N1-Nony1-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice
N1-Nony1-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice
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DOI：
10.1016/j.neulet.2018.01.054
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发表时间：
2018-04-13
影响因子：
2.5
通讯作者：
Sugita, Yoshiaki
中科院分区：
文献类型：
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作者：
Masuko, Takashi;Takao, Koichi;Sugita, Yoshiaki
设计了多胺氧化酶抑制剂精胺氧化酶（SMOX）和N-1-乙酰多胺氧化酶（PAOX），并在光化学诱导血栓形成（PIT）小鼠模型中评价了它们的有效性。N-1-壬基-1，4-二氨基丁烷（C9-4）和N-1-十三烷基-1，4-二氨基丁烷（C13-4）以与N-1，N-4-双（2，3-丁二烯基）-1，4-丁二胺（MDL 72527）（两种酶的不可逆抑制剂）相当的方式竞争性抑制PAOX和SMOX的活性。然后测试这两种化合物在PIT模型中的作用。均腹膜内（i. p.）和脑室内（i. c. v.）C9-4的给药显著降低了梗塞体积。相比之下，C13-4通过i. c. v.给药减少了脑梗死体积，但在i. p.给药后未观察到减少。通过腹膜内注射施用的C9-4在大于3 mg/kg的剂量下显著减少脑梗塞体积，并且5 mg/kg或10 mg/kg的剂量显示出最有效的作用，并且比等效剂量的其他抑制剂如MDL 72527和N-苄基羟胺更有效。腹腔注射5 mg/kg C9-4提供了超过12 h的治疗时间窗。本报告表明，C9-4是一种有效的多胺氧化酶抑制剂，是一个有用的先导化合物的候选药物具有较长的治疗时间窗，用于治疗缺血性中风。
Inhibitors for polyamine oxidizing enzymes, spermine oxidase (SMOX) and N-1-acetylpolyamine oxidase (PAOX), were designed and evaluated for their effectiveness in a photochemically induced thrombosis (PIT) mouse model. N-1-Nonyl-1,4-diaminobutane (C9-4) and N-1-tridecyl-1,4-diaminobutane (C13-4) competitively inhibited the activity of PAOX and SMOX in a manner comparable to N-1,N-4-bis(2,3-butadienyl)-1,4-butanediamine (MDL72527), an irreversible inhibitor of both enzymes. The two compounds were then tested for their effects in the PIT model. Both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of C9-4 decreased infarct volumes significantly. By contrast, C13-4 reduced the volume of brain infarction by i.c.v. administration, but no reduction was observed after i.p. administration. C9-4 administered by i.p. injection reduced the volume of brain infarction significantly at doses of more than 3 mg/kg, and the dosage of 5 mg/kg or 10 mg/kg demonstrated the most potent effect and were more effective than equivalent doses of the other inhibitors such as MDL72527 and N-benzylhydroxylamine. I.P. injection of 5 mg/kg of C9-4 provided a therapeutic time window of longer than 12 h. This report demonstrates that C9-4 is a potent inhibitor of the polyamine oxidizing enzymes and is useful lead compound for candidate drugs with a long therapeutic time window, to be used in the treatment of ischemic stroke.