Measurement Of Hippocampal Progenitor Cell (PC) Proliferation Rates In Vivo: A Biomarker For Discovering Novel Neurogenic Agents

The objective of this study was to screen approved drugs for neurogenic activity using a recently developed stable isotope method. During hippocampal neurogenesis in adult animals, neurons are formed from proliferating PC. In vivo proliferation of hippocampal PC, isolated by Percoll gradient, was quantified from incorporation of 2 H from heavy water ( 2 H 2 O) into the deoxyribose moiety of DNA, by gas chromatography‐mass spectrometry. 2 H 2 O (10% in drinking water) was given during the final week of drug treatment. Antidepressant drugs fluoxetine (10 mg/kg), imipramine (20 mg/kg), and venlafaxine (10 mg/kg) significantly increased PC proliferation, as shown previously. Isolation of hippocampal neuronal cells 4 weeks after fluoxetine treatment confirmed increased neurogenesis. In the initial screen of drugs, 3‐week treatment with atorvastatin (10 mg/kg) and topiramate (100 mg/kg) significantly increased PC proliferation, these are novel findings for these agents in normal mice. No stimulatory effects were seen for aspirin, calcitriol, clofibrate, enalapril, flurbiprofen, ibuprofen, ketoconazole, methotrexate or rosiglitazone. Follow‐up studies of both “hits” showed dose‐response relationships and revealed another statin (simvastatin) and two other anticonvulsants that increased PC proliferation. In summary, heavy water labeling is a relatively high‐throughput, quantitative and highly reproducible method for measuring hippocampal PC proliferation, and is useful for screening and discovering novel neurogenic drugs. Support: KineMed, Inc.