Testosterone amplifies excitotoxic damage of cultured oligodendrocytes.
An overactivation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage in demyelinating disorders of the CNS. We decided to examine the effect of testosterone on excitotoxic death of oligodendrocytes because a gender difference exists in the incidence and disease course of multiple sclerosis. Short-term pure cultures of oligodendrocytes (4 days in vitro) were exposed to a brief pulse with kainate or AMPA + cyclothiazide for the induction of excitotoxicity. Exposure to testosterone enantate was slightly toxic per se and amplified both AMPA and kainate toxicity. Testosterone treatment induced all gene targets of p53, and amplified the induction of these genes induced by kainate. The effect of testosterone was mediated by the activation of androgen receptors and was resistant to the aromatase inhibitors, dl-aminoglutethimide and 4-hydroxyandrost-4-ene-3,17-dione. Testosterone treatment also potentiated the stimulation of 45Ca2+ influx induced by AMPA + cyclothiazide or kainate without changing the expression of the glutamate receptor (GluR) 1, -2/3, and -4 subunits of AMPA receptors or the GluR6/7 subunits of kainate receptors. We conclude that testosterone amplifies excitotoxic damage of oligodendrocytes acting at an early step of the death cascade triggered by AMPA/kainate receptors.
Department of Human Physiology and Pharmacology, University of Rome, La Sapienza, Rome, Italy.
A
A
Caruso
V
V
Di Giorgi Gerevini
M
M
Castiglione
F
F
Marinelli
V
V
Tomassini
C
C
Pozzilli
A
A
Caricasole
V
V
Bruno
F
F
Caciagli
A
A
Moretti
F
F
Nicoletti
D
D
Melchiorri
D000818:Animals; D001581:Benzothiadiazines / Q000633:toxicity; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007608:Kainic Acid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D001581:Benzothiadiazines; D002118:Calcium; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007608:Kainic Acid; D007770:L-Lactate Dehydrogenase; D009498:Neurotoxins; D011810:Quinoxalines; D018091:Receptors, AMPA; D011944:Receptors, Androgen; D018092:Kainic Acid Receptors; D013739:Testosterone; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C056723:FG 9041; C004639:cyclothiazide