Rapid correction of hyponatremia, a common medical condition, may cause pontine and extrapontine demyelination in both animals and humans. Recent reports reveal that rapid increases in plasma sodium and osmolality disrupt the blood-brain barrier (BBB) of chronic hyponatriemic rats at a lower plasma osmolality values than in either acute hyponatriemic or normonatriemic control rats; that rapid increases in plasma sodium markedly increased cerebral perfusion; and that disruption of the BBB occurring after rapid correction of chronic hyponatremia preceded and appeared to be related to the development of demyelination. The overall study objective, therefore, is to determine how these alterations in BBB permeability and cerebral perfusion relate to the subsequent development of neurologic symptoms and demyelination which follows rapid correction of chronic hyponatremia. Experiments will use a stable CHN rat model which on rapid correction of hyponatremia produces demyelination in 50-60 percent of rats. Uncorrected CHN rats will serve as controls. Studies will include: 1) immunocytochemical analyses of brains for IgG and albumin to determine when and where BBB permeability increases during correction and the relationship to demyelination determined by luxol blue histopathology. 2) Immunocytochemical analyses of brain tissue to determine if complement, leukocytes and the C5b-9 complex membrane attack may contribute to demyelination. 3) in vivo h-NMR arterial spin tagging or 14C-IAP measurement of cerebral perfusion to determine the effect of correction on global and regional cerebral perfusion and identification of mediators responsible for alterations in perfusion. 4) Determining whether prevention of perfusion changes will affect the threshold for BBB disruption measured by NMR determination of gadolinium-DTPA leakage into brain. 5) Examining whether increased osmolality alters cerebral energy metabolism by measuring 14C-2DG uptake and using 31P-NMR spectroscopy to measure bioenergetics. 6) Determining the effect of alterations in BBB permeability, cerebral perfusion, cerebral energy metabolism and complement activation on the development of neurologic dysfunction and demyelination. These experiments should identify the mechanisms by which correction of hyponatremia causes demyelination and should provide a model for studying other demyelinating diseases such as MS and other CNS diseases such as head trauma and AIDS, each of which exhibits BBB disruption.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026610-07
Application #
2714471
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Jacobs, Tom P
Project Start
1992-04-30
Project End
2001-05-31
Budget Start
1998-06-01
Budget End
2001-05-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Adler, S; Verbalis, J G; Meyers, S et al. (2000) Changes in cerebral blood flow and distribution associated with acute increases in plasma sodium and osmolality of chronic hyponatremic rats. Exp Neurol 163:63-71
Baker, E A; Tian, Y; Adler, S et al. (2000) Blood-brain barrier disruption and complement activation in the brain following rapid correction of chronic hyponatremia. Exp Neurol 165:221-30
Adler, S; Martinez, J; Williams, D S et al. (2000) Positive association between blood brain barrier disruption and osmotically-induced demyelination. Mult Scler 6:24-31
Adler, S; Verbalis, J G; Williams, D (1995) Effect of rapid correction of hyponatremia on the blood-brain barrier of rats. Brain Res 679:135-43
Adler, S; Verbalis, J G; Williams, D (1994) Brain buffering is restored in hyponatremic rats by correcting their plasma sodium concentration. J Am Soc Nephrol 5:85-92
Adler, S; Williams, D; Verbalis, J G (1993) Effect of acute and chronic hyponatremia on blood-brain barrier function in the rat. NMR Biomed 6:119-24
Adler, S; Verbalis, J G; Williams, D (1993) Effect of acute and chronic hyponatremia on brain buffering in rats. Am J Physiol 264:F968-74