A hypothalamic digoxin mediated model for conscious and subliminal perception.
The isoprenoid pathway and its metabolites--digoxin, dolichol and ubiquinone were assessed in schizophrenia. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in schizophrenia. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead on to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites--serotonin and quinolinic acid (NMDA agonist), and decreased levels of hyperpolarising tyrosine catabolites--dopamine and noradrenaline contributing to membrane Na+-K+ ATPase inhibition. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistance important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging & defective apoptosis leading on to abnormal synaptogenesis. Schizophrenia can thus be considered as a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway.
Kumar
A R
AR
Department of Neurology, Medical College Hospital, Trivandrum, India.
Kurup
P A
PA
D000328:Adult; D003243:Consciousness / Q000502:physiology*; D004077:Digoxin / Q000097:blood*; D004286:Dolichols / Q000097:blood; D004791:Enzyme Inhibitors / Q000097:blood; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000097:blood; D007031:Hypothalamus / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D008960:Models, Psychological; D012559:Schizophrenia / Q000097:blood / Q000201:enzymology; D013360:Subliminal Stimulation
D004286:Dolichols; D004791:Enzyme Inhibitors; D004077:Digoxin; D006903:Hydroxymethylglutaryl CoA Reductases