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.

Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats

“…Behavioral outcome measures are essential to this purpose. PROG has been shown to promote functional recovery in different brain injury models including stroke and TBI (Djebaili et al, 2004;Gibson and Murphy, 2004;Grossman et al, 2004;Gibson et al, 2005;Chen et al, 2007;Wali et al, 2011;Tang et al, 2013;Geddes et al, 2014;Robertson and Saraswati, 2014;Wali et al, 2014;Yousuf et al, 2014a,b;Peterson et al, 2015). Our results in the present study show that besides reducing the water content in the penumbral region at one day after TBI, EIDD-1723 significantly improved functional recovery and reduced accumulation of astrocytes and microglia, cells associated with post-injury inflammatory processes that can impair recovery of function.…”

Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

“…The 8 mg/kg dose is based on previous dose response studies in rodents demonstrating that this amount provides maximal protective benefits in the treatment of various types of brain injury (Ishrat et al, 2009; Wali et al, 2014; Yousuf et al, 2014). …”

Prophylactic Edaravone Prevents Transient Hypoxic-Ischemic Brain Injury

“…To evaluate working (short-term, trial-to-trial) and reference (longer-term, day-to-day) memory MWM procedure was performed as described 24 . Briefly, the animal position in the maze and latency to reach platform was recorded and analyzed using computer-assisted tracking system (Clever System Inc., Reston, Virginia).…”