Background
Sodium and potassium-activated adenosine triphosphatase (Na+, K+-ATPase) and endogenous digitalis-like compounds (DLC) in the brain have been implicated
in the pathogenesis of mood disorders. This hypothesis was examined by the determination
of Na+, K+-ATPase/DLC system in parietal cortex of patients with different mood disorders and
two animal models of depression.
Methods
Na+, K+-ATPase concentrations in human brain synaptosomal fractions, from patients with mood
disorders, schizophrenia, and normal individuals, were determined by 3H-ouabain binding assay. Alpha isoforms were quantified by Western blotting. Brain
DLC were measured using sensitive enzyme linked immunosorbant assay (ELISA). The effects
of ouabain and ouabain-antibodies on behavior were determined in two animal models
of depression.
Results
3H-ouabain binding in bipolar patients was significantly lower than in major depressed
and schizophrenic patients. Na+, K+-ATPase α isoforms in synaptosomal fractions were not different among the groups.
DLC levels in the parietal cortex of bipolar patients were significantly higher than
in normal individuals and depressed patients. Injection of lipopolysaccharide (intraperitoneally)
to rats elicited depression-like symptoms, which were significantly attenuated by
pre-injection of ouabain-antibodies. Injection of ouabain and ouabain-antibodies (intracerebroventricular)
reduced depression-like symptoms in the forced swimming test in rats.
Conclusions
The results support the possibility that Na+, K+-ATPase and endogenous DLC participate in the pathogenesis of depressive disorders.
Key Words
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References
- Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 are associated with Rapid-Onset Dystonia Parkinsonism.Neuron. 2004; 43: 169-175
- Ouabain, a steroid hormone that signals with slow calcium oscillations.Proc Natl Acad Sci USA. 2001; 98: 13420-13424
- Cardiotonic steroids differentially affect intracellular Na+ and [Na+]i/[K+]i-independent signaling in C7-MDCK cells.J Biol Chem. 2005; 280: 832-839
- Endogenous digitalis-like ligands of the sodium pump.European Neuropsychopharmacol. 2002; 12: 1-12
- Cardenolide and bufadienolide ligand of the sodium pump. How they work together in NaCl sensitive hypertension.Frontiers in Bioscience. 2005; 10: 2250-2256
- Isozymes of the Na-K-ATPase.Am J Physiol. 1998; 275: F633-F650
- Desipramine restricts estrous cycle oscillations in swimming. Prog.. Neuro psychopharmacol.Biol Psychiatry. 1998; 22: 1121-1128
- Lateral septal neural firing rate increasing during proestrus-estrus in the rat.Physiol Behav. 2000; 68: 279-284
- Mineral metabolism in mania.Br Med J. 1966; 5479: 71-75
- Finding the intracellular signaling pathways affected by mood disorder treatments.Neuron. 2003; 38: 157-160
- Possible role of endogenous ouabain-like compounds in the pathophysiology of bipolar illness.Med Hypotheses. 1993; 41: 378-383
- Intracerebroventricular administration of ouabain as a model of mania in rats.Bipolar Disord. 2003; 5: 362-365
- The Na, K-ATPase hypothesis for bipolar illness.Biol Psychiatry. 1995; 37: 235-244
- Endogenous ligand of alpha(1) sodium pump, marinobufagenin, is a novel mediator of sodium chloride–dependent hypertension.Circulation. 2002; 105: 1122-1127
- Opioid tolerance and the emergence of new opioid receptor-coupled signaling.Mol Neurobiol. 2000; 21: 21-33
- Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides.J Gen Physiol. 2002; 19: 297-312
- Isolation of a urinary digitalis-like factor indistinguishable from digoxin.Biochem Biophys Res Commun. 1990; 173: 1093-1101
- Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls.J Affective Disorders. 1999; 54: 261-267
- Corticosteroid and corticosteroid metabolite levels in animals immunized against corticosteroids.J Steroids Biochem. 1979; 11: 971-980
- Biosynthesis of endogenous cardiac glycosides by mammalian adrenocortical cells.Clin Chem. 2004; 50: 469-470
- Identification and characterization of ouabain-like compound from human plasma.Proc Natl Acad Sci USA. 1991; 88: 6259-6263
- Ouabain-induced cell signaling.Frontiers in Bioscience. 2005; 10: 2011-2017
- Simultaneous isolation of endogenous digoxin-like immunoreactive factor, ouabain-like factor, and deglycosylated congeners from mammalian tissues.Arch Biochem Biophys. 1996; 328: 193-200
- An inhibitor of the sodium pump obtained from human placenta.Lancet. 1996; 348: 303-305
- Brain ouabain, sodium, and arterial baroreflex in spontaneous hypertensive rats.Hypertension. 1995; 25: 814-817
- Pharmacological treatment of heart failure.in: Herdamn J.G. Limbird L.E. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th Edition. McGraw-Hill, 1996: 809-838
- Ouabain is secreted by bovine adrenocortical cells.Endocrinology. 1994; 135: 794-797
