A Novel Embolic Model of Cerebral Infarction and Evaluation of Stachybotrys microspora Triprenyl Phenol-7 (SMTP-7), a Novel Fungal Triprenyl Phenol Metabolite

Abstract

Abstract. The aim of the present study was to establish a novel embolic model of cerebral infarction and to evaluate the effect of Stachybotrys microspora triprenyl phenol-7 (SMTP-7), a novel fungal triprenyl phenol metabolite. Thrombotic occlusion was induced by transfer of acetic acid-induced embolus into the brain. The regional cerebral blood flow was measured by a laser Doppler flowmeter to check the ischemic condition. Infarction area was assessed by 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological scores were determined by a modified version of the method described by Longa et al. Emboli were accumulated at the temporal or parietal region of the middle cerebral artery. Additionally, we found that this model showed decreased cerebral blood flow and increased infarction area and neurological scores. Treatment with tissue plasminogen activator (t-PA) reduced infarction area and the neurological scores in a dose-dependent manner; moreover, the decreased cerebral blood flow recovered. SMTP-7 also reduced these values. The therapeutic time window of SMTP-7 was longer than that of t-PA. These results indicate that this model may be useful for understanding the pathophysiological mechanisms of cerebral infarction and evaluating the effects of therapeutic agents. Additionally, SMTP-7 is a promising approach to extend the therapeutic time window. Therefore, this novel compound may represent a novel approach for the treatment of cerebral infarction.

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

“…DISCUSSION SMTP-7 has a plasminogen modulation activity that leads to a thrombolytic enhancement as observed in several animal models (14,16,20). SMTP-7 effectively treats thrombotic and embolic stroke models (17,18,20), and the involvement of an additional mechanism that leads to anti-inflammation has been suggested (16,18,19,21). In the present study we observed the SMTP anti-inflammatory action that is independent of the plasminogen modulation activity.…”

“…1A), one of the SMTP family compounds with profound biological activities, enhances plasminogen activation by modulating plasminogen conformation (10,(13)(14)(15). SMTP-7 thus promotes plasmin formation and clot clearance in vivo (14,16), and it has been used to treat thrombotic and embolic strokes in experimental models in rodents and nonhuman primates (17)(18)(19)(20). Unexpectedly, SMTP-7 was demonstrated to reduce hemorrhagic transformation and to have a wide therapeutic time window (17,18,20).…”

“…SMTP-7 thus promotes plasmin formation and clot clearance in vivo (14,16), and it has been used to treat thrombotic and embolic strokes in experimental models in rodents and nonhuman primates (17)(18)(19)(20). Unexpectedly, SMTP-7 was demonstrated to reduce hemorrhagic transformation and to have a wide therapeutic time window (17,18,20). These excellent activities are partly explained by the finding that, unlike tissue plasminogen activator, SMTP-7 suppresses inflammatory/oxidative responses after thrombolytic reperfusion (16,18,19,21).…”

“…In thrombotic and embolic stroke models in rodents and primates, SMTP-7 exhibited excellent activities, with a wide therapeutic time window and a reduced cerebral hemorrhage (17,18,20), that were not achieved by the conventional thrombolytic therapy. The finding that SMTP-7 inhibits sEH suggests that this activity, aside from the thrombolytic enhancement by plasminogen modulation, may account for these additional pharmacological potentials of SMTP-7.…”

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.…”