Plasma HMG CoA Reductase Activity Research Articles

Hypothalamic digoxin, hemispheric chemical dominance and syndrome X with multiple lacunar state. A hypothesis

This study assessed the changes in digoxin and some other metabolites of the isoprenoid pathway in metabolic syndrome X presenting with multiple lacunar state. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to find out the role of cerebral dominance in the genesis of syndrome X. There was an increase in plasma HMG CoA reductase activity with a consequent increase in serum digoxin, which caused a reduction in RBC membrane Na+-K+ ATPase activity. There was an increase in serum tryptophan and its metabolites and a decrease in tyrosine and its metabolites. Serum magnesium was decreased with consequent alteration in the metabolism of glycosaminoglycans and glycolipids. Increase in dolichol, another product of the isoprenoid pathway, resulted in alteration in glycoprotein metabolism. Changes in the composition of membrane glycosaminoglycans, glycoproteins and cholesterol:phospholipid ratio were also observed in this disorder leading to decreased lysosomal stability. Decrease in ubiquinone, another isoprenoid metabolite, resulted in alteration in the free radical generation. Membrane Na+-K+ ATPase inhibition due to digoxin, altered membrane structure, increased tryptophan catabolites and decreased tyrosine catabolites can lead to increased intracellular calcium and reduced intracellular magnesium which can account for the symptoms of syndrome X. The biochemical patterns including hyperdigoxinemia observed in syndrome X correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for syndrome X with multiple lacunar state.

HYPOTHALAMIC DIGOXIN, CEREBRAL CHEMICAL DOMINANCE, AND NITRIC OXIDE SYNTHESIS

The biochemical differences between right hemispheric dominant and left hemispheric dominant individuals are assessed with regard to nitric oxide synthesis. Nitric oxide is an important neurotransmitter involved in erectile function. The following parameters were evaluated: the plasma HMG CoA reductase activity, isoprenoid metabolite - digoxin, plasma magnesium and RBC membrane Na + -K + ATPase activity, and NO levels. The results showed that right hemispheric dominant individuals had increased plasma HMG CoA reductase activity and elevated digoxin levels, decreased plasma magnesium and RBC membrane Na + -K + ATPase activity, and increased levels of NO. Left hemispheric dominant individuals had the opposite patterns with reduced nitric oxide synthesis. Cerebral chemical dominance can regulate nitric oxide synthesis.

Isoprenoid pathway related cascade in multiple myeloma.

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in multiple myeloma. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+ - K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, nicotine, strychnine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins, cholesterol and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of lipid peroxidation products and NO increased. Hyperdigoxinemia related altered intracellular Ca++ mediated oncogene activation, dolichol induced altered glycoconjugate metabolism and ubiquinone deficiency related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical findings reported could be the cause or the consequence of multiple myeloma.

Hypothalamic digoxin-mediated model for epileptogenesis.

This study assessed the changes in the isoprenoid pathway and its metabolites in seizure disorder (ILAE classification - I generalized - idiopathic generalized epilepsy with age-related onset - epilepsy with generalized tonic clonic seizures on awakening) and the metabolic cascade produced by isoprenoid pathway dysregulation. The following parameters were assessed in seizure disorder: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugates metabolism and red blood cell (RBC) membrane composition. There was elevation in plasma HMG-CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na-K+ ATPase activity, serum magnesium and ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine and quinolinic acid were elevated while tyrosine, dopamine, morphine and norepinephrine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulfate), the activity of glycosaminoglycans (GAG) degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. Total serum cholesterol, LDL cholesterol and free fatty acids were increased while HDL cholesterol and triglycerides were unaltered. The concentration of membrane hexose, fucose, cholesterol and phospholipids in the RBC membrane decreased significantly but the total RBC membrane GAG was unaltered. Epileptogenesis could be due to a dysfunctional isoprenoidal pathway and paroxysmal hypothalamic digoxin hypersecretion.

Hypothalamic digoxin, cerebral chemical dominance, and nitric oxide synthesis.

The biochemical differences between right hemispheric dominant and left hemispheric dominant individuals are assessed with regard to nitric oxide synthesis. Nitric oxide is an important neurotransmitter involved in erectile function. The following parameters were evaluated: the plasma HMG CoA reductase activity, isoprenoid metabolite-digoxin, plasma magnesium and RBC membrane Na(+)-K(+) ATPase activity, and NO levels. The results showed that right hemispheric dominant individuals had increased plasma HMG CoA reductase activity and elevated digoxin levels, decreased plasma magnesium and RBC membrane Na(+)-K(+) ATPase activity, and increased levels of NO. Left hemispheric dominant individuals had the opposite patterns with reduced nitric oxide synthesis. Cerebral chemical dominance can regulate nitric oxide synthesis.

