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- Title
Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.
- Authors
Wali, Bushra; Ishrat, Tauheed; Won, Soonmi; Stein, Donald G.; Sayeed, Iqbal
- Abstract
Progesterone has a neuroprotective effect in preclinical models of stroke and traumatic brain injury, but the therapeutic window remains uncertain. Wali et al. examine infarct size, and sensory, motor and cognitive measures, and report a neuroprotective effect of progesterone when administered as late as 6 hours after experimental stroke onset.Currently, the only approved treatment for ischaemic stroke is tissue plasminogen activator, a clot-buster. This treatment can have dangerous consequences if not given within the first 4 h after stroke. Our group and others have shown progesterone to be beneficial in preclinical studies of stroke, but a progesterone dose-response and time-window study is lacking. We tested male Sprague-Dawley rats (12 months old) with permanent middle cerebral artery occlusion or sham operations on multiple measures of sensory, motor and cognitive performance. For the dose-response study, animals received intraperitoneal injections of progesterone (8, 16 or 32 mg/kg) at 1 h post-occlusion, and subcutaneous injections at 6 h and then once every 24 h for 7 days. For the time-window study, the optimal dose of progesterone was given starting at 3, 6 or 24 h post-stroke. Behavioural recovery was evaluated at repeated intervals. Rats were killed at 22 days post-stroke and brains extracted for evaluation of infarct volume. Both 8 and 16 mg/kg doses of progesterone produced attenuation of infarct volume compared with the placebo, and improved functional outcomes up to 3 weeks after stroke on locomotor activity, grip strength, sensory neglect, gait impairment, motor coordination and spatial navigation tests. In the time-window study, the progesterone group exhibited substantial neuroprotection as late as 6 h after stroke onset. Compared with placebo, progesterone showed a significant reduction in infarct size with 3- and 6-h delays. Moderate doses (8 and 16 mg/kg) of progesterone reduced infarct size and improved functional deficits in our clinically relevant model of stroke. The 8 mg/kg dose was optimal in improving motor, sensory and memory function, and this effect was observed over a large therapeutic time window. Progesterone shows promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischaemic stroke.
- Subjects
PROGESTERONE; STROKE treatment; DOSE-effect relationship in pharmacology; NEUROPROTECTIVE agents; BRAIN injuries; CEREBRAL infarction; TISSUE plasminogen activator; THERAPEUTICS
- Publication
Brain: A Journal of Neurology, 2014, Vol 137, Issue 2, p486
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/awt319