Glutamate and GABA synthesis, release, transport and metabolism as targets for seizure control.

The synthesis, release, reuptake, and metabolism of the excitatory and inhibitory neurotransmitters glutamate and GABA, respectively, are tightly controlled. Given the role that these two neurotransmitters play in normal and abnormal neurotransmission, it is important to consider the processes whereby they are regulated. This brief review is focused entirely on the metabolic aspects of glutamate and GABA synthesis and neurotransmission. It describes in limited detail the synthesis, release, reuptake, metabolism, cellular compartmentation and pharmacology of the glutamatergic and GABAergic synapse. This review also provides a summary and brief description of the pathologic and phenotypic features of the various genetic animal models that have been developed in an effort to provide a greater understanding of the role that each of the aforementioned metabolic processes plays in controlling excitatory and inhibitory neurotransmission and how their use will hopefully facilitate the development of safer and more efficacious therapies for the treatment of epilepsy and other neurological disorders.

Hippocampal betaine/GABA transporter mRNA expression is not regulated by inflammation or dehydration post-status epilepticus.

Seizure activity can alter GABA transporter and osmoprotective gene expression, which may be involved in the pathogenesis of epilepsy. However, the response of the betaine/GABA transporter (BGT1) is unknown. The goal of the present study was to compare the expression of BGT1 mRNA to that of other osmoprotective genes and GABA transporters following status epilepticus (SE). The possible contributory role of dehydration and inflammation was also investigated because both have been shown to be involved in the regulation of GABA transporter and/or osmoprotective gene expression. BGT1 mRNA was increased 24 h post-SE, as were osmoprotective genes. BGT1 was decreased 72 h and 4 weeks post-SE, as were the GABA transporter mRNAs. The mRNA values for osmoprotective genes following 24-h water withdrawal were significantