Abstract WP95: Delayed Progesterone Treatment Attenuates Infarct and Behavioral Deficits Induced by Permanent Middle Cerebral Artery Occlusion (pMCAO) in Middle-Aged Rats: Therapeutic Time Window Study
BACKGROUND: Previously we carried out a dose response study and reported 8 mg/kg PROG to be the optimal therapeutic dose following in pMCAO. A systematic preclinical progesterone (PROG) therapeutic time window study is lacking. In the present study we used a clinically relevant middle-aged rat and long-term sensory, motor, and cognitive outcome measures to determine the effects of delayed PROG treatment.
METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. Beginning 3, 6, or 24 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 5 h after the first IP injection and then every 24 h for 7 days. The dose was tapered over the final 2 treatments. Behavioral recovery was evaluated at repeated intervals on sensory, motor, and cognitive tasks. Rats were killed at 22 days post-stroke and brains perfused for infarct evaluation.
RESULTS: Three weeks post-pMCAO, PROG treatment delayed by 3 h improved grip strength by 64.48%, rotarod stability by 94.29%, sensory neglect by 94.48%, and long-term memory deficits by 60.56%. PROG treatment delayed by 6 h improved grip strength by 82.62%, rotarod stability by 75.89%, sensory neglect by 60.14%, and long-term memory deficits by 60.16%. Automated, computer-assisted gait assessment showed that PROG treatments significantly improved motor deficits in the affected limb on parameters like stride length, paw print and swing speed. When PROG treatment was compared to non-treated group, a significant reduction of 49.59 and 58.06% in infarct size was observed with 3- (F(1,14) = 8.25, p<0.01) and 6-h delay of treatment (F(1,13) = 4.44, p<0.05), respectively.
CONCLUSION: The therapeutic dose of 8 mg/kg PROG was found to be effective within a large therapeutic time window. After both 3- and 6-h delays, PROG was effective in improving motor, sensory and memory function deficit. A 24-h treatment delay did not produce significant improvement in most of the outcome measures. PROG shows pre-clinical promise and should be examined for safety and efficacy in a clinical trial for ischemic stroke.
- © 2012 by American Heart Association, Inc.