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Author Notes:

Address correspondence and reprint requests to Donald G Stein, Department of Emergency, Medicine Brain Research Laboratory, Emory University, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA 30322. Phone: 404-712-9704; Fax: 404-727-2388; Email: dstei04@emory.edu.

The authors would like to thank Leslie McCann for invaluable editorial assistance.

DG Stein is entitled to royalties from products of BHR Pharmaceuticals Ltd related to the research described in this presentation and may receive research funding from BHR Pharmaceuticals, which is developing products related to this research. In addition, he serves as a consultant to BHR Pharmaceuticals and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

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Research Funding:

This research was supported by NIH grant R01SO4851.

Progesterone with Vitamin D Affords Better Neuroprotection against Excitotoxicity in Cultured Cortical Neurons than Progesterone Alone

Tools:

Journal Title:

Molecular Medicine

Volume:

Volume 15, Number 9-10

Publisher:

, Pages 328-336

Type of Work:

Article | Final Publisher PDF

Abstract:

Because the complex heterogeneity of traumatic brain injury (TBI) is believed by many to be a major reason for the failed clinical trials of monotherapies, combining two (or more) drugs with some potentially different mechanisms of action may produce better effects than administering those agents individually. In this study, we investigated whether combinatorial treatment with progesterone (PROG) and 1,25-dihydroxyvitamin D3 hormone (VDH) would produce better neuroprotection than PROG alone following excitotoxic neuronal injury in vitro. E18 rat primary cortical neurons were pretreated with various concentrations of PROG and VDH separately or in combination for 24 h and then exposed to glutamate (0.5 μmol/L) for the next 24 h. Lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assays were used to measure cell death. Both PROG and VDH significantly (P < 0.001) reduced neuronal loss when tested independently. Primary cortical cultures treated with VDH exhibited a U-shaped concentration-response curve. PROG at 20 μmol/L and VDH at 100 nmol/L concentrations were the most neuroprotective. When the drugs were combined, the “best” doses of PROG (20 μmol/L) and VDH (100 nmol/L), used individually, did not show substantial efficacy; rather, the lower dose of VDH (20 nmol/L) was most effective when used in combination with PROG (P < 0.01). We also examined the effect of combinatorial treatment on mitogen-activated protein kinase (MAPK) activation as a potential neuroprotective mechanism and observed that PROG and VDH activated MAPK alone and in combination. Interestingly, the best combination dose of PROG and VDH (20 μmol/L and 20 nmol/L, respectively), as observed in cell death assays (LDH and MTT), resulted in increased MAPK activation compared with either the most neuroprotective concentration of individual PROG (20 μmol/L) and VDH (100 nmol/L) or the combination of these individual best doses. Such interactions must be considered in planning individualized combinatorial therapies. In conclusion, the findings of the present study can be taken to suggest that VDH warrants study as a potential partner for combination therapy with PROG.

Copyright information:

Copyright 2009, The Feinstein Institute for Medical Research

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