Evaluation of neuroprotection by lithium and valproic acid against ouabain-induced cell damage.
BACKGROUND
The pathophysiology of manic-depression may be associated with dysregulation of ion homeostasis. Ouabain is a potent inhibitor of the sodium-potassium adenosine triphosphatase and has been purported to mimic abnormalities seen in acute mania. As manic episodes are believed to be neurotoxic and mood stabilizers have recently been implicated as neuroprotectants, it is of interest to determine if lithium and valproic acid antagonize ouabain-induced neurotoxicity.


METHODS
Human neuroblastoma SH-SY5Y cells were differentiated for 12 days then pretreated with lithium or valproic acid for 24 h and then challenged with a 10 microM ouabain insult. Cellular damage was assessed with lactate dehydrogenase (LDH) release, and apoptotic potential of ouabain was evaluated with DNA fragmentation.


RESULTS
Ouabain significantly increased LDH release after 72 h of treatment. Lithium pretreatment at 1 mM diminished ouabain-induced LDH release. Valproic acid alone at 100 and 1000 micrograms/mL significantly increased LDH release from the cells. Furthermore, it significantly potentiated ouabain-induced LDH release. DNA fragmentation suggests that ouabain induces apoptosis.


CONCLUSIONS
Lithium at the therapeutic level of 1 mM limits the extent of cellular damage caused by 10 microM ouabain in SH-SY5Y cells as measured by LDH release. Valproic acid alone at the therapeutic concentration of 100 micrograms/mL induces LDH release and does not prevent ouabain-induced LDH release.
Hennion
J P
JP
Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY 40292, USA.
el-Masri
M Adnan
MA
Huff
Mary O
MO
el-Mailakh
Rif S
RS
D018692:Antimanic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010042:Ouabain / Q000633:toxicity*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D018696:Neuroprotective Agents; D010042:Ouabain; D014635:Valproic Acid; D008094:Lithium; D007770:L-Lactate Dehydrogenase; D000254:Sodium-Potassium-Exchanging ATPase