Soluble epoxide hydrolase as an anti-inflammatory target of the thrombolytic stroke drug SMTP-7

Autor(es): Matsumoto Naoki,Suzuki Eriko,Ishikawa Makoto,Shirafuji Takumi,Hasumi Keiji

Resumo: 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.

Palavras-Chave: Enzyme Inhibitor; Enzyme Kinetics; Inflammation; Proteolysis; Stroke

Imprenta: The Journal of Biological Chemistry, v. 289, n. 52, p. 35826-35838, 2014

Identificador do objeto digital: 10.1074/jbc.M114.588087

Descritores: Guillain-Barre Syndrome - Biosynthesis ; Guillain-Barre Syndrome - Cell ; Guillain-Barre Syndrome - Molecular Structure ; Guillain-Barre Syndrome - Proteins ; Guillain-Barre Syndrome - Inflammation

Data de publicação: 2014