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.
Kurup
Ravi Kumar
RK
Department of Neurology, Medical College Hospital, Trivandrum, Kerala, India. kvgnair@satyam.net.in
Kurup
Parameswara Achutha
PA
D000368:Aged; D004077:Digoxin / Q000097:blood*; D004286:Dolichols / Q000097:blood; D004791:Enzyme Inhibitors / Q000097:blood; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006001:Glycoconjugates / Q000097:blood; D006025:Glycosaminoglycans / Q000097:blood; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014364:Tryptophan / Q000097:blood; D014443:Tyrosine / Q000097:blood; D014451:Ubiquinone / Q000097:blood
D004286:Dolichols; D004791:Enzyme Inhibitors; D006001:Glycoconjugates; D006025:Glycosaminoglycans; D008565:Membrane Proteins; D011106:Polyisoprenyl Phosphates; D014451:Ubiquinone; D014443:Tyrosine; D004077:Digoxin; D014364:Tryptophan; D006903:Hydroxymethylglutaryl CoA Reductases; D000254:Sodium-Potassium-Exchanging ATPase