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Author Notes:

Correspondence: Donald G. Stein, Department of Emergency Medicine, Brain Research Laboratory, 1365B Clifton Road NE, Suite 5100, Emory University, Atlanta, GA 30322; Phone: (404) 712-2540; Fax: (404) 727-2388; Email: donald.stein@emory.edu

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

Disclosures: DG Stein is entitled to royalties from products of BHR Pharmaceuticals Ltd related to the use of P4 in TBI and stroke, 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, which receives the largest share of fees in accordance with its conflict of interest policies.

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Research Funding:

This research was supported by NIH grant RO1 HD061971.

DG Stein may receive research funding from BHR Pharmaceuticals, which is developing products related to this research.

Keywords:

  • Cerebral ischemia
  • Combination treatment
  • Progesterone
  • Vitamin D
  • BDNF/TrkB/Erk1/2 signaling

Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection

Tools:

Journal Title:

Neuropharmacology

Volume:

Volume 67

Publisher:

, Pages 78-87

Type of Work:

Article | Post-print: After Peer Review

Abstract:

We investigated whether combinatorial post-injury treatment with progesterone (P4) and vitamin D hormone (VDH) would reduce ischemic injury more effectively than P4 alone in an oxygen glucose deprivation (OGD) model in primary cortical neurons and in a transient middle cerebral artery occlusion (tMCAO) model in rats. In the OGD model, P4 and VDH each showed neuroprotection individually, but combination of the “best” doses did not show substantial efficacy; instead, the lower dose of VDH in combination with P4 was the most effective. In the tMCAO model, P4 and VDH were given alone or in combination at different times post-occlusion for 7 days. In vivo data confirmed the in vitro findings and showed better infarct reduction at day 7 and functional outcomes (at 3, 5 and 7 days post-occlusion) after combinatorial treatment than when either agent was given alone. VDH, but not P4, upregulated heme oxygenase-1, suggesting a pathway for the neuroprotective effects of VDH differing from that of P4. The combination of P4 and VDH activated brain-derived neurotrophic factor and its specific receptor, tyrosine kinase receptor-B. Under specific conditions VDH potentiates P4’s neuroprotective efficacy and should be considered as a potential partner of P4 in a low-cost, safe and effective combinatorial treatment for stroke.

Copyright information:

© 2012 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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