title: Carbofuran-induced oxidative stress in slow and fast skeletal muscles: prevention by memantine and atropine.
abstract: Acute toxic effects of acetylcholinesterase (AChE) inhibitors on skeletal muscles are thought to involve oxidative stress with increased generation of free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Muscle hyperactivity with its increased oxygen and energy consumption appear to be the primary cause of oxidative stress. The present investigation was therefore undertaken to establish the normal levels of F(2)-isoprostanes (F(2)-IsoPs, specific markers of ROS/oxidative stress), citrulline (determinant of NO/NOS and marker of RNS), and high-energy phosphates (HEP: adenosine triphosphate, ATP and phosphocreatine, PCr) in slow (soleus) and fast (extensor digitorum longus, EDL) muscles of rats. In addition, we aimed to determine if memantine HCl (MEM), in combination with atropine sulfate (ATS), prevents carbofuran-induced changes in markers of oxidative stress. Control values were not significantly different for F(2)-IsoPs (1.142 +/- 0.027 and 1.177 +/- 0.092 ng/g) and citrulline (469.7 +/- 31.8 and 417.8 +/- 18.5 nmol/g) in soleus and EDL muscles, while the values were different for HEP (ATP, 3.66 +/- 0.11 and 5.85 +/- 0.14 micromol/g; PCr, 7.91 +/- 0.26 and 13.14 +/- 0.31 micromol/g). Rats acutely intoxicated with carbofuran (1.5 mg/kg, s.c.) showed the signs of maximal toxicity including muscle hyperactivity within 60 min of exposure. At this time, F(2)-IsoPs (177 and 153%) and citrulline (267 and 304%) levels were significantly increased, while ATP (46 and 43%) and PCr (44 and 46%) levels were decreased in soleus and EDL, respectively. Rats pretreated with MEM (18 mg/kg, s.c.) and ATS (16 mg/kg, s.c.), 60 and 15 min prior to carbofuran, respectively, showed no signs of toxicity. MEM in combination with ATS protected muscles from carbofuran-induced hyperactivity and attenuated increases in F(2)-IsoPs and citrulline, and depletion of HEP. Carbofuran-induced changes and protection by MEM and ATS were of similar magnitude in both muscles. These findings indicate that carbofuran-induced muscle hyperactivity produces oxidative stress as measured by increased ROS and RNS generation, and HEP depletion. MEM and ATS prevent the carbofuran-induced chain of events involved in oxidative stress.
authors.affiliation: University Washington, Seattle, WA, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Milatovic
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dekundy
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Wolf-D
authors.initials: WD
authors.lastname: Dettbarn
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002235:Carbofuran / Q000009:adverse effects*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D002956:Citrulline / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000931:Antidotes; D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D028441:F2-Isoprostanes; D010725:Phosphocreatine; D002956:Citrulline; D001285:Atropine; D000255:Adenosine Triphosphate; D002235:Carbofuran; D008559:Memantine