Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.
The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.
Fraser
C M
CM
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
Sills
G J
GJ
Butler
E
E
Thompson
G G
GG
Lindsay
K
K
Duncan
R
R
Howatson
A
A
Brodie
M J
MJ
D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005333:Fetus; D050485:GABA Plasma Membrane Transport Proteins; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000502:physiology; D026901:Membrane Transport Proteins; D009433:Neural Inhibition / Q000187:drug effects; D009557:Nipecotic Acids / Q000494:pharmacology*; D027361:Organic Anion Transporters; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D013702:Temporal Lobe / Q000187:drug effects* / Q000196:embryology; D000078308:Tiagabine; D014635:Valproic Acid / Q000494:pharmacology*; D020888:Vigabatrin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; C493413:SLC6A1 protein, human; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D020888:Vigabatrin; D000078308:Tiagabine