CNB-001, a pleiotropic drug is efficacious in embolized agyrencephalic New Zealand white rabbits and ischemic gyrencephalic cynomolgus monkeys

Abstract

Abstract Ischemic stroke is an acute neurodegenerative disease that is extremely devastating to patients, their families and society. Stroke is inadequately treated even with endovascular procedures and reperfusion therapy. Using an extensive translational screening process, we have developed a pleiotropic cytoprotective agent with the potential to positively impact a large population of brain ischemia patients and revolutionize the process used for the development of new drugs to treat complex brain disorders. In this unique translational study article, we document that the novel curcumin‐based compound, CNB‐001, when administered as a single intravenous dose, has significant efficacy to attenuate clinically relevant behavioral deficits following ischemic events in agyrencephalic rabbits when administered 1 h post‐embolization and reduces infarct growth in gyrencephalic non‐human primates, when administered 5 min after initiation of middle cerebral artery occlusion. CNB‐001 is safe and does not increase morbidity or mortality in either research species. Mechanistically, CNB‐001 inhibits human 5‐ and 15‐lipoxygenase in vitro, and can attenuate ischemia‐induced inflammatory markers, and oxidative stress markers, while potentially promoting synaptic plasticity mediated by enhanced brain‐derived neurotrophic factor (BDNF). HighlightsCNB‐001 is a curcumin‐based therapeutic targeting 5‐ and 15‐lipoxygenase, inflammation, oxidative stress and plasticity mechanismsCNB‐001 was studied in small clot‐embolized rabbits and non‐human primatesCNB‐001 promoted significant behavioral improvement in embolized rabbitsCNB‐001reduced infarct expansion in non‐human primatesCNB‐001administration was safe