Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

Matsumoto, Naoki; Suzuki, Eriko; Ishikawa, Makoto; Shirafuji, Takumi; Hasumi, Keiji

doi:10.1074/jbc.m114.588087

Cited by 44 publications

(60 citation statements)

References 63 publications

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“…There is additional evidence that the phosphatase domain regulates cholesterol levels (EnayetAllah et al, 2008) and endothelial nitric oxide synthase activity (Hou et al, 2012); however, it is unclear what the exact substrates are for the phosphatase domain. The simultaneous inhibition of both the epoxide hydrolase and phosphatase activities of sEH by the thrombolysis drug Stachybotrys microspora triprenylphenol-7 (SMTP-7) suggests a possible clinical role for dual inhibitors (Matsumoto et al, 2014). In nematodes, homologs of the phosphatase domain are separate enzymes (Harris et al, 2008) as they are in plants.…”

Section: Future Challenges In Epoxide Hydrolasesmentioning

confidence: 99%

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Kodani¹,

Hammock²

2015

Drug Metab Dispos

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Dr. Bernard Brodie's legacy is built on fundamental discoveries in pharmacology and drug metabolism that were then translated to the clinic to improve patient care. Similarly, the development of a novel class of therapeutics termed the soluble epoxide hydrolase (sEH) inhibitors was originally spurred by fundamental research exploring the biochemistry and physiology of the sEH. Here, we present an overview of the history and current state of research on epoxide hydrolases, specifically focusing on sEHs. In doing so, we start with the translational project studying the metabolism of the insect juvenile hormone mimic R-20458 [(E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene], which led to the identification of the mammalian sEH. Further investigation of this enzyme and its substrates, including the epoxyeicosatrienoic acids, led to insight into mechanisms of inflammation, chronic and neuropathic pain, angiogenesis, and other physiologic processes. This basic knowledge in turn led to the development of potent inhibitors of the sEH that are promising therapeutics for pain, hypertension, chronic obstructive pulmonary disorder, arthritis, and other disorders.

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Section: Future Challenges In Epoxide Hydrolasesmentioning

confidence: 99%

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Kodani¹,

Hammock²

2015

Drug Metab Dispos

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“…Another possibility is the involvement of the anti‐inflammatory and anti‐oxidative actions of SMTP‐7 . Inflammatory and oxidative reactions play crucial roles in the development of ischemia‐reperfusion injury .…”

Section: Discussionmentioning

confidence: 99%

“…PAP was determined using a zymographic method as described previously . Four regioisomers of DHET [(±)‐5,6‐DHET, (±)‐8,9‐DHET, (±)‐11,12‐DHET, and (±)‐14,15‐DHET] were determined using an LC‐MS/MS method . MMP‐9, CRP, MCP‐1, and S100B were determined by enzyme‐linked immunosorbent assays using commercially available kits (Human MMP‐9 Quantikine ELISA kit, R&D Systems, Minneapolis, MN; Human C‐Reactive Protein ELISA kit, Merck Millipore, Tokyo, Japan; Human MCP‐1/CCL2 ELISA MAX™ Deluxe kit, Bio Legend, San Diego, CA; and S100B Human ELISA kit, BioVendor, Brno, Czech Republic, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…SMTP‐7 (2,5‐bis[2‐[(3 E )‐4,8‐dimethylnona‐3,7‐dienyl]‐3,5‐dihydroxy‐2‐methyl‐7‐oxo‐4,9‐dihydro‐3 H ‐pyrano[2,3‐ e ]isoindol‐8‐yl]pentanoic acid), one of the most intensively studied SMTP congeners, relaxes plasminogen conformation and, thereby, enhances plasminogen‐fibrin binding and plasminogen activator‐catalyzed activation of plasminogen, leading to a promotion of thrombus clearance in vivo . On the other hand, SMTP‐7 exhibits anti‐inflammatory activities in vivo in disease models that are irrelevant to thromboembolism . Inhibition of soluble epoxide hydrolase (sEH) may account for the anti‐inflammatory mechanism …”

Section: Introductionmentioning

confidence: 99%

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Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

Suzuki

Nishimura²,

Yoshikawa

et al. 2018

Pharmacology Res & Perspec

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SMTP‐7 (Stachybotrys microspora triprenyl phenol‐7) is a small molecule that promotes thrombolysis and suppresses inflammation possibly through plasminogen modulation and soluble epoxide hydrolase (sEH) inhibition, respectively. Here, we demonstrate an efficacy of SMTP‐7 in a severe embolic stroke model in monkeys. The middle cerebral artery was embolized by an autologous blood clot. Saline, SMTP‐7, or tissue‐type plasminogen activator (t‐PA) (n = 5 in each group) was given after 3 hours, and neurologic deficit scoring and infarct characterization were performed after 24 hours. Hemorrhagic infarct‐accompanied premature death was observed for two animals in t‐PA group. SMTP‐7 treatment significantly reduced the sizes of infarct by 65%, edema by 37%, and clot by 55% compared to saline treatment. Plasma levels of the products of plasminogen activation (plasmin‐α2‐antiplasmin complex) and sEH reaction (dihydroxyeicosatrienoic acid) in SMTP‐7 group were 794% (P < 0.05) and 60% (P = 0.085) compared to saline group, respectively. No significant changes in the plasma levels of MMP‐9, CRP, MCP‐1, and S100B were found. There was an inverse correlation between plasmin‐α2‐antiplasmin complex level and infarct volume (r = 0.93, P < 0.05), suggesting a role of thrombolysis in the SMTP‐7 action to limit infarct development. In conclusion, SMTP‐7 is effective in treating severe embolic stroke in monkeys under conditions where t‐PA treatment tends to cause hemorrhagic infarct‐associated premature death.

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“…More recent studies have confirmed the importance of dimerization for enzymatic activity (Nelson et al, 2013). Moreover, it has been suggested that the dimer interface may make an attractive target for small molecule therapeutics designed against sEH (Nelson et al, 2013;Matsumoto et al, 2014).…”

Section: Measurement Of Intermolecular Binding Constants and Reactionmentioning

confidence: 92%

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

Pandey¹,

Henderson²,

Ishii³

et al. 2018

Frontiers Research Topics

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Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

Cited by 44 publications

References 63 publications

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

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