Abstract 3101: Post-ischemic Development and Resolution of Infarct and Behavioral Deficits Induced by Permanent Middle Cerebral Artery Occlusion in Middle-aged Rats: A Progesterone Dose-response Study
BACKGROUND: There is currently no safe, effective, widely applicable post-stroke treatment for ischemic stroke, especially when treatment is delayed beyond a few hours. Our group and others have shown progesterone (PROG) to be beneficial after brain injury in several injury models. A systematic pre-clinical PROG dose-response study in ischemic stroke models is lacking. Since focal pMCAO models better simulate the typical human stroke injury without reperfusion, our study sought to determine PROG's dose-response effects on behavioral performance after pMCAO. We used a clinically relevant, middle-aged rat model and long-term sensory, motor, and cognitive outcome measures.
METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. At 1h post-pMCAO, the animals were given an intraperitoneal injection of one of three doses of PROG (8, 16, or 32 mg/kg), followed by subcutaneous injections 6h post-injury and then once every 24h for the next 7 days. The dose was tapered over the final 2 treatments. Behavioral recovery was evaluated at repeated intervals for locomotor activity, grip strength, rotarod performance, sensory neglect, gait impairment and spatial navigation learning and memory. Rats were killed at 22 days post-stroke and brains perfused for evaluation of infarct volume.
RESULTS: Repeated measures ANOVA showed significant group (F(4,88) = 17.15, p<0.001) effects in grip strength, significant group (F(4,41) = 3.5, p < 0.05) and time (F(4,164) = 2.6, p < 0.05) effects on rotarod, significant group (F(4,41) = 2.94, p < 0.05) effects on latency to remove sticky paper from the affected contralateral forepaw, and significant group (F(4,41) = 14.63, p < 0.0001) effects on total distance traveled. The best recovery in grip strength, rotarod and sensory neglect was seen in the 8mg/kg PROG group. In spatial learning memory, percent time spent in the platform quadrant of the MWM showed that progesterone improved performance (F(4, 40)=2.7, p<0.05). Automated, computer-assisted, gait assessment showed that PROG significantly improved gait deficits in the affected limb. Significant decreases in stride length, print area and swing speed were observed. Both 8mg/kg ansd 16mg/kg of PROG treatment produced significant attenuation in infarct volume compared to the vehicle-alone group (F(3, 19) = 4.38, p < 0.05).
CONCLUSION: All doses of PROG improved functional deficits in a clinically relevant model of stroke. The 8mg/kg dose was optimal in improving motor, sensory and memory function. PROG shows pre-clinical promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischemic stroke.
- © 2012 by American Heart Association, Inc.