The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells.
Valproate, an anticonvulsant drug used to treat bipolar disorder, was studied for its ability to promote neurogenesis from embryonic rat cortical or striatal primordial stem cells. Six days of valproate exposure increased by up to fivefold the number and percentage of tubulin beta III-immunopositive neurons, increased neurite outgrowth, and decreased by fivefold the number of astrocytes without changing the number of cells. Valproate also promoted neuronal differentiation in human fetal forebrain stem cell cultures. The neurogenic effects of valproate on rat stem cells exceeded those obtained with the neurotrophins brain-derived growth factor (BDNF) or NT-3, and slightly exceeded the effects obtained with another mood stabilizer, lithium. No effect was observed with carbamazepine. Most of the newly formed neurons were GABAergic, as shown by 10-fold increases in neurons that immunostained for GABA and the GABA-synthesizing enzyme GAD65/67. Double immunostaining for bromodeoxyuridine and tubulin beta III showed that valproate increased by four- to fivefold the proliferation of neuronal progenitors derived from rat stem cells and increased cyclin D2 expression. Valproate also regulated the expression of survival genes, Bad and Bcl-2, at different times of treatment. The expression of prostaglandin E synthase, analyzed by quantitative RT-PCR, was increased by ninefold as early as 6 h into treatment by valproate. The enhancement of GABAergic neuron numbers, neurite outgrowth, and phenotypic expression via increases in the neuronal differentiation of neural stem cell may contribute to the therapeutic effects of valproate in the treatment of bipolar disorder.
Laeng
Pascal
P
Gene Discovery, Psychiatric Genomics, Inc., Gaithersburg, Maryland 20878, USA. plaeng@psygenomics.com
Pitts
Richard L
RL
Lemire
Andrew L
AL
Drabik
Christopher E
CE
Weiner
Arin
A
Tang
Haiping
H
Thyagarajan
Rathi
R
Mallon
Barbara S
BS
Altar
C Anthony
CA
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D018021:Lithium Chloride / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016548:Prosencephalon / Q000166:cytology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D051025:bcl-Associated Death Protein; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C494819:BAD protein, human; C494821:Bad protein, rat; C080336:CCND2 protein, human; D002352:Carrier Proteins; D056742:Cyclin D2; D016213:Cyclins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D006657:Histones; D006877:Hydroxamic Acids; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D015534:Trans-Activators; D014404:Tubulin; D051025:bcl-Associated Death Protein; C012589:trichostatin A; D005680:gamma-Aminobutyric Acid; D014212:Tretinoin; D014635:Valproic Acid; D005968:Glutamate Decarboxylase; D001973:Bromodeoxyuridine; D018021:Lithium Chloride