Role of high-energy phosphates and their metabolites in protection of carbofuran-induced biochemical changes in diaphragm muscle by memantine.
A combined antidotal treatment with memantine HCI (MEM, 18 mg/kg, s.c.) and atropine sulfate (ATS, 16 mg/kg, s.c.) provided complete protection against acute carbofuran toxicity (1.5 mg/kg, s.c.) in rats by multiple mechanisms. Carbofuran, in addition to inhibiting serine-containing esterases, also perturbed the activities of mitochondrial/cytoplasmic biomarker enzymes (creatine kinase, CK; and lactic dehydrogenase, LDH) in diaphragm muscle. The observed changes in the activity of biomarker enzymes were reflected in serum as a result of their leakage from the diaphragm due to a depletion of high-energy phosphates, such as adenosine triphosphate (ATP, 27%) and phosphocreatine (PCr, 33%) and their metabolites (ADP, 36%; AMP, 35%; and Cr, 38%). Combined treatment with MEM and ATS provided protection and reversal of the induced changes in biomarkers by preventing depletion of high-energy phosphates and thus maintaining normal cell membrane characteristics, including permeability and integrity. These results, along with those reported previously, indicate that MEM antagonizes carbofuran toxicity by multiple mechanisms.
Gupta
R C
RC
Murray State University, Breathitt Veterinary Center, Toxicology Department, Hopkinsville, KY 42241-2000, USA. ramesh.gupta@murraystate.edu
Goad
J T
JT
D000110:Acetylcholinesterase / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002235:Carbofuran / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003402:Creatine Kinase / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010710:Phosphates / Q000737:chemistry*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D010710:Phosphates; D010725:Phosphocreatine; D000244:Adenosine Diphosphate; D001285:Atropine; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D000110:Acetylcholinesterase; D002235:Carbofuran; D008559:Memantine