Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons.

OBJECTIVES: The mood-stabilizing drug valproic acid (VPA) exerts a neurotrophic effect on the human neuroblastoma cell line, SH-SY5Y. We aimed to establish whether other mood-stabilizing drugs have a similar action and which signalling pathways mediate this process. METHODS: We analysed the effects of the mood stabilizers VPA, lithium, carbamazepine and lamotrigine on proliferation, survival, neurite outgrowth and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) activation using the SH-SY5Y cell line. We also compared their effects in primary neurons. RESULTS: We found that VPA promotes neurite outgrowth and prevents cell death in SH-SY5Y cells, but has no effect on cell proliferation. This neurotrophic effect does not involve inhibition of glycogen synthase kinase-3, histone deacetylase or prolyl oligopeptidase; the effect also does not seem to involve protein kinase C. In contrast, VPA activates ERK/MAPK and the survival effect of VPA is blocked by inhibition of the ERK/MAPK signalling pathway. Moreover, other activators of ERK/MAPK, such as epidermal growth factor and phorbol 12-myristate 13-acetate, mimic the neurotrophic effects of VPA. Other mood stabilizers do not activate ERK/MAPK and do not promote neurite outgrowth or survival of SH-SY5Y cells. In contrast, both lithium and VPA activate ERK/MAPK in rat primary cortical neurons. CONCLUSIONS: We investigated four mood stabilizers that are effective in the treatment of bipolar disorder. Our results suggest that, while some mood stabilizers may have additional neuroprotective effects, activation of ERK/MAPK does not appear to be a mechanism common to all mood-stabilizing drugs.