Potentiation of malaoxon-induced convulsions by lithium: early neuronal injury, phosphoinositide signaling, and calcium.
Convulsions, neuronal morphology, brain phosphoinositide (PI) signaling, and calcium levels were studied in rats 1, 4, and 72 hr after malaoxon (MO; 26.2 or 39.2 mg/kg ip) subsequent to pretreatment with saline or LiCl (10 meq/kg ip). The high dose of MO induced convulsions in 60% of the rats whereas the low dose was ineffective. In nonconvulsing rats, MO transiently increased cerebral inositol 1-phosphate (Ins1P), an intermediate in PI cycle, but consistently elevated brain Ins1P in convulsing rats. LiCl did not induce convulsions, but elevated the resting level of Ins1P and decreased that of inositol. Lithium also increased the potential of MO to cause convulsions but attenuated MO-induced elevations of Ins1P. Moreover, total Ca2+ in cortex increased in LiCl-pretreated convulsing and nonconvulsing rats after MO. Astrocytic edema and cytoplasmic vacuolation and/or shrinkage of neurons in cortical layers 2-3 and in the hippocampus as well as in some subcortical structures occurred only in convulsing rats. These results suggest that PI signaling may be involved in convulsions and contribute to the early neuronal injury. Cerebral Ca2+ elevations seemed to precede permanent neuronal injury. A target other than the inhibition of the hydrolysis of inositol phosphates may be the site of lithium's action in cholinergic convulsions.
Hirvonen
M R
MR
National Public Health Institute, Department of Environmental Hygiene and Toxicology, Kuopio, Finland.
Paljärvi
L
L
Naukkarinen
A
A
Komulainen
H
H
Savolainen
K M
KM
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000378:metabolism / Q000494:pharmacology*; D008294:Malathion / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D007295:Inositol Phosphates; C002647:inositol 1-phosphate; C100082:malaoxon; D008094:Lithium; D002118:Calcium; D008294:Malathion