neriifolin and cannogenin-thevetoside

Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na(+)K(+)-ATPase. The fourth compound, suloctidil, is a calcium channel blocker.

Topics: Apoptosis; Calcium Channels; Cardenolides; Caspase 3; Caspases; Cells, Cultured; Digitoxin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Muscular Disorders, Atrophic; Mutation; Peptides; Receptors, Androgen; Sodium-Potassium-Exchanging ATPase; Suloctidil; Trinucleotide Repeats

Effects of peruvoside and neriifolin, main components of neriperside, a tevetoside extracted from Thevitia neriifolia Juss, on Na+, K(+)-ATPase activities and on [3H] ouabain binding to the Na+, K(+)-ATPase isolated from hearts of guinea pigs, dogs and cats and kidneys of guinea pigs and cats were compared with digoxin and ouabain. It was found that peruvoside and neriifolin inhibited Na+, K(+)-ATPase activities and they showed a strong competitive inhibition on [3H] ouabain binding to the enzymes isolated from various tissues. A marked species difference existed as great as that of digitalis. The mechanism of action of these 2 drugs may be similar to that of digitalis. Their inhibitory effects on the enzyme activity were stronger than their positive inotropic effects, while both actions of digitalis were parallel quantitatively. There may be some differences in the modulation of the intracellular Ca2+ between neripersides and digitalis.

Topics: Animals; Binding, Competitive; Cardenolides; Cardiotonic Agents; Cats; Digoxin; Dogs; Guinea Pigs; Kidney; Myocardium; Ouabain; Sodium-Potassium-Exchanging ATPase; Species Specificity

Topics: Animals; Cardenolides; Cardiac Output, Low; Cardiotonic Agents; Female; Guinea Pigs; Male

Topics: Animals; Biological Availability; Cardenolides; Female; Guinea Pigs; Male; Radioimmunoassay

Topics: Animals; Cardenolides; Cardiotonic Agents; Cardiovascular System; Dogs; Female; Heart Failure; Male; Oxygen Consumption

Topics: Animals; Cardenolides; Cardiotonic Agents; Cats; Guinea Pigs; Heart Failure; In Vitro Techniques; Myocardial Contraction