PROTECTION AND REVERSAL BY MEMANTINE AND ATROPINE OF CARBOFURAN-INDUCED CHANGES IN BIOMARKERS

Male Sprague-Dawley rats injected with a single acute dose of carbofuran (1.5 mg/kg, sc) developed chewing movements and fine tremors within 5-7 min. The signs of maximal severity with hypercholinergic preponderance including muscle fasciculations, convulsions, tracheobronchial secretions, and diarrhea were evident within 15-30 min and lasted for about 2 h. Toxic signs were of central, as well as peripheral, origins. Rats were free from toxic signs by 3.5 h. Various antidotal drugs, alone or in combination with atropine sulfate (ATS), were administered as pretreatment or as therapeutic measures to alleviate carbofuran-induced cholinergic toxicity. In fact, pyridine-2-aldoxime methylchloride (2-PAM) or diazepam alone or in combination with ATS did not provide any beneficial antidotal effects. Combined pretreatment with memantine (MEM, 18 mg/kg, sc) and ATS (16 mg/kg, sc) provided complete protection against carbofuran toxicity and reversal of clinical evidence when given therapeutically. Carbofuran intoxication caused significant alterations in the activities of biomarker enzymes such as creatine kinase (CK) and lactic dehydrogenase (LDH) and their isoenzymes patterns in serum as a result of their leakage from the target organs (brain, muscles, and heart). Significant increases in the levels of transaminases (GOT and GPT) and glucose were also noted. MEM in combination with ATS provided significant protection and reversal of the induced changes in the aforementioned parameters, in addition to similar protective effects reported on target enzyme acetylcholinesterase (AChE). These results, along with those reported previously, indicate that MEM antagonizes carbamates toxicity by maintaining cell membrane permeability and integrity through multiple mechanisms, in addition to muscarinic receptor blocking effect of ATS.