Putative agmatinase inhibitor for hypoxic-ischemic new born brain damage Journal Article

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Authors: Piletz, J. E.; Klenotich, S.; Lee, K. S.; Zhu, Q. L.; Valente, E.; Collins, M. A.; Jones, V.; Lee, S. N.; Yangzheng, F.
Article Title: Putative agmatinase inhibitor for hypoxic-ischemic new born brain damage
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 mug/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.
Journal Title: Neurotoxicity research
Volume: 24
Issue: 2
ISSN: 1476-3524; 1029-8428
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: 176
End Page: 190
Language: eng
DOI/URL:

10.1007/s12640-013-9376-5
Notes: LR: 20141104; GR: R21 NS054862/NS/NINDS NIH HHS/United States; GR: R21 NS054862-1-3/NS/NINDS NIH HHS/United States; JID: 100929017; 0 (Enzyme Inhibitors); 0 (Guanidines); 0 (Neuroprotective Agents); 0 (Piperazines); 0 (piperazine-1-carboxamidine); EC 3.5.3.- (Ureohydrolases); EC 3.5.3.11 (agmatinase); NIHMS437633; OID: NLM: NIHMS437633; OID: NLM: PMC3692582; 2012/08/16 [received]; 2013/01/08 [accepted]; 2012/12/10 [revised]; 2013/01/19 [aheadofprint]; ppublish