title: Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury.
abstract: Systemic injections of the neurosteroid progesterone improve cognitive recovery after traumatic brain injury (TBI) and stroke, and decrease molecular indicators of neuronal damage. Suddenly withdrawing progesterone after repeated dosing (PW) exacerbates ischemia and causes increased anxiety, seizure susceptibility, and excitotoxicity. Adult male Sprague-Dawley rats received either bilateral medial frontal cortex contusions or sham surgery. Injections were administered at 1 and 6 h post-injury, then every 24 h for 7 days. Vehicle-treated rats received 2-hydroxypropyl-beta-cyclodextrin (HBC). Acute PW (AW) rats received a full 16 mg/ml of progesterone for 7 days, and tapered PW (TW) rats received 5 days at full dosage, then 2 days with progressively halved dosages. Anxiety behaviors were observed pre- and post-surgery, and compared to levels at the peak of withdrawal. AW rats with lesions exhibited significantly more anxiety than any other treatment group, while both lesion- and sham-operated TW rats were indistinguishable from vehicle-treated intact animals. After behavioral tests were complete, the brains were extracted and prepared for Western blotting. TNFalpha, cFos, Caspase-3, and NFkappaB, among others, were investigated. While all progesterone treatments resulted in improved molecular recovery, TW animals had significantly fewer active markers for apoptosis and inflammation than AW animals. In conclusion, although progesterone treatment decreases inflammation and apoptosis, acute withdrawal increases activity in some apoptotic and inflammatory pathways and increases anxiety behavior during the acute healing phase. A tapered withdrawal of the hormone further enhances short-term recovery after TBI.
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA. gt7812c@mail.gatech.edu
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cutler
authors.forename: Edward H
authors.initials: EH
authors.lastname: Pettus
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Hoffman
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D001930:Brain Injuries / Q000188:drug therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011374:Progesterone / Q000008:administration & dosage* / Q000009:adverse effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000008:administration & dosage; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D053148:Caspase 3; D020169:Caspases; D011374:Progesterone; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; D000097782:NF-kappaB-Inducing Kinase; C505410:Casp3 protein, rat