QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.110510v1 319/3/1172    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shankaran, M. Articles by Hellerstein, M. K. Search for Related Content PubMed PubMed Citation Articles by Shankaran, M. Articles by Hellerstein, M. K.

NEUROPHARMACOLOGY

Discovery of Novel Hippocampal Neurogenic Agents by Using an in Vivo Stable Isotope Labeling Technique

KineMed, Inc., Emeryville, California (M.S., C.K., J.L., R.B., M.W.); and Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California (M.K.H.)

Neurogenesis occurs in discrete regions of adult mammalian brain, including the subgranular zone of the hippocampus. Hippocampal neurogenesis is enhanced by different classes of antidepressants, but screening for neurogenic actions of novel antidepressants has been inefficient because of limitations of 5-bromo-2'-deoxyuridine labeling techniques. We describe an efficient in vivo method for measuring hippocampal neurogenesis involving incorporation of the stable isotope, ²H, into genomic DNA during labeling with ²H₂O (heavy water). Male rodents received 8 to 10% ²H₂O in drinking water; DNA was isolated from hippocampal progenitor cells or neurons. Label incorporation into progenitor cells of Swiss-Webster mice revealed subpopulation kinetics: 16% divided with t_1/2 of 2.7 weeks; the remainder did not divide over 1 year. Progenitor cell proliferation rates in mice were strain-dependent. Chronic antidepressant treatment for 3 weeks, with ²H₂O administered during the final week, increased progenitor cell proliferation across all the strains tested. Fluoxetine treatment increased ²H incorporation into DNA of gradient-enriched neurons or flow-sorted neuronal nuclei 4 weeks after ²H₂O labeling, representing the survival and differentiation of newly divided cells into neurons. By screening 11 approved drugs for effects on progenitor cell proliferation, we detected previously unrecognized, dose-dependent enhancement of hippocampal progenitor cell proliferation by two statins and the anticonvulsant topiramate. We also confirmed stimulatory activity of other anticonvulsants and showed inhibition of progenitor cell proliferation by isotretinoin and prednisolone. In conclusion, stable isotope labeling is an efficient, high-throughput in vivo method for measuring hippocampal progenitor cell proliferation that can be used to screen for novel neurogenic drugs.

Address correspondence to: Dr. Mahalakshmi Shankaran, KineMed, Inc., 5980 Horton Street, Suite 400, Emeryville, CA 94608. E-mail: mshankaran{at}kinemed.com

This article has been cited by other articles:

				M. P. Keller, Y. Choi, P. Wang, D. Belt Davis, M. E. Rabaglia, A. T. Oler, D. S. Stapleton, C. Argmann, K. L. Schueler, S. Edwards, et al. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility Genome Res., May 1, 2008; 18(5): 706 - 716. [Abstract] [Full Text] [PDF]

				M. K. Hellerstein Exploiting Complexity and the Robustness of Network Architecture for Drug Discovery J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 1 - 9. [Abstract] [Full Text] [PDF]