Lithium-methomyl induced seizures in rats: a new model of status epilepticus?
Behavioral, electroencephalographic (EEG) and neuropathological effects of methomyl, a carbamate insecticide reversibly inhibiting acetylcholinesterase activity, were studied in naive or lithium chloride (24 h, 3 mEq/kg, s.c.) pretreated male Wistar rats. In naive animals, methomyl with equal potency produced motor limbic seizures and fatal status epilepticus. Thus, the CD50 values (50% convulsant dose) for these seizure endpoints were almost equal to the LD50 (50% lethal dose) of methomyl (13 mg/kg). Lithium pretreated rats were much more susceptible to convulsant, but not lethal effect of methomyl. CD50 values of methomyl for motor limbic seizures and status epilepticus were reduced by lithium pretreatment to 3.7 mg/kg (a 3.5-fold decrease) and 5.2 mg/kg (a 2.5-fold decrease), respectively. In contrast, lithium pretreatment resulted in only 1.3-fold decrease of LD50 value of methomyl (9.9 mg/kg). Moreover, lithium-methomyl treated animals developed a long-lasting status epilepticus, which was not associated with imminent lethality observed in methomyl-only treated rats. Scopolamine (10 mg/kg) or diazepam (10 mg/kg) protected all lithium-methomyl treated rats from convulsions and lethality. Cortical and hippocampal EEG recordings revealed typical epileptic discharges that were consistent with behavioral seizures observed in lithium-methomyl treated rats. In addition, convulsions induced by lithium-methomyl treatment were associated with widespread neurodegeneration of limbic structures. Our observations indicate that lithium pretreatment results in separation between convulsant and lethal effects of methomyl in rats. As such, seizures induced by lithium-methomyl administration may be an alternative to lithium-pilocarpine model of status epilepticus, which is associated with high lethality.
Kaminski
Rafal M
RM
Department of Toxicology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950 Lublin, Poland. kaminskr@mail.nih.gov <kaminskr@mail.nih.gov>
Blaszczak
Piotr
P
Dekundy
Andrzej
A
Parada-Turska
Jolanta
J
Calderazzo
Lineu
L
Cavalheiro
Esper A
EA
Turski
Waldemar A
WA
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004569:Electroencephalography; D018021:Lithium Chloride / Q000633:toxicity*; D008297:Male; D008724:Methomyl / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D013226:Status Epilepticus / Q000139:chemically induced*
D000927:Anticonvulsants; D008724:Methomyl; D012601:Scopolamine; D018021:Lithium Chloride; D003975:Diazepam