A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice

Abstract

Tissue plasminogen activator (t-PA) has a short therapeutic time window for administration (3 h) and carries a risk of promoting intracerebral hemorrhage. The aim of the present study was to investigate a therapeutic time window and frequency of hemorrhagic region by treatment with Stachybotrys microspora triprenyl phenol-7 (SMTP-7). Thrombotic occlusion was induced by transfer of acetic acid-induced thrombus at the right common carotid artery into the brain of mice. Infarction area, neurological score, edema percentage, and regional cerebral blood flow (CBF) were determined as the index of the efficacy of SMTP-7. In order to evaluate the mechanism of SMTP-7, plasmin activities and the expressions of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 mRNA were examined. SMTP-7 (0.1, 1, 10 mg/kg) dose dependently reduced infarction area, neurological score, and edema percentage. Additionally, its therapeutic time window was longer than that of t-PA, a high-molecular-weight compound. In addition, little hemorrhagic region was induced by treatment with SMTP-7. SMTP-7 showed plasmin activity in vivo and caused a decreased CBF to recover. Furthermore, the expressions of inflammatory cytokine mRNA (IL-1β, TNF-α, IL-6) were increased by t-PA treatment 3 h after ischemia but were not induced by SMTP-7 treatment. These results indicate that SMTP-7 shows potential thrombolytic and anti-inflammatory effects as well as a wide therapeutic time window and little hemorrhagic region compared with that of t-PA. Therefore, this novel low-molecular-weight compound may represent a novel approach for the treatment of cerebral infarction.

A new series of the SMTP plasminogen modulators with a phenylamine-based side chain

“…5 SMTPs, a family of triprenyl phenol metabolites produced by Stachybotrys microspora, enhance plasminogen activation by modulating plasminogen conformation. [5][6][7] SMTP-7, one of the most potent congeners, is effective in treating thrombotic stroke in animal models, [8][9][10][11] possibly involving a neuroprotective mechanism. [10][11][12] The SMTP molecule consists of a tricyclic g-lactam moiety, a geranylmethyl group, and an N-linked side chain.…”

A new series of the SMTP plasminogen modulator with a phenylglycine-based side chain

“…5-7 SMTP-7, one of the most potent congeners, is effective in treating thrombotic stroke. [8][9][10][11] The SMTP molecule consists of a tricyclic g-lactam moiety, a geranylmethyl group, and an N-linked side chain. Our previous studies identified 26 SMTP congeners, most of which differ in the side chain.…”

Structure–activity relationships of 11 new congeners of the SMTP plasminogen modulator

“…[10][11][12][13][14][15][16] SMTP enhances both activation and fibrin binding of plasminogen by modulating plasminogen conformation, [12][13][14]17,18 and one of the SMTP congeners is effective in treating thrombotic stroke. 19,20 The SMTP molecule consists of a tricyclic g-lactam moiety, an isoprene side-chain and an N-linked side-chain. Our previous studies identified 15 SMTP congeners, including staplabin and the 'D-series' stereoisomers.…”