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July 1967, Vol 17, No. 1 >
Article | July 1967

Experimental Uremic Encephalopathy: Title and subTitle BreakPermeability and Electrolyte Metabolism of Brain and Other Tissues

Robert A. Fishman, MD; Neil H. Raskin, MD
[+] Author Affiliations

Submitted for publication Feb 20, 1967; accepted March 3.

Read in part before the 1965 meeting of the American Neurological Association, June 14, 1965.

Reprint requests to Department of Neurology, University of California Medical Center, San Francisco 94122 (Dr. Fishman).


Arch Neurol. 1967;17(1):10-21. doi:10.1001/archneur.1967.00470250014002
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CLINICAL experience with the artificial kidney has established that toxic factors responsible for uremic encephalopathy are readily dialyzable, and thereby the neurological manifestation of uremia may be reversed rapidly. Despite greater sophistication in the management of renal insufficiency, the pathophysiology of the encephalopathy is poorly understood, and analyses of brain with traditional neuropathological techniques have failed to yield any specific structural correlations.1 Therefore, an experimental model of uremia was established in rats in order to characterize physiologically the encephalopathy in terms of several aspects of brain metabolism. Permeability of brain and other tissues was studied, using two nonmetabolized sugars, inulin14C (molecular weight 5,000) and sucrose14C (mol wt 342), and sulfate35S, when the latter was corrected for metabolic incorporation into plasma and brain.2 Sodium24 and potassium42 transfers were studied because of their pertinence to neural function, and the enzyme,

