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The Journal of Neuroscience, May 11, 2005, 25(19):4706-4718; doi:10.1523/JNEUROSCI.4520-04.2005

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Development/Plasticity/Repair
The Neurosteroid Allopregnanolone Promotes Proliferation of Rodent and Human Neural Progenitor Cells and Regulates Cell-Cycle Gene and Protein Expression

Jun Ming Wang,¹ Patrick B. Johnston,² Bret Gene Ball,³ and Roberta Diaz Brinton¹

¹Department of Molecular Pharmacology and Toxicology and Program in Neuroscience, Pharmaceutical Science Center, University of Southern California, Los Angeles, California 90033, ²Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, and ³Gene Therapy Laboratories, Department of Biochemistry, Keck School of Medicine, University of Southern California, Los Angeles, California 90033

Our previous research demonstrated that the neuroactive progesterone metabolite allopregnanolone (3-hydroxy-5-pregnan-20-one) rapidly induced hippocampal neuron neurite regression (Brinton, 1994). We hypothesized that allopregnanolone-induced neurite regression was a prelude to mitogenesis initiated by a rise in intracellular calcium. Supporting this hypothesis, the current data demonstrate that allopregnanolone, in a dose-dependent manner, induces a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSCs) derived from the cerebral cortex. Proliferation was determined by incorporation of bromodeoxyuridine and [³H]thymidine, fluorescence-activated cell sorter analysis of murine leukemia virus-green fluorescent protein-labeled mitotic NPCs, and total cell number counting. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3-hydroxy-5-pregnan-20-one and related steroids did not increase [³H]thymidine uptake. Immunofluorescent analyses for the NPC markers nestin and Tuj1 indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell-cycle genes and real-time reverse transcription-PCR and Western blot validation revealed that allopregnanolone increased the expression of genes that promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage-gated L-type calcium channel (VGLCC) blocker nifedipine, consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor-activated VGLCC (Son et al., 2002). These data demonstrate that allopregnanolone significantly increased rat NPC and hNSC proliferation with concomitant regulation in mitotic cell-cycle genes via a VGLCC mechanism. The therapeutic potential of allopregnanolone as a neurogenic molecule is discussed.

Key words: allopregnanolone; neurogenesis; hippocampus; cell-cycle genes; L-type calcium channel; therapeutics

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Received Nov 3, 2004; revised March 23, 2005; accepted March 26, 2005.

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