Effects of some new antiepileptic drugs and progabide on glucocorticoid receptor-mediated gene transcription in LMCAT cells.
Antiepileptic drugs affect endocrine and immune system activity, however, it is not clear whether these effects are indirect, via interference with neurotransmitters, membrane receptors and ion channels or maybe independent of neuronal mechanisms. In order to shed more light on this problem, in the present study, we evaluated effects of some new-generation antiepileptic drugs and progabide as a GABA-mimetic on the corticosterone-induced chloramphenicol acetyltransferase (CAT) activity in mouse fibroblast cells stably transfected with mouse mammary tumor virus (MMTV)-CAT plasmid. Treatment of cells with felbamate for five days inhibited in a concentration-dependent manner (3-100 microM) the corticosterone-induced reporter gene transcription. Progabide and loreclezole also inhibited the corticosterone-induced CAT activity, but with lower potency, and significant effects were observed at 10 to 100 microM concentration. Tiagabine and stiripentol showed less potent inhibitory effect on functional activity of glucocorticoid receptors (GR). In contrast, topiramate and lamotrigine (3-100 microM) failed to affect the corticosterone-induced gene transcription. These data indicate that some new antiepileptic drugs and progabide may suppress glucocorticoid effects via the inhibition of GR-mediated gene transcription. In turn, attenuation of GR function could influence antiepileptic drug effect on seizures, neuronal degeneration and immune system activity.
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Agnieszka
A
Basta-Kaim
Bogusława
B
Budziszewska
Monika
M
Leśkiewicz
Magdalena
M
Regulska
Magdalena
M
Otczyk
Marta
M
Kubera
Grzegorz
G
Jagła
Wojciech
W
Nowak
Jarogniew J J
JJ
Luszczki
Stanisław J
SJ
Czuczwar
Władysław
W
Lasoń
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis* / Q000235:genetics; D003345:Corticosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000201:enzymology; D017930:Genes, Reporter; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; D011965:Receptors, Glucocorticoid; C017985:progabide; D005680:gamma-Aminobutyric Acid; D015500:Chloramphenicol O-Acetyltransferase; D003345:Corticosterone