title: Progesterone and low-dose vitamin D hormone treatment enhances  sparing of memory following traumatic brain injury.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA. fhua2@emory.edu
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Jenny I
authors.initials: JI
authors.lastname: Reiss
authors.forename: Huiling
authors.initials: H
authors.lastname: Tang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Xavier
authors.initials: X
authors.lastname: Fowler
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications* / Q000523:psychology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005625:Frontal Lobe / Q000293:injuries / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology* / Q000517:prevention & control* / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012678:Sensation Disorders / Q000209:etiology / Q000517:prevention & control; D013534:Survival; D014807:Vitamin D / Q000008:administration & dosage / Q000494:pharmacology*; D014815:Vitamins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D014815:Vitamins; C534582:fluoro-jade C; D014807:Vitamin D; D011374:Progesterone