NDLI: Putative Agmatinase Inhibitor for Hypoxic-Ischemic New Born Brain Damage

Content Provider	Springer Nature Link
Author	Piletz, John E. Klenotich, Stephanie Lee, Ken S. Zhu, Qian Long Valente, Edward Collins, Michael A. Jones, Vyvyca Lee, Soeb Nam Yangzheng, Feng
Copyright Year	2013
Abstract	Agmatine is an endogenous brain metabolite, decarboxylated arginine, which has neuroprotective properties when injected intraperitoneally (i.p.) into rat pups following hypoxic-ischemia. A previous screen for compounds based on rat brain lysates containing agmatinase with assistance from computational chemistry, led to piperazine-1-carboxamidine as a putative agmatinase inhibitor. Herein, the neuroprotective properties of piperazine-1-carboxamidine are described both in vitro and in vivo. Organotypic entorhinal-hippocampal slices were firstly prepared from 7-day-old rat pups and exposed in vitro to atmospheric oxygen depletion for 3 h. Upon reoxygenation, the slices were treated with piperazine-1-carboxamidine or agmatine (50 μg/ml agents), or saline, and 15 h later propidium iodine was used to stain. Piperazine-1-carboxamidine or agmatine produced substantial in vitro protection compared to post-reoxygenated saline-treated controls. An in vivo model involved surgical right carotid ligation followed by exposure to hypoxic-ischemia (8 % oxygen) for 2.5 h. Piperazine-1-carboxamidine at 50 mg/kg i.p. was given 15 min post-reoxygenation and continued twice daily for 3 days. Cortical agmatine levels were elevated (+28.5 %) following piperazine-1-carboxamidine treatment with no change in arginine or its other major metabolites. Histologic staining with anti-Neun monoclonal antibody also revealed neuroprotection of CA1-3 layers of the hippocampus. Until endpoint at 22 days of age, no adverse events were observed in treated pups’ body weights, rectal temperatures, or prompted ambulation. Piperazine-1-carboxamidine therefore appears to be a neuroprotective agent of a new category, agmatinase inhibitor.
Starting Page	176
Ending Page	190
Page Count	15
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	24
Issue Number	2
e-ISSN	14763524
Language	English
Publisher	Springer-Verlag
Publisher Date	2013-01-19
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Agmatine Neuroprotection Agmatinase Hypoxia Ischemia Neurosciences Neurology Neurochemistry Pharmacology/Toxicology Neurobiology Cell Biology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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