Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons.
OBJECTIVE
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.
Di Daniel
Elena
E
Schizophrenia and Bipolar Disorder Research Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK. elena.2.didaniel@gsk.com
Mudge
Anne W
AW
Maycox
Peter R
PR
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011518:Proto-Oncogene Proteins; D011619:Psychotropic Drugs; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3