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 β III‐immunopositive ne...

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Bibliographic Details
Published in:	Journal of neurochemistry Vol. 91; no. 1; pp. 238 - 251
Main Authors:	Laeng, Pascal, Pitts, Richard L., Lemire, Andrew L., Drabik, Christopher E., Weiner, Arin, Tang, Haiping, Thyagarajan, Rathi, Mallon, Barbara S., Altar, C. Anthony
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Science Ltd 01-10-2004 Blackwell
Subjects:	Animals Astrocytes - drug effects Astrocytes - physiology bcl-Associated Death Protein Biological and medical sciences bipolar disorder Blotting, Western - methods Bromodeoxyuridine - metabolism Carrier Proteins - genetics Carrier Proteins - metabolism Cell Count - methods Cell Differentiation - drug effects Cells, Cultured Cyclin D2 Cyclins - metabolism differentiation Dose-Response Relationship, Drug Embryo, Mammalian Enzyme Inhibitors - pharmacology forebrain gamma-Aminobutyric Acid - metabolism Glial Fibrillary Acidic Protein - metabolism Glutamate Decarboxylase - metabolism Histones - metabolism Humans Hydroxamic Acids - pharmacology Immunohistochemistry - methods Interleukin-6 - pharmacology Leukemia Inhibitory Factor lithium Lithium Chloride - pharmacology Medical sciences mood stabilizer Neurons - drug effects Neurons - physiology Neuropharmacology Pharmacology. Drug treatments Prosencephalon - cytology Proto-Oncogene Proteins c-bcl-2 - metabolism Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Reverse Transcriptase Polymerase Chain Reaction - methods RNA, Messenger - biosynthesis stem cell Stem Cells - drug effects Stem Cells - physiology Time Factors Trans-Activators - genetics Trans-Activators - metabolism Tretinoin - pharmacology Tubulin - metabolism Valproic Acid - pharmacology Mood disorder Rat Stem cell Rodentia Central nervous system Lithium Valproic acid Neurogenesis Prosencephalon Vertebrata bipolar disorder Mammalia Mood stabilizer Animal Neurotransmitter GABA forebrain Differentiation
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Summary:	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 β 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 β 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3042 1471-4159
DOI:	10.1111/j.1471-4159.2004.02725.x