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

Abstract

Inhibitors for polyamine oxidizing enzymes, spermine oxidase (SMOX) and N1-acetylpolyamine oxidase (PAOX), were designed and evaluated for their effectiveness in a photochemically induced thrombosis (PIT) mouse model. N1-Nonyl-1,4-diaminobutane (C9-4) and N1-tridecyl-1,4-diaminobutane (C13-4) competitively inhibited the activity of PAOX and SMOX in a manner comparable to N1,N4-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.

• Authors: Takashi Masuko, Koichi Takao, Keijiro Samejima, Akira Shirahata, Kazuei Igarashi, Robert A Casero Jr, Yasuo Kizawa, Yoshiaki Sugita
• Journal: Neuroscience letters (Neurosci Lett) Vol. 672 Pg. 118-122 (04 13 2018) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 29477597 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Oxidoreductases Acting on CH-NH Group Donors

Topics

• Animals
• Brain (drug effects, pathology)
• Brain Infarction (drug therapy, pathology)
• Disease Models, Animal
• Mice
• Oxidoreductases Acting on CH-NH Group Donors (antagonists & inhibitors)
• Thrombosis (drug therapy, pathology)
• Polyamine Oxidase