Abstract W MP37: A Novel Homocysteine Inhibitor Enhances Neurological Recovery after Cerebral Ischemia in Mice and Non-Human Primates

Background: Hyperhomocyteinemia is associated with cardiovascular and cerebrovascular diseases. Many studies have investigated the deleterious effects of intercellular homocysteine (Hcy) accumulation on vascular and brain tissue. AEB-577 is a potent Hcy synthesis inhibitor based on a non-adenosine analog. We hypothesized that AEB-577 could normalize Hcy content in brain tissue, reduce cytotoxicity of Hcy and ameliorate neurological dysfunction after stroke. Method: Male C57BL/6N mice were subjected to photochemically induced thrombosis, and treated orally with AEB-577 (1, 3, 10 mg/kg) or vehicle 10 minutes after the infarction. Infarct volume was assessed by tetrazolium staining and motor incoordination was evaluated using rota-rod test at 24 hours after infarction. In the second experiment, Hcy content in peri-infarct area was measured at 3 days after infarction by HPLC. In a non-human primate experiment, male cynomolgus monkeys were subjected to permanent middle artery occlusion (pMCAO), and divided into 3 groups based on infarction volume assessed by MRI images 18 hours after the onset. And then, vehicle or AEB-577 (4, 12 mg/body) was orally administered once a day for 84 days. The neurological deficits including paralysis, sensory dysfunction, and deficiencies of consciousness and motility were assessed at 3, 5, 7, 11, 14, 28, 56, 84 days after the onset of MCA occlusion. Plasma Hcy level and brain Hcy content were assessed at 84 days. Result: AEB-577 reduced infarct volume and improved motor deficit compared with vehicle treated mice. Hcy content in peri-infarct area significantly increased. AEB-577 decreased elevated Hcy content to normal level. In the monkey study, AEB-577 treatment starting 24 hours after stroke onset significantly promoted neurological recovery. AEB-577 decreased Hcy level in plasma and brain tissue compared with the placebo group at 84 days after stroke onset. Conclusion: Our results indicate that the novel Hcy synthesis inhibitor, AEB-577, can improve functional recovery after cerebral infarction modulating not only plasma Hcy level also Hcy content in brain tissue.