Mood Stabilizing Drugs Expand the Neural Stem Cell Pool in the Adult
Brain Through Activation of Notch Signaling
First Published: May 8, 2008
* To whom correspondence should be addressed. E-mail:
shitoshi@nips.
Neural stem cells (NSCs) have attracted considerable attention as a
potential source of cells for therapeutic treatment of impaired areas
of the central nervous system. However, efficient and clinically
feasible strategies for expansion of the endogenous NSC pool are
currently unavailable. In this study, we demonstrate that mood
stabilizing drugs, which are used to treat patients with bipolar
disorder, enhance the self-renewal capability of mouse NSCs in vitro
and that this enhancement is achieved at therapeutically relevant
concentrations in the cerebrospinal fluid. The pharmacological
effects are mediated by the activation of Notch signaling in the NSC.
Treatment with mood stabilizers increased an active form of Notch
receptor and upregulated its target genes in neural stem/progenitor
cells, whereas co-culture with -secretase inhibitor or the presence
of mutation in the presenilin1 gene blocked the effects of mood
stabilizers. In addition, chronic administration of mood stabilizers
expanded the NSC pool in the adult brain, which subsequently
increased the cell supply to the olfactory bulb. We suggest that
treatment with mood stabilizing drugs could be used to facilitate
regeneration following insult to the central nervous system.
Mikito Higashi 1, Noriko Maruta 2, Alan Bernstein 3, Kazuhiro Ikenaka
1, Seiji Hitoshi 1*
1 Department of Physiological Sciences, School of Life Sciences,
Graduate University for Advanced Studies, Kanagawa 240-0193, Japan.;
Division of Neurobiology and Bioinformatics, National Institute for
Physiological Sciences, Okazaki 444-8787, Japan.
2 Department of Psychiatry, Health Service Center, University of
Tokyo, Tokyo 113-8655, Japan.
3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,
Ontario M5G 1X5, Canada.
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StemCells subscribers may also be interested in these sites:
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Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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