Astrocytes as potential modulators of mercuric chloride neurotoxicity.
1. MC has been shown to inhibit the uptake of L-glutamate and increase D-aspartate release from preloaded astrocytes in a dose-dependent fashion. 2. Two sulfhydryl (SH-)-protecting agents; reduced glutathione (GSH), a cell membrane-nonpenetrating compound, and the membrane permeable dithiothreitol (DTT), have been shown consistently to reverse the above effects. MC-induced D-aspartate release is completely inhibited by the addition of 1 mM DTT or GSH during the actual 5-min perfusion period with MC (5 microM); when added after MC treatment, DTT fully inhibits the MC-induced D-aspartate release, while GSH does not. 3. Neither DTT nor GSH, in the absence of MC, have any effect on the rate of astrocytic D-aspartate release. Other studies demonstrate that although MC treatment (5 microM) does not induce astrocytic swelling, its addition to astrocytes swollen by exposure to hypotonic medium leads to their failure to volume regulate. 4. Omission of calcium from the medium greatly potentiates the effect of MC on astrocytic D-aspartate release, an effect which can be reversed by cotreatment of astrocytes with the dihydropyridine Ca(2+)-channel antagonist nimodipine (10 microM), indicating that one possible route of MC entry into the cells is through voltage-gated L-type channels.
Aschner
M
M
Department of Pharmacology and Toxicology, Albany Medical College, New York 12208, USA.
Mullaney
K J
KJ
Fehm
M N
MN
Wagoner
D E
DE
Vitarella
D
D
D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology*; D007700:Kinetics; D008627:Mercuric Chloride / Q000633:toxicity*; D009553:Nimodipine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D015220:Calcium Channels; D001224:Aspartic Acid; D018698:Glutamic Acid; D008627:Mercuric Chloride; D009553:Nimodipine; D005978:Glutathione; D004229:Dithiothreitol