Putative agmatinase inhibitor for hypoxic-ischemic new born brain damage.
Putative agmatinase inhibitor for hypoxic-ischemic new born brain damage.
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DOI：
10.1007/s12640-013-9376-5
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发表时间：
2013-08
影响因子：
3.7
通讯作者：
Feng Yangzheng
中科院分区：
文献类型：
--
作者：
Piletz, John E.;Klenotich, Stephanie;Lee, Ken S.;Qian Long Zhu;Valente, Edward;Collins, Michael A.;Jones, Vyvyca;Lee, Soeb Nam;Feng Yangzheng
胍丁胺是一种内源性脑代谢产物，脱羧精氨酸，在缺氧缺血后腹膜内 (i.p.) 注射到大鼠幼崽中时具有神经保护特性。之前在计算化学的帮助下，基于含有凝胺酶的大鼠脑裂解物筛选化合物，结果发现哌嗪-1-甲脒可以作为一种假定的凝胺酶抑制剂。本文描述了哌嗪-1-甲脒的体外和体内神经保护特性。首先从 7 日龄幼鼠身上制备器官型内嗅海马切片，并在体外暴露于大气缺氧 3 小时。再充氧后，用哌嗪-1-甲脒或胍丁胺（50μg/ml试剂）或盐水处理切片，15小时后用碘化丙啶染色。与复氧盐水处理后的对照相比，哌嗪-1-甲脒或胍丁胺产生了显着的体外保护作用。体内模型涉及手术右颈动脉结扎，然后暴露于缺氧缺血（8% 氧气）2.5 小时。哌嗪-1-甲脒 50 mg/kg 腹膜内注射复氧后 15 分钟给予治疗，每天两次，持续 3 天。哌嗪-1-甲脒治疗后，皮质胍丁胺水平升高（+28.5%），而精氨酸或其其他主要代谢物没有变化。抗 Neun 单克隆抗体的组织学染色也揭示了海马 CA1-3 层的神经保护作用。直到 22 日龄终点为止，在接受治疗的幼犬的体重、直肠温度或提示行走方面均未观察到不良事件。因此，Piperrazine-1-carboxamidine 似乎是一种新类别的神经保护剂，即胍丁胺酶抑制剂。
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 seven-day-old rat pups and exposed in vitro to atmospheric oxygen depletion for 3 hrs. Upon reoxygenation the slices were treated with piperazine-1-carboxamidine or agmatine (50 μg/ml agents), or saline, and 15 hours 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 hours. Piperazine-1-carboxamidine at 50 mg/kg i.p. was given 15 minutes 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. Histological 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.
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DOI：
10.1016/j.jchromb.2011.11.016
发表时间：
2012-01-01
影响因子：
3
作者：
Betancourt, Luis;Rada, Pedro;Hernandez, Luis
通讯作者：
Hernandez, Luis
影响因子：
4.7
作者：
Demehri, S;Homayoun, H;Dehpour, AR
通讯作者：
Dehpour, AR
DOI：
10.1111/j.1749-6632.1995.tb32418.x
发表时间：
1995-07-12
影响因子：
5.2
作者：
Li, G;Regunathan, S;Reis, D J
通讯作者：
Reis, D J
影响因子：
3.3
作者：
Liu, P.;Bergin, D. H.
通讯作者：
Bergin, D. H.
影响因子：
4.1
作者：
Coleman, CS;Hu, GR;Pegg, AE
通讯作者：
Pegg, AE