N1-Nony1-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice

NEUROSCIENCE LETTERS

卷:672

Article

Masuko, Takashi¹  Takao, Koichi²  Samejima, Keijiro³  Shirahata, Akira⁴  Igarashi, Kazuei^5,6  Casero, Robert A., Jr.⁷  Kizawa, Yasuo¹  Sugita, Yoshiaki² 

[1] Nihon Univ, Sch Pharm, Lab Physiol & Anat, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan

[2] Josai Univ, Fac Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Lab Bioorgan Chem, 1-1 Keyaki Dai, Sakado, Saitama 3500295, Japan

[3] Tokyo Metropolitan Inst Med Sci, Translat Med Res Ctr, Setagaya Ku, 2-1-6 Kamikitazawa, Tokyo 1568506, Japan

[4] Josai Univ, Fac Pharm & Pharmaceut Sci, 1-1 Keyaki Dai, Sakado, Saitama 3500295, Japan

[5] Chiba Univ, Amine Pharma Res Inst, Chuo Ku, Innovat Plaza,1-8-15 Inohana, Chiba 2600856, Japan

[6] Chiba Univ, Grad Sch Pharmaceut Sci, Chuo Ku, 1-8-1 Inohana, Chiba 2608675, Japan

[7] Johns Hopkins Univ, Sydney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

关键词: Spermine oxidase;    N-1-Acetylolyamine oxidase;    Polyamine;    Inhibitor;    Stroke;    Ischemia-reperfusion;   

DOI  :  10.1016/j.neulet.2018.01.054

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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