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Author Notes:

Correspondence: Donald G. Stein, Ph.D., Department of Emergency Medicine, Emory University, 1365 B Clifton Rd NE, Suite 5100, Atlanta GA 30322 USA, 404-712-2540, 404-727-2388 fax, dstei04@emory.edu

F. Hua and J. I. Reiss contributed equally to this work


Research Funding:

This work was supported by NIH 5R01NS048451 and 1R01HD061971 to DGS. A portion of this research was supported by a gift from BHR Pharma, AHA National Program SDG 0830481N to FH, and AHA 11SDG5430002 to IS. The authors thank Dr. Xiaobo Ma for his contribution to the evaluation of the necrotic cavity.


  • Traumatic brain injury
  • combination treatments
  • functional repair
  • progesterone
  • Vitamin D3 hormone

Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury


Journal Title:

Hormones and Behavior


Volume 61, Number 4


, Pages 642-651

Type of Work:

Article | Post-print: After Peer Review


Progesterone (PROG) has been shown to protect the brain from traumatic injury and is now in Phase III clinical trials. Our work shows that PROG's beneficial effects can be reduced in vitamin D hormone (VDH) –deficient subjects. VDH can modulate neuronal apoptosis, trophic factors, inflammation, oxidative stress, excitotoxicity, and myelin and axon repair. We investigated whether VDH combined with PROG could improve behavioral outcomes more than PROG alone in VDH-sufficient rats given bilateral contusions of the medial frontal cortex. PROG and different doses of VDH (1 µg/kg, VDH1; 2.5 µg/kg, VDH2; 5 µg/kg, VDH3) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were given subcutaneously over 8 days with tapering over the last two days. Neurobehavioral tests, necrotic cavity, neuronal death and activation of astrocytes were evaluated 21 days post-injury. We found that PROG and PROG+VDH preserve spatial memory processing. VDH1+PROG improved performance in acquisition more effectively than PROG alone, indicating that the low VDH dose is optimal for combination therapy. There were no significant differences in necrotic cavity size among the groups. The density of positive staining for reactive astrocytes (glial fibrillary acidic protein (GFAP)) increased and the cell bodies and processes of GFAP-positive cells were enlarged in the PROG+VDH1 group. Our data indicate that the combination of PROG and VDH is more effective than PROG alone in preserving spatial and reference memory, and that PROG plus low-dose VDH can activate GFAP reactions up to 21 days after injury. This effect may be one of the mechanisms underlying PROG's neuroprotective effects in combination with VDH.

Copyright information:

© 2012 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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