REFERENCES

1 +
Olsen, S.:  The Brain in Uremia , Acta Psychiat Scand 36( (suppl 156) ):1-128, 1961;.
2 +
Barlow, C.R., et al:  Extracellular Brain Space Measured by S35 Sulfate , Arch Neurol 5:102-110, 1961;.
3 +
McIlwain, H.: Chemical Exploration of the Brain: A Study of Cerebral Excitability and Ion Movement , New York: Elsevier Publishing Co., 1963;.
4 +
Raskin, N.H., and Fishman, R.A.:  Effects of Thyroid on Permeability, Composition, and Electrolyte Metabolism of Brain and Other Tissues , Arch Neurol 14:21-30, 1966;.
5 +
Lowry, O.H., et al:  The Quantitative Histochemistry of Brain: I. Chemical Methods , J Biol Chem 207:1-17, 1954;.
6 +
Cotlove, E.; Trantham, H.V.; and Bowman, R.L.:  An Instrument and Method for Automatic, Rapid, Accurate, and Sensitive Titration of Chloride in Biologic Samples , J Lab Clin Med 51:461-468, 1958;.
7 +
Schwartz, A.; Bachelard, H.S.; and McIlwain, H.:  The Sodium-Stimuated Adenosine-Triphosphatase Activity and Other Properties of Cerebral Microsomal Fractions and Subfractions , Biochem J 84:626-637, 1962;.
8 +
Noda, L.; Kuby, S.; and Lardy, H.: " ATPCreatine Transphosphorylase ," in Colowick, S.P., and Kaplan, N.O. (eds.): Methods in Enzymology , New York: Academic Press, vol 2, pp 605-610, 1955;.
9 +
Schreiner, G.E., and Maher, J.F.: Uremia: Biochemistry, Pathogenesis and Treatment , Springfield, Ill: Charles C Thomas, Publishers, 1961;.
10 +
Ginsburg, J.M., and Wilde, W.S.:  Distribution Kinetics of Intravenous Radiopotassium , Amer J Physiol 179:63-75, 1954;.
11 +
Wilde, W.S.: " Potassium ," in Colmar, C.L., and Bronner, F. (eds.): Mineral Metabolism: An Advanced Treatise , New York: Academic Press, vol 2, p 73, 1962;.
12 +
Knutson, J., and Baker. A.B.:  Central Nervous System in Uremia: Clinicopathologic Study , Arch Neurol 54:130-140, 1945;.
13 +
von Monakow, P.:  Urämie and Plexus Choriodei , Schweiz Arch Neurol Psychiat 13:515-525, 1923;.
14 +
Maher, J.F.; Freeman. R.B.: and Schreiner, G.E.:  Hemodialysis for Chronic Renal Failure: II. Biochemical and Clinical Aspects , Ann Intern Med 62:535-557, 1965;.
15 +
Clayton, E.M.; Seligson, D.; and Seligson, H.:  Inhibition of Protein Synthesis by N-methyl-2-pyridone-5-formamidoacetic Acid and Other Compounds Isolated From Uremic Patients , Yale J Biol Med 38:273-281, 1965;.
16 +
Seligson, H., and Seligson, D.:  N-methyl-2pyridone-5-carboxylic Acid and N-methyl-2-pyridone-5-formamidoacetic Acid Isolated From Dialysis Fluids of Uremic Patients , Clin Chim Acta 12:137-143, 1965;.
17 +
Kramer, B., et al:  The Isolation of Several Aromatic Acids From the Hemodialysis Fluids of Uremic Patients , Clin Chim Acta 11:363-371, 1965;.
18 +
Hicks, J.M.; Young, D.S.; and Wootton, I.D.P.:  The Effect of Uraemic Blood Constituents on Certain Cerebral Enzymes , Clin Chim Acta 9:228-235, 1964;.
19 +
Fishman, R.A.:  Blood-Brain and CSF Barriers to Penicillin and Related Organic Acids , Arch Neurol 15:113-124, 1966;.
20 +
Barlow, C.R.:  Clinical Aspects of the Blood-Brain Barrier , Ann Rev Med 15:187-202, 1964;.
21 +
