title: Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA, USA.
authors.forename: Bushra
authors.initials: B
authors.lastname: Wali
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Soonmi
authors.initials: S
authors.lastname: Won
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018737:Hand Strength / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011374:Progesterone / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone
keywords: dose response; functional recovery; progesterone; stroke; therapeutic time window