S-methylcysteine may be a causal factor in monohalomethane neurotoxicity.
S-methylcysteine (SMC) is formed after exposure to monohalomethanes in rodents as well as in humans. The present study was performed to study whether SMC, directly or indirectly, contributes to the well-known neurotoxicity of monohalomethanes. We have investigated the effects of acute exposure to SMC by means of electrophysiolocal measurements in freshly prepared hippocampal slices and dissociated hippocampal neurons in culture. For longer-term exposures (24 h) we have used organotypic cultures (2 weeks in culture), taking electrophysiologic recordings and assessing membrane integrity with propidium iodide (PI) fluorescence. We found that only high concentrations of SMC (10(-2) M; exposure time 30 min) in freshly isolated slices of adult rats reduce synaptically evoked population spikes in the CA1 region. This effect was at least partially reversible. In organotypic cultures, at 5 x 10(-5) M after 24 h of exposure, SMC compromises membrane integrity as revealed by PI fluorescence, only in the dentate gyrus, spreading to pyramidal cell layers at 50 x 10(-4) M. At 5 x 10(-6) and 2 x 10(-5) M, under the same experimental conditions, no changes were seen with the PI method, but we recorded increased population spike amplitudes, repetitive discharges and frequency potentiation (at a stimulus repetition rate of 0.05 Hz). Using whole-cell patch clamp in hippocampal dissociated neurons we have found that SMC (applied for approximately 1s) reduces GABA-induced currents ( IC(50) = 4.4 x 10(-4) M) without having an effect of its own, acting like a competitive antagonist at GABA(A) receptors. Our findings are in line with the view that the ability of monohalomethanes to induce the formation of SMC is an important factor for their neurotoxicity, provided that SMC is allowed to act at least for several hours. The effects exerted by SMC seem to be due, at least in part, to its interaction with GABA receptors.
Pancetti
Floria
F
Department of Management in Agriculture, Technological Faculty, University of Santiago de Chile, Santiago, Chile.
Oyarce
Marcelo
M
Aranda
Marcela
M
Parodi
Jorge
J
Aguayo
Luis G
LG
Morales
Bernardo
B
Westphal
Götz
G
Müller
Michael
M
Hallier
Ernst
E
Zeise
Marc L
ML
D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D008297:Male; D008856:Microscopy, Fluorescence; D009473:Neuronal Plasticity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011419:Propidium / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D006846:Hydrocarbons, Halogenated; D011963:Receptors, GABA-A; D011419:Propidium; D005680:gamma-Aminobutyric Acid; C008425:S-methylcysteine; D003545:Cysteine