The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats.
This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid.
Djebaili
Myriam
M
Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Guo
Qingmin
Q
Pettus
Edward H
EH
Hoffman
Stuart W
SW
Stein
Donald G
DG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D011374:Progesterone; D011280:Pregnanolone; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases