To date, clinical trials for the treatment of ischemic stroke after it has occurred have been disappointing. However, in a recently completed Phase lla, single-center, randomized, double-blind trial in patients with moderate to severe traumatic brain injury (TBI), progesterone (PROG), given intravenously for three days after injury, reduced mortality by almost 60% and significantly improved functional outcome at 30 days survival compared to patients given state-of-the-art treatment and placebo. Preliminary data with PROG in the treatment of stroke are promising, but before PROG can be tested in a clinical trial for stroke, more animal studies are needed to determine whether dose response relationships and window of treatment opportunity differ between stroke and TBI. We will establish the safety, dosing parameters, and effects on physiological and functional outcomes of PROG in the target class of animal subjects. We will then apply for, and gain, FDA approval to use PROG in a clinical trial for the treatment of ischemic stroke. In the present proposal we will use both transient and permanent cerebral ischemic stroke models in both female and male rats. Our Primary goal will be to determine whether PROG will work effectively in """"""""middle-aged"""""""" male and female rats (about 15 months), which are better models of the middle-aged population more at risk for stroke than younger counterparts. Second, we will collaborate with three laboratories known for their animal stroke research to model a randomized, double-blind """"""""multi-laboratory trial"""""""" in rats. Third, we will examine long- term functional outcomes after the injury and treatment to see whether PROG's effects are enduring. Fourth, we will extend our treatment parameters to stroke-prone rats, so our stroke models are more characteristic of the risk factors seen in humans. Fifth, we will use these data to apply to the FDA for an IND to test PROG in human stroke patients. We believe the U01 cooperative agreement for translational research is an ideal way for our laboratory and those of our collaborators to provide the translational data needed to move to clinical testing of PROG as a treatment for stroke.
Stroke remains a major public health problem worldwide. Aside from tPA, of the more than 700 drugs studied, none have proven effective in clinical trial. PROG has been shown to be safe and effective in clinical TBI and we now need to determine whether it can be as effective in the clinical treatment of ischemic stroke. The studies proposed here move us closer to that possibility.
|Wali, Bushra; Ishrat, Tauheed; Stein, Donald G et al. (2016) Progesterone improves long-term functional and histological outcomes after permanent stroke in older rats. Behav Brain Res 305:46-56|
|Yousuf, Seema; Atif, Fahim; Sayeed, Iqbal et al. (2015) Long-term behavioral deficits and recovery after transient ischemia in middle-aged rats: Effects of behavioral testing. Restor Neurol Neurosci 33:251-61|
|Remus, Ebony Washington; Sayeed, Iqbal; Won, Soonmi et al. (2015) Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration. Exp Neurol 271:401-8|
|Yousuf, Seema; Atif, Fahim; Sayeed, Iqbal et al. (2014) Progesterone in transient ischemic stroke: a dose-response study. Psychopharmacology (Berl) 231:3313-23|
|Won, Soonmi; Lee, Jin Hwan; Wali, Bushra et al. (2014) Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway. J Cereb Blood Flow Metab 34:72-80|
|Wali, Bushra; Ishrat, Tauheed; Won, Soonmi et al. (2014) Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study. Brain 137:486-502|
|Yousuf, Seema; Sayeed, Iqbal; Atif, Fahim et al. (2014) Delayed progesterone treatment reduces brain infarction and improves functional outcomes after ischemic stroke: a time-window study in middle-aged rats. J Cereb Blood Flow Metab 34:297-306|
|Yousuf, S; Atif, F; Sayeed, I et al. (2013) Post-stroke infections exacerbate ischemic brain injury in middle-aged rats: immunomodulation and neuroprotection by progesterone. Neuroscience 239:92-102|
|Ishrat, T; Sayeed, I; Atif, F et al. (2012) Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. Neuroscience 210:442-50|
|Barha, Cindy K; Ishrat, Tauheed; Epp, Jonathan R et al. (2011) Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurol 231:72-81|