A novel approach to screening for new neuroprotective compounds for the treatment of stroke.
Despite the significant advances that have been made in understanding the pathophysiology of cerebral ischemia on the cellular and molecular level, only one drug, the thrombolytic tissue plasminogen activator (rt-PA), is approved by the FDA for use in patients with acute ischemic stroke. Therefore, there is a critical need for additional safe and effective treatments for stroke. In order to identify novel compounds that might be effective, we have developed a cell culture-based assay with death being an endpoint as a screening tool. We have performed an initial screening for potential neuroprotective drugs among a group of flavonoids by using the mouse hippocampal cell line, HT22, in combination with chemical ischemia. Further screens were provided by biochemical assays for ATP and glutathione, the major intracellular antioxidant, as well as for long-term induction of antioxidant proteins. Based upon the results of these screens, we tested the best flavonoid, fisetin, in the small clot embolism model of cerebral ischemia in rabbits. Fisetin significantly reduced the behavioral deficits following a stroke, providing proof of principle for this novel approach to identifying new compounds for the treatment of stroke.
Maher
Pamela
P
The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA. pmaher@salk.edu
Salgado
Karmen F
KF
Zivin
Justin A
JA
Lapchak
Paul A
PA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D019807:Iodoacetic Acid / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors; D018675:Toxicity Tests
D004791:Enzyme Inhibitors; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; D005978:Glutathione; D019807:Iodoacetic Acid