The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury.
Previous work shows that neurosteroid enantiomers activate specific molecular receptors that relay neuroprotection. However, the actions of the enantiomer of progesterone (ent-PROG) at the PROG receptor (PR) are unknown. PR binding and transcriptional assays were performed to determine the actions of ent-PROG at the classical PR. Additionally, the neuroprotective effects of ent-PROG in traumatic brain injury (TBI) were investigated and compared to the actions of PROG and its metabolite allopregnanolone (ALLO), both of which have been shown to have neuroprotective properties when given after TBI. Binding studies performed in COS cells over-expressing the PR showed that ent-PROG inhibited PROG binding to the PR. In contrast, ent-PROG did not activate PR-mediated transcription. Rats received bilateral medial frontal cortex injury followed by treatments at 1, 6, 24 and 48h with PROG, ALLO or ent-PROG. Brains were processed for edema, protein and enzyme activity. ent-PROG treatment in vivo decreased cerebral edema, cell death mediators, inflammatory cytokines, and reactive gliosis, and increased antioxidant activity. These findings suggest that the progestin-mediated pro-survival response seen with TBI is regulated either independently of the classical PR or via nongenomic PR-regulated actions.
VanLandingham
Jacob W
JW
Department of Emergency Medicine, Emory University, Atlanta, GA, USA. jvanlan@emory.edu
Cutler
Sarah M
SM
Virmani
Sharad
S
Hoffman
Stuart W
SW
Covey
Douglas F
DF
Krishnan
Kathiresan
K
Hammes
Stephen R
SR
Jamnongjit
Michelle
M
Stein
Donald G
DG
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53 / Q000502:physiology; D005911:Gliosis / Q000473:pathology; D005980:Glutathione Reductase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D011374:Progesterone / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics; D013237:Stereoisomerism
D000975:Antioxidants; D015415:Biomarkers; D016207:Cytokines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011980:Receptors, Progesterone; D011374:Progesterone; D005980:Glutathione Reductase