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 2 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 activateGFAP reactions up to 21 days after injury. 
This effect may be one of the mechanisms underlying PROG's neuroprotective 
effects in combination with VDH.