TY - JOUR
T1 - The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury
AU - VanLandingham, Jacob W.
AU - Cutler, Sarah M.
AU - Virmani, Sharad
AU - Hoffman, Stuart W.
AU - Covey, Douglas F.
AU - Krishnan, Kathiresan
AU - Hammes, Stephen R.
AU - Jamnongjit, Michelle
AU - Stein, Donald G.
N1 - Funding Information:
We would like to acknowledge Leslie McCann for her help and patience in assisting with the editing and proofing of this manuscript. This work was supported by funds from the NIH grants 1RO1N540825, 1RO1N538664 and 5P01GM47969.
PY - 2006/11
Y1 - 2006/11
N2 - 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 48 h 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.
AB - 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 48 h 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.
KW - Allopregnanolone
KW - Enantiomer
KW - Neuroprotection
KW - Progesterone
KW - Progesterone receptor
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=33750726032&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2006.07.015
DO - 10.1016/j.neuropharm.2006.07.015
M3 - Article
C2 - 16926035
AN - SCOPUS:33750726032
SN - 0028-3908
VL - 51
SP - 1078
EP - 1085
JO - Neuropharmacology
JF - Neuropharmacology
IS - 6
ER -