HYPOTHALAMIC DIGOXIN, HEMISPHERIC CHEMICAL DOMINANCE, AND ALZHEIMER'S DISEASE

This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Alzheimer's disease (AD). The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find the role of cerebral dominance in the genesis of Alzheimer's disease. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels, and a reduction in serum magnesium, RBC membrane Na+-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while serum tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated in Alzheimer's disease. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid increased. The activity of all free radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's disease, while the concentration of lipid peroxidation products and NO increased. The hypomagnesemia-related NMDA excitotoxicity, ubiquinone deficiency related mitochondrial dysfunction, and altered glycoconjugates/lysosomal stability could contribute to the pathogenesis of Alzheimer's disease. The biochemical patterns, including hyperdigoxinemia observed in Alzheimer's disease, correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for Alzheimer's disease.

HYPOTHALAMIC DIGOXIN-MEDIATED MODEL FOR PARKINSON'S DISEASE

The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na+-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na+-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.

HYPOTHALAMIC DIGOXIN, HEMISPHERIC CHEMICAL DOMINANCE, AND ONCOGENESIS: EVIDENCE FROM MULTIPLE MYELOMA

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with multiple myeloma were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Multiple myeloma occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function

SCHIZOID NEUROCHEMICAL PATHOLOGY-INDUCED MEMBRANE NA+-K+ ATPASE INHIBITION IN RELATION TO NEUROLOGICAL DISORDERS

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na+-K+ ATPase activity. Membrane Na+-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na+-K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na+-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na+-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature

HYPOTHALAMIC DIGOXIN, CEREBRAL DOMINANCE, AND MITOCHONDRIAL FUNCTION/FREE RADICAL METABOLISM

The present study assessed the biochemical differences of free radical metabolism and mitochondrial function between right hemispheric dominant and left hemispheric dominant individuals. The following parameters were measured: (1) plasma HMG CoA reductase activity, (2) isoprenoid metabolites--digoxin and ubiquinone, (3) plasma magnesium and RBC membrane Na+-K+ ATPase activity, (4) lipid peroxidation products--malondialdehyde, hydroperoxides and conjugated dienes, and NO, (5) reduced glutathione, and (6) activity of superoxide dismutase, catalase, GSH peroxidase, and GSH reductase. The results showed that right hemispheric dominant individuals had (i) increased plasma HMG CoA reductase activity and elevated digoxin levels, (ii) decreased plasma magnesium and RBC membrane Na+-K+ ATPase activity, (iii) reduced ubiquinone levels, (iv) with increased levels of lipid peroxidation products and NO, (v) decreased levels of reduced glutathione and free radical scavenging enzymes, and (vi) increased tryptophan and reduced tyrosine levels. Left hemispheric dominant individuals had the opposite patterns. Right hemispheric dominance represents a hyperdigoxinemic state with membrane sodium-potassium ATPase inhibition and increased lipid peroxidation. Left hemispheric dominance represents the reverse pattern with hypodigoxinemic/membrane sodium-potassium ATPase stimulation and decreased lipid peroxidation. Cerebral dominance can regulate mitochondrial function and free radical metabolism.

Hypothalamic digoxin and hypomagnesemia in relation to the pathogenesis of multiple sclerosis

AbstractThis study assessed the isoprenoid pathway‐related biochemical cascade in multiple sclerosis, and in this work we discuss the pivotal role of hypothalamic digoxin and membrane sodium‐potassium ATPase inhibition in the pathogenesis of multiple sclerosis. Our results showed that there was an elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels and a reduction in red blood cell (RBC) membrane sodium potassium ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated whereas tyrosine, dopamine, morphine, and noradrenaline were decreased. The total serum glycosaminoglycans, hyaluronic acid, heparin, and heparan sulphate were elevated and levels of chondroitin sulphates and dermatan sulphate were reduced in multiple sclerosis. The serum glycolipids as well as the hexose, fucose, and sialic acid carbohydrate residues of serum glycoproteins were elevated. The activity of glycosaminoglycan degrading enzymes was elevated. The activity of glycohydrolases—beta galactosidase and beta fucosidase—were increased and beta glucosidase reduced in the serum. The RBC membrane glycosaminoglycan, the hexose and fucose carbohydrate residues of glycoproteins, and the cholesterol:phospholipid ratio of the RBC membrane were decreased in multiple sclerosis. Membrane Na+‐K+ ATPase inhibition‐related increased intracellular calcium can produce immune activation via the calcineurin signal transduction system in T cells. Digoxin‐induced altered glycoconjugate metabolism can change the structural integrity of myelin as well as result in immune dysregulation caused by defective presentation of myelin glycoprotein antigens to CD8 cells. Digoxin‐induced defective membrane formation of oligodendrocyte membrane can inhibit remyelination. Digoxin‐related mitochondrial dysfunction can contribute to free radical generation, microglial activation, and oligodendrocyte apoptosis that are important in demyelination. J. Trace Elem. Exp. Med. 15:211–220, 2002. © 2002 Wiley‐Liss, Inc.