Pappenheimer, J.R.; Heisey, S.R.; and Jordon, E.F.:  Active Transport of Diodrast and Phenolsulfonphthalein From Cerebrospinal Fluid to Blood , Amer J Physiol 200:1-10, 1961;.
22 +
Rail, D.P., and Zubrod, C.G.:  Mechanisms of Drug Absorption and Excretion: Passage of Drugs In and Out of the Central Nervous System , Ann Rev Pharmacol 2:109-128, 1962;.
23 +
Schanker, L.S.:  Passage of Drugs Across Body Membranes , Pharmacol Rev 14:501-530, 1962;.
24 +
Rail, D.P.; Stabenau, J.R.; and Zubrod, C.G.:  Distribution of Drugs Between Blood and Cerebrospinal Fluid: General Methodology and Effect of pH Gradients , J Pharm Exp Ther 125:185-197, 1959;.
25 +
Christy, N.P., and Fishman, R.A.:  Studies of the Blood-Cerebrospinal Fluid Barrier to Cortisol in the Dog , J Clin Invest 40:1997-2006, 1961;.
26 +
Coben, L.A.; Loeffler, J.D.; and Elsasser, J.C.:  Spinal Fluid Iodide Transport in the Dog , Amer J Physiol 206:1373-1378, 1964;.
27 +
Cserr, H.:  Potassium Exchange Between Cerebrospinal Fluid. Plasma, and Brain , Amer J Physiol 209:1219-1226, 1965;.
28 +
Katzman, R., et al:  Exchange of Cerebrospinal Fluid Potassium With Blood and Brain , Arch Neurol 13:513-524, 1965;.
29 +
Reed, D.J., et al:  Factors Affecting Distribution of Iodide in Brain and Cerebrospinal Fluid , Amer J Physiol 209:757-764, 1965;.
30 +
Fishman, R.A.:  Factors Influencing the Exchange of Sodium Between Plasma and Cerebrospinal Fluid , J Clin Invest 38:1698-1708, 1959;.
31 +
Lajtha, A.:  Protein Metabolism of the Nervous System , Int Rev Neurobiol 6:1-98, 1964;.
32 +
Fishman, R.A.:  Carrier Transport of Glucose Between Blood and Cerebrospinal Fluid , Amer J Physiol 206:836-844, 1964;.
33 +
Crone, C.:  Facilitated Transfer of Glucose From Blood into Brain Tissue , J Physiol 181:103-113, 1965;.
34 +
Freeman, R.B., et al:  The Blood-Cerebrospinal Fluid Barrier in Uremia , Ann Intern Med 56:233-240, 1962;.
35 +
Reed, D.J., and Woodbury, D.M.:  Kinetics of Movement of Iodide, Sucrose, Inulin, and Radioiodinated Serum Albumin in the Central Nervous System and Cerebrospinal Fluid of the Rat , J Physiol 169:816-850, 1963;.
36 +
van Harreveld, A.; Cromwell, J.; and Malhotra, S.K.:  A Study of the Extracellular Space in Central Nervous Tissue by Freeze-Substitution , J Cell Biol 25:117-137, 1965;.
37 +
Davson, H., and Bradbury, M.: " The Extracellular Space of the Brain ," in De Robertis, E.D.P., and Carrea, R. (eds.): Biology of Neuroglia Progress in Brain Research , Elsevier: Amsterdam, vol 15, pp 124-134, 1965;.
38 +
Katzman, R., and Wilson, C.E.:  Extraction of Lipid and Lipid Cation From Frozen Brain Tissue , J Neurochem 7:113-127, 1961;.
39 +
Wagner, J.W., and Garoutte, B.:  Relation Between Myelination and Binding of Sodium and Potassium in Rat Brain , Proc Soc Exp Biol Med 112:42-46, 1963;.
40 +
Katzman, R., and Leiderman, P.H.:  Brain Potassium Exchange in Normal Adult and Immature Rats, Amer J . Physiol 175:263-275, 1953;.
41 +
Glynn, I.M.:  The Action of Cardiac Glycosides on Ion Movements , Pharm Rev 16:381-407, 1964;.
42 +
Smith, E.K.M., and Welt, L.G.:  A Reversible Defect of Membrane ATPase in the Red Cells of Uremic Patients , Clin Res 15:51, 1967;.

