February 17, 2006
International Stroke Conference 2006 , Kissimmee, Florida
Presentation #427

Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is Neuroprotective in a Mouse Model of Permanent Focal Ischemia. Ingrid Langsetmo, Christopher Jacob, Wen Bin Ho, Robert Stephenson, Oksana Sirenko, Parmjeet Sidhu, Lee Flippin, Todd Seeley, Steve Klaus, Al Lin, David Liu

FibroGen, Inc. 225 Gateway Blvd., South San Francisco, CA 94080.

Abstract: Stroke remains the third most common cause of death in the industrialized world behind heart disease and cancer. Current pharmacotherapy for stroke is severely limited and presents a major unmet medical need. FG-4539 is a novel HIF-prolyl hydroxylase inhibitor (PHI) that has been shown to stabilize HIF in vitro, protect against chemical ischemia in neuronal cell cultures and to increase expression of HIF responsive cytoprotective genes including erythropoietin in the brain after i.v. administration in mice. By analogy to hypoxic preconditioning, FG-4539 is neuroprotective when administered 6 or 24 hours prior to permanent middle cerebral artery occlusion in the mouse (pMCAO). To further examine the potential of FG-4539 as a neuroprotective agent for the treatment of stroke, the dose response and therapeutic window were evaluated in the pMCAO model. The right middle cerebral artery of male C57BL/6 mice was surgically exposed and coagulated by bipolar diathermy. Body temperature was maintained by use of a heating pad during and after surgery. Ischemic damage in the brain was assessed 24 hours after pMCAO by TTC staining. In a dose response study, animals that were administered FG-4539 at 6, 20 or 60mg/kg immediately after pMCAO demonstrated significant dose-dependent reductions in infarct volume (36-59%). In a time-course study designed to evaluate the therapeutic window, animals treated with 60 mg/kg of FG-4539 exhibited a significant reduction in infarct volume (55%) when FG-4539 was administered as late as 5 hours (longest time tested) after occlusion. These results show that FG-4539 and PHI can limit ischemic damage when given up to five hours after the ischemic insult and demonstrate proof of concept that cytoprotective PHI may be useful in the treatment of ischemic stroke.