Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine

被引:37
作者
Gupta, Ramesh C.
Milatovic, Snjezana
Dettbarn, Wolf-D.
Aschner, Michael
Milatovic, Dejan
机构
[1] Murray State Univ, Breathitt Vet Ctr, Dept Toxicol, Hopkinsville, KY 42240 USA
[2] Vanderbilt Univ, Ctr Med, Nashville, TN 37232 USA
关键词
carbofuran; memantine; oxidative stress; neuronal injury; neuroprotection;
D O I
10.1016/j.taap.2006.10.028
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82-90%), radical oxygen species (ROS) markers (F-2-isoprostanes, F-2-IsoPs; and F-4-neuroprostanes, F-4-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43-56%; and phosphocreatine, by 37-48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41-56% and 35-45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, se), significantly attenuated carbofuran-induced changes in AChE activity and levels of F-2-IsoPs and F-4-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:97 / 105
页数:9
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