Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures.
Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of FeCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, i.p.). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was i.p. injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA. Although many antiepileptic drugs have effects on ion channels when measured in vitro our study suggests that additional mechanisms of action may be operant. Molecular effects on regulation of transporter proteins may aid in understanding epileptogenesis and inform investigators about future design and development of drugs to treat epilepsy.
Ueda
Yuto
Y
Department of Psychiatry, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. usan@post1.miyazaki-med.ac.jp
Doi
Taku
T
Tokumaru
Jun
J
Willmore
L James
LJ
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002712:Chlorides; D002908:Chronic Disease; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005290:Ferric Compounds / Q000633:toxicity; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D051381:Rats; D017208:Rats, Wistar; D000078305:Zonisamide
D027322:Amino Acid Transport System X-AG; D000927:Anticonvulsants; D002352:Carrier Proteins; D002712:Chlorides; D005290:Ferric Compounds; D050485:GABA Plasma Membrane Transport Proteins; D007555:Isoxazoles; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C493415:Slc6a1 protein, rat; D000078305:Zonisamide; C024555:ferric chloride