A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency.
Both lithium and valproate have been used in the treatment of manic-depressive illness with very limited understanding of their therapeutic mechanism of action. Recent literature suggests that blocking of potassium channels may be a common therapeutic mechanism of many antidepressant agents. To determine whether the commonly used antimanic agents could prevent potassium efflux-induced cell damage and apoptosis and the underlying mechanisms, we treated SH-SY5Y human neuroblastoma cells with the potassium ionophore, valinomycin (2-100 microM) and observed cell shrinkage, mitochondria damage, a significant increase in of lactate dehydrogenase (LDH) activity and caspase-3 protein expression. Cells treated with lithium (0.5-3 mM) or valproate (0.07-1.4 mM) alone produced no apoptotic morphological and biochemical changes while both mood stabilizers pretreatment reduced or prevented the apoptotic morphological changes. However, valinomycin-induced caspase-3 elevation was only prevented by lithium pretreatment while both lithium and valproate attenuated valinomycin-induced LDH release. Our results suggest that lithium and valproate share a common neuroprotective action against potassium efflux-induced cell apoptosis with different mechanisms.
Li
R
R
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. rli@mail.sunhealth.org
El-Mallahk
R S
RS
D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014634:Valinomycin / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D018692:Antimanic Agents; D007476:Ionophores; D014634:Valinomycin; D014635:Valproic Acid; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D018021:Lithium Chloride