Abstracts

RATIONALE: Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the excitatory neurotransmitter glutamate, or from inadequate inhibitory effects of gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are regulated 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 GLAST and GLT-1, and the neuronal transporter EAAC-1. GABA is removed from synaptic regions by the action of the transporter proteins GAT-1 and GAT-3. At the end of this activity participitants will have better understanding of the molecular effects of zonisamide.
METHODS: Albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of FeCl3 were treated for 14 days with zonisamide (ZNS) (40 mg per kg, i.p.). Control animals had saline injection into amygdalar regions. Treatment control for both groups of intracerebrally injected animals was i.p. saline. Western blotting was used to measure glutamate and GABA transporters in hippocampus and frontal cortex.
RESULTS: Epileptogenesis correlates with collapse of glutamate regulation, with down-regulation of glial glutamate transporters associated with up-regulation of neuronal EAAC-1. Zonisamide had unique effects with increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporters GAT-1 and GAT-3. These changes occurred in both experimental and ZNS treated control animals.
CONCLUSIONS: These data demonstrate that zonisamide has molecular effects in that up-regulation of EAAC-1 and decreased production of GABA transporters will increase tissue and synaptic concentrations of GABA. In vitro assessment of the mechanisms of action of various antiepileptic drugs have shown effect on ionic channels. However, our study suggests that the impact of drugs on molecular function of neural tissue is of critical importance both in understanding all of the mechanisms of action of drugs and in the future design and development of drugs that may have pharmacogenetic effects.
[Supported by: a Grant-in-Aid for Encouragement of Young Scientists (12770537) from the Ministry of Education, Science, Sport and Culture of Japan (to Y.U.).]; (Disclosure: Honoraria - Elan Pharmaceuticals)