title: Soluble epoxide hydrolase as an anti-inflammatory target of the thrombolytic stroke drug SMTP-7.
abstract: Although ischemic stroke is a major cause of death and disability worldwide, only a small fraction of patients benefit from the current thrombolytic therapy due to a risk of cerebral hemorrhage caused by inflammation. Thus, the development of a new strategy to combat inflammation during thrombolysis is an urgent demand. The small molecule thrombolytic SMTP-7 effectively treats ischemic stroke in several animal models with reducing cerebral hemorrhage. Here we revealed that SMTP-7 targeted soluble epoxide hydrolase (sEH) to suppress inflammation. SMTP-7 inhibited both of the two sEH enzyme activities: epoxide hydrolase (which inactivates anti-inflammatory epoxy-fatty acids) and lipid phosphate phosphatase. SMTP-7 suppressed epoxy-fatty acid hydrolysis in HepG2 cells in culture, implicating the sEH inhibition in the anti-inflammatory mechanism. The sEH inhibition by SMTP-7 was independent of its thrombolytic activity. The simultaneous targeting of thrombolysis and sEH by a single molecule is a promising strategy to revolutionize the current stroke therapy.
authors.affiliation: From the Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: From the Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Laboratory, Nihon Pharmaceutical, 34 Shin-izumi, Narita, Chiba 286-0825, Japan, and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Pharmaceutical Research Laboratory, Nihon Pharmaceutical, 34 Shin-izumi, Narita, Chiba 286-0825, Japan, and.
authors.forename: Takumi
authors.initials: T
authors.lastname: Shirafuji
authors.affiliation: From the Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan, TMS Co., Ltd., 1-32-1-102 Fuchucho, Fuchu, Tokyo 183-0055, Japan hasumi@cc.tuat.ac.jp.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hasumi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000201:enzymology; D003424:Crohn Disease / Q000188:drug therapy / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D020275:Guillain-Barre Syndrome / Q000188:drug therapy / Q000201:enzymology; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D011917:Rats, Inbred Lew
chemical_list: D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; C409191:SMTP 7; D010958:Plasminogen; D004851:Epoxide Hydrolases
keywords: Enzyme Inhibitor; Enzyme Kinetics; Inflammation; Proteolysis; Stroke