Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine.
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, sc), 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.
Gupta
Ramesh C
RC
Toxicology Department, Murray State University, Breathitt Veterinary Center, Hopkinsville, KY 42240-2000, USA. ramesh.gupta@murraystate.edu <ramesh.gupta@murraystate.edu>
Milatovic
Snjezana
S
Dettbarn
Wolf-D
WD
Aschner
Michael
M
Milatovic
Dejan
D
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002235:Carbofuran / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002956:Citrulline / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
D002800:Cholinesterase Inhibitors; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D002956:Citrulline; D019001:Nitric Oxide Synthase; D000110:Acetylcholinesterase; D002235:Carbofuran; D008559:Memantine