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

Abstract

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{sub 2}-isoprostanes, F{sub 2}-IsoPs; and F{sub 4}-neuroprostanes, F{sub 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, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F{sub 2}-IsoPs and F{sub 4}-NeuroPs, declines in HEPs, asmore » 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.« less

Authors:
 [1];  [2];  [2];  [2];  [2]
  1. Toxicology Department, Murray State University, Breathitt Veterinary Center, P.O. Box 2000, 715 North Drive, Hopkinsville, KY 42240-2000 (United States). E-mail: ramesh.gupta@murraystate.edu
  2. Vanderbilt University Medical Center, Nashville, TN 37232 (United States)
Publication Date:
OSTI Identifier:
20976873
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 219; Journal Issue: 2-3; Other Information: DOI: 10.1016/j.taap.2006.10.028; PII: S0041-008X(06)00408-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENINES; ATP; ATROPINE; CARBAMATES; CITRULLINE; CREATINE; DAMAGE; DENDRITES; ELECTROMECHANICS; HIPPOCAMPUS; INJURIES; INSECTICIDES; MORPHOLOGY; NERVE CELLS; OXIDATION; PHOSPHATES; PHOSPHOCREATINE; RATS; RECEPTORS; VERTEBRAE

Citation Formats

Gupta, Ramesh C., Milatovic, Snjezana, Dettbarn, Wolf-D., Aschner, Michael, and Milatovic, Dejan. Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.10.028.
Gupta, Ramesh C., Milatovic, Snjezana, Dettbarn, Wolf-D., Aschner, Michael, & Milatovic, Dejan. Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine. United States. doi:10.1016/j.taap.2006.10.028.
Gupta, Ramesh C., Milatovic, Snjezana, Dettbarn, Wolf-D., Aschner, Michael, and Milatovic, Dejan. Thu . "Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine". United States. doi:10.1016/j.taap.2006.10.028.
@article{osti_20976873,
title = {Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine},
author = {Gupta, Ramesh C. and Milatovic, Snjezana and Dettbarn, Wolf-D. and Aschner, Michael and Milatovic, Dejan},
abstractNote = {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{sub 2}-isoprostanes, F{sub 2}-IsoPs; and F{sub 4}-neuroprostanes, F{sub 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, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F{sub 2}-IsoPs and F{sub 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.},
doi = {10.1016/j.taap.2006.10.028},
journal = {Toxicology and Applied Pharmacology},
number = 2-3,
volume = 219,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}