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

Ramesh C. Gupta, Snjezana Milatovic, Wolf D. Dettbarn, Michael Aschner, Dejan Milatovic

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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 (F2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-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 F2-IsoPs and F4-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.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalToxicology and Applied Pharmacology
Volume219
Issue number2-3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Carbofuran
  • Memantine
  • Neuronal injury
  • Neuroprotection
  • Oxidative stress

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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