distribution of demyelinative lesions induced by rapid correction of hyponatremia in rats was studied by 7). They demonstrated that after ...

Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

“…One important clue is that the distribution of astrocyte loss after ODS induction in this study seems to correlate with both the distribution of the main organic osmolyte transporter in the rat brain and the gradient of osmolyte depletion during chronic hyponatremia. 8,44 Another key observation was that supplementation with the osmolyte myo-inositol prevented experimental ODS 45 and astrocyte death upon hyperosmotic challenge in vitro. 46 By studying the temporal relationship between astrocyte and myelin loss, we showed that astrocyte death precedes demyelination.…”

“…Therefore, the overshooting of the optimal sodium concentration in the brain occurs in the context of depleted organic osmolytes. 7 Interestingly, regional differences in organic osmolyte reaccumulation have been associated with particular patterns of demyelination in ODS, 8 but the mechanisms connecting impaired osmolyte reaccumulation, myelin loss, and the cells involved in this process remain elusive.…”

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

“…In experimental models, brain regions that are slowest to recover osmolytes are the most severely affected by myelinolysis. 70 Uremia protects against myelinolysis and brain osmolytes are recovered more rapidly during correction of hyponatremia in animals that are uremic than in nonuremic animals. 71 Finally, infusion of myoinositol (a major osmolyte lost in the adaptation to hyponatremia) protects against mortality and myelinolysis from rapid correction of hyponatremia.…”

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