Statins potentiate caspase-3 activity in immortalized murine neurons.
Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. However, there is growing evidence from epidemiological studies that long-term treatment with statins has unwanted effects on extrahepatic tissue and increases the risk for neuropathy. To investigate underlying molecular mechanisms we analyzed whether statins influence the activity of caspase-3 in immortalized neurons. Lovastatin and mevastatin are not able to activate caspase-3 but they strongly potentiate its activity when apoptotic signal transduction is initiated by staurosporine. The increase in caspase-3 activity after coincubation with statins and staurosporine was paralleled by an increase in the protein level of the pro-apoptotic GTPase RhoB. Our data provide evidence that statins enhance neuronal apoptosis and therefore give reasons for a careful evaluation when patients with neurological diseases are treated with these drugs.
Föcking
M
M
Max-Planck-Institute for Neurological Research, European Graduate School for Neuroscience (EURON), Gleueler Strasse 50, D-50931 Cologne, Germany.
Besselmann
M
M
Trapp
T
T
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D002461:Cell Line, Transformed; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000819:agonists / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019311:Staurosporine / Q000819:agonists / Q000494:pharmacology; D020743:rhoB GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C012258:mevastatin; D008148:Lovastatin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020743:rhoB GTP-Binding Protein; D019311:Staurosporine