Progesterone and its metabolite allopregnanolone differentially regulate hemostatic proteins after traumatic brain injury.
Our laboratory has shown in numerous experiments that the neurosteroids progesterone (PROG) and allopregnanolone (ALLO) improve molecular and functional outcomes after traumatic brain injury (TBI). As coagulopathy is an important contributor to the secondary destruction of nervous tissue, we hypothesized that PROG and ALLO administration may also have a beneficial effect on coagulation protein expression after TBI. Adult male Sprague-Dawley rats were given bilateral contusions of the medial frontal cortex followed by treatments with PROG (16 mg/kg), ALLO (8 mg/kg), or vehicle (22.5% hydroxypropyl-beta-cyclodextrin). Controls received no injury or injections. Progesterone generally maintained procoagulant (thrombin, fibrinogen, and coagulation factor XIII), whereas ALLO increased anticoagulant protein expression (tissue-type plasminogen activator, tPA). In addition, PROG significantly increased the ratio of tPA bound to neuroserpin, a serine protease inhibitor that can reduce the activity of tPA. Our findings suggest that in a model of TBI, where blood loss may exacerbate injury, it may be preferable to treat patients with PROG, whereas it might be more appropriate to use ALLO as a treatment for thrombotic stroke, where a reduction in coagulation would be more beneficial.
VanLandingham
Jacob W
JW
Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Cekic
Milos
M
Cutler
Sarah M
SM
Hoffman
Stuart W
SW
Washington
Ebony R
ER
Johnson
Sarah J
SJ
Miller
Darren
D
Stein
Donald G
DG
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001930:Brain Injuries / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005176:Factor XIII / Q000235:genetics; D005340:Fibrinogen / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D009479:Neuropeptides / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology* / Q000627:therapeutic use; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000378:metabolism; D013917:Thrombin / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D000097522:Neuroserpin
D005176:Factor XIII; D005340:Fibrinogen; D009479:Neuropeptides; D011280:Pregnanolone; D011374:Progesterone; D012333:RNA, Messenger; D015843:Serpins; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin