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 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.
authors: Department of Psychiatry, Stritch School of Medicine, Loyola University Chicago, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153, USA. jpiletz@lumc.edu
authors: John E
authors: JE
authors: Piletz
authors: Stephanie
authors: S
authors: Klenotich
authors: Ken S
authors: KS
authors: Lee
authors: Qian Long
authors: QL
authors: Zhu
authors: Edward
authors: E
authors: Valente
authors: Michael A
authors: MA
authors: Collins
authors: Vyvyca
authors: V
authors: Jones
authors: Soeb Nam
authors: SN
authors: Lee
authors: Feng
authors: F
authors: Yangzheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014512:Ureohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D018696:Neuroprotective Agents; D010879:Piperazines; C586664:piperazine-1-carboxamidine; D014512:Ureohydrolases; C019625:agmatinase