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1 +
Olsen, S.:  The Brain in Uremia , Acta Psychiat Scand 36( (suppl 156) ):1-128, 1961;.
2 +
Barlow, C.R., et al:  Extracellular Brain Space Measured by S35 Sulfate , Arch Neurol 5:102-110, 1961;.
3 +
McIlwain, H.: Chemical Exploration of the Brain: A Study of Cerebral Excitability and Ion Movement , New York: Elsevier Publishing Co., 1963;.
4 +
Raskin, N.H., and Fishman, R.A.:  Effects of Thyroid on Permeability, Composition, and Electrolyte Metabolism of Brain and Other Tissues , Arch Neurol 14:21-30, 1966;.
5 +
Lowry, O.H., et al:  The Quantitative Histochemistry of Brain: I. Chemical Methods , J Biol Chem 207:1-17, 1954;.
6 +
Cotlove, E.; Trantham, H.V.; and Bowman, R.L.:  An Instrument and Method for Automatic, Rapid, Accurate, and Sensitive Titration of Chloride in Biologic Samples , J Lab Clin Med 51:461-468, 1958;.
7 +
Schwartz, A.; Bachelard, H.S.; and McIlwain, H.:  The Sodium-Stimuated Adenosine-Triphosphatase Activity and Other Properties of Cerebral Microsomal Fractions and Subfractions , Biochem J 84:626-637, 1962;.
8 +
Noda, L.; Kuby, S.; and Lardy, H.: " ATPCreatine Transphosphorylase ," in Colowick, S.P., and Kaplan, N.O. (eds.): Methods in Enzymology , New York: Academic Press, vol 2, pp 605-610, 1955;.
9 +
Schreiner, G.E., and Maher, J.F.: Uremia: Biochemistry, Pathogenesis and Treatment , Springfield, Ill: Charles C Thomas, Publishers, 1961;.
10 +
Ginsburg, J.M., and Wilde, W.S.:  Distribution Kinetics of Intravenous Radiopotassium , Amer J Physiol 179:63-75, 1954;.
11 +
Wilde, W.S.: " Potassium ," in Colmar, C.L., and Bronner, F. (eds.): Mineral Metabolism: An Advanced Treatise , New York: Academic Press, vol 2, p 73, 1962;.
12 +
Knutson, J., and Baker. A.B.:  Central Nervous System in Uremia: Clinicopathologic Study , Arch Neurol 54:130-140, 1945;.
13 +
von Monakow, P.:  Urämie and Plexus Choriodei , Schweiz Arch Neurol Psychiat 13:515-525, 1923;.
14 +
Maher, J.F.; Freeman. R.B.: and Schreiner, G.E.:  Hemodialysis for Chronic Renal Failure: II. Biochemical and Clinical Aspects , Ann Intern Med 62:535-557, 1965;.
15 +
Clayton, E.M.; Seligson, D.; and Seligson, H.:  Inhibition of Protein Synthesis by N-methyl-2-pyridone-5-formamidoacetic Acid and Other Compounds Isolated From Uremic Patients , Yale J Biol Med 38:273-281, 1965;.
16 +
Seligson, H., and Seligson, D.:  N-methyl-2pyridone-5-carboxylic Acid and N-methyl-2-pyridone-5-formamidoacetic Acid Isolated From Dialysis Fluids of Uremic Patients , Clin Chim Acta 12:137-143, 1965;.
17 +
Kramer, B., et al:  The Isolation of Several Aromatic Acids From the Hemodialysis Fluids of Uremic Patients , Clin Chim Acta 11:363-371, 1965;.
18 +
Hicks, J.M.; Young, D.S.; and Wootton, I.D.P.:  The Effect of Uraemic Blood Constituents on Certain Cerebral Enzymes , Clin Chim Acta 9:228-235, 1964;.
19 +
Fishman, R.A.:  Blood-Brain and CSF Barriers to Penicillin and Related Organic Acids , Arch Neurol 15:113-124, 1966;.
20 +
Barlow, C.R.:  Clinical Aspects of the Blood-Brain Barrier , Ann Rev Med 15:187-202, 1964;.
21 +
Pappenheimer, J.R.; Heisey, S.R.; and Jordon, E.F.:  Active Transport of Diodrast and Phenolsulfonphthalein From Cerebrospinal Fluid to Blood , Amer J Physiol 200:1-10, 1961;.
22 +
Rail, D.P., and Zubrod, C.G.:  Mechanisms of Drug Absorption and Excretion: Passage of Drugs In and Out of the Central Nervous System , Ann Rev Pharmacol 2:109-128, 1962;.
23 +
Schanker, L.S.:  Passage of Drugs Across Body Membranes , Pharmacol Rev 14:501-530, 1962;.
24 +
Rail, D.P.; Stabenau, J.R.; and Zubrod, C.G.:  Distribution of Drugs Between Blood and Cerebrospinal Fluid: General Methodology and Effect of pH Gradients , J Pharm Exp Ther 125:185-197, 1959;.
25 +
Christy, N.P., and Fishman, R.A.:  Studies of the Blood-Cerebrospinal Fluid Barrier to Cortisol in the Dog , J Clin Invest 40:1997-2006, 1961;.
26 +
Coben, L.A.; Loeffler, J.D.; and Elsasser, J.C.:  Spinal Fluid Iodide Transport in the Dog , Amer J Physiol 206:1373-1378, 1964;.
27 +
Cserr, H.:  Potassium Exchange Between Cerebrospinal Fluid. Plasma, and Brain , Amer J Physiol 209:1219-1226, 1965;.
28 +
Katzman, R., et al:  Exchange of Cerebrospinal Fluid Potassium With Blood and Brain , Arch Neurol 13:513-524, 1965;.
29 +
Reed, D.J., et al:  Factors Affecting Distribution of Iodide in Brain and Cerebrospinal Fluid , Amer J Physiol 209:757-764, 1965;.
30 +
Fishman, R.A.:  Factors Influencing the Exchange of Sodium Between Plasma and Cerebrospinal Fluid , J Clin Invest 38:1698-1708, 1959;.
31 +
Lajtha, A.:  Protein Metabolism of the Nervous System , Int Rev Neurobiol 6:1-98, 1964;.
32 +
Fishman, R.A.:  Carrier Transport of Glucose Between Blood and Cerebrospinal Fluid , Amer J Physiol 206:836-844, 1964;.
33 +
Crone, C.:  Facilitated Transfer of Glucose From Blood into Brain Tissue , J Physiol 181:103-113, 1965;.
34 +
Freeman, R.B., et al:  The Blood-Cerebrospinal Fluid Barrier in Uremia , Ann Intern Med 56:233-240, 1962;.
35 +
Reed, D.J., and Woodbury, D.M.:  Kinetics of Movement of Iodide, Sucrose, Inulin, and Radioiodinated Serum Albumin in the Central Nervous System and Cerebrospinal Fluid of the Rat , J Physiol 169:816-850, 1963;.
36 +
van Harreveld, A.; Cromwell, J.; and Malhotra, S.K.:  A Study of the Extracellular Space in Central Nervous Tissue by Freeze-Substitution , J Cell Biol 25:117-137, 1965;.
37 +
Davson, H., and Bradbury, M.: " The Extracellular Space of the Brain ," in De Robertis, E.D.P., and Carrea, R. (eds.): Biology of Neuroglia Progress in Brain Research , Elsevier: Amsterdam, vol 15, pp 124-134, 1965;.
38 +
Katzman, R., and Wilson, C.E.:  Extraction of Lipid and Lipid Cation From Frozen Brain Tissue , J Neurochem 7:113-127, 1961;.
39 +
Wagner, J.W., and Garoutte, B.:  Relation Between Myelination and Binding of Sodium and Potassium in Rat Brain , Proc Soc Exp Biol Med 112:42-46, 1963;.
40 +
Katzman, R., and Leiderman, P.H.:  Brain Potassium Exchange in Normal Adult and Immature Rats, Amer J . Physiol 175:263-275, 1953;.
41 +
Glynn, I.M.:  The Action of Cardiac Glycosides on Ion Movements , Pharm Rev 16:381-407, 1964;.
42 +
Smith, E.K.M., and Welt, L.G.:  A Reversible Defect of Membrane ATPase in the Red Cells of Uremic Patients , Clin Res 15:51, 1967;.

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