- Dietary sodium and central vs. peripheral ouabain-like activity in Dahl salt-sensitive vs. salt-resistant rats.Am J Physiol. 1994; 267: H1916-H1920
- Brain “ouabain” mediates sympathetic hyperactivity in congestive heart failure.Circ Res. 1995; 77: 993-1000
- Structural and functional interaction sites between Na, K-ATPase and FXYD proteins.J Biol Chem. 2004; 279: 38895-38902
- Lithium prevents ouabain-induced behavioral changes. Toward an animal model for manic depression.Mol Chem Neuropathol. 1997; 31: 65-72
- Identification of digitalis-like compounds in human cataractous lenses.Eur J Biochem. 1993; 216: 261-268
- The effects of digitalis-like compounds on rat lenses.Invest Ophthalmol Vis Sci. 1999; 40: 407-413
- Endogenous digitalis-like Na+, K+-ATPase inhibitors and brain function.Neurochem Res. 2001; 26: 971-978
- Characterization of the stimulation of neuronal Na+, K+-ATPase activity by low concentrations of ouabain.Neurochem Int. 1985; 7: 709-715
- Biosynthesis of digitalis-like compounds in rat adrenal cells.Life Sci. 1998; 62: 2109-2126
- Meta-analysis of erythrocyte Na,K-ATPase activity in bipolar illness.Depress Anxiet. 1997; 5: 53-65
- Increased cerebrospinal fluid levels of S100B protein in rat model of mania induced by ouabain.Life Sci. 2004; 76: 805-811
- The cellular neurobiology of depression.Nat Med. 2001; 7: 541-547
- Thalamo-cortical projections to the posterior parietal cortex in the monkey.Neurosci Lett. 2004; 355: 113-116
- Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions.Biosci Rep. 2000; 20: 51-91
- Evidence for an allelic association between bipolar disorder and a Na+K+ adenosine triphosphatase alpha subunit gene (ATP1A3).Biol Psychiatry. 1998; 44: 47-51
- Changes in erythrocyte sodium and potassium on recovery from depressive illness.Br J Psychiatry. 1971; 118: 219-223
- Neurobiology of depression.Neuron. 2002; 34: 13-25
- Red cell ouabain-sensitive Na+-K+-adenosine triphosphatase.Biol Psychiatry. 1982; 17: 981-992
- Projection from the thalamic intralaminar nuclei on the isocortex of the rat.Exp Brain Res. 1989; 75: 543-554
- Immobility induced by forced swimming in rats.Eur J Pharmacol. 1979; 57: 201-210
- Depression.Nature. 1977; 266: 730-732
- Behavioral models of depression.in: Elliot J.M. Heal D.J. Maisden C.A. Experimental Approaches to Anxiety and Depression. John Wiley & Sons Ltd, New York1992: 73-85
- Cytokine-associated emotional and cognitive disturbances in humans.Arch Gen Psychiatry. 2001; 58: 445-452
- Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion.Psychoneuroendocrinology. 2002; 27: 945-956
- Neuroendocrinology of acute immunity.J Endocrinol Invest. 2004; 27: 48-56
- Alpha2 isoform of the Na,K-Adenosine Triphosphatase is reduced in temporal cortex of bipolar individuals.Biol Psychiatry. 1998; 44: 892-897
- Cardiac steroids induce changes in recycling of the plasma membrane in human NT2 cells.Mol Biol Cell. 2004; 15: 1044-1054
- The sodium pump, its molecular properties and mechanics of ion transport.Eur J Biochem. 2002; 269: 2424-2433
- Ouabain as a mammalian hormone.Ann N Y Acad Sci. 2003; 986: 678-684
- Mineral metabolism, mania, and melancholia.Br Med J. 1966; 5508: 262-267
- Pulse pressure correlates in humans with a Proscillaridin A immunoreactive compound.Hypertension. 1996; 27: 1073-1078
- Alternating hemiplegia of childhood or Familial Hemiplegic Migraine?.Annals of Neurol. 2004; 55: 884-887
- The Stanley foundation brain collection and neuropathology consortium.Schizophr Res. 2000; 44: 151-155
- The mood cycle hypothesis.J Basic Clin Physiol Pharmacol. 2000; 11: 375-394
- Physicochemical characterization of a ouabain isomer isolated from bovine hypothalamus.Proc Natl Acad Sci USA. 1993; 90: 8189-8193
- Regulation of muscarinic acetylcholine receptor signaling.Pharmacol Ther. 2003; 98: 197-220
- The beta-adrenergic receptors.Herz. 2002; 27: 683-690
- Direct studies of ligand-receptor interactions and ion channel blocking.Mol Membr Biol. 2002; 19 (Review): 267-275
- Validity, reliability and utility of the chronic mild stress model of depression.Psychopharmacology. 1997; 134: 319-329
- Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons.J Neurosci. 2002; 22: 1350-1362
- Na+-K+-ATPase-mediated signal transduction.Mol Interv. 2003; 3: 157-168
- Endotoxin produces a depressive-like episode in rats.Brain Res. 1996; 711: 163-174
- Behavioral and psychological effects of immune activation.Current Opinion in Psychiatry. 1997; 10: 470-476
- Antidepressants modulate the behavioral and physiological responses to endotoxin in rats and mice.Neuropsychopharmacol. 2001; 24: 531-544
Article info
Publication history
Published online: May 24, 2006
Accepted:
December 5,
2005
Received in revised form:
November 17,
2005
Received:
July 28,
2005
Identification
Copyright
© 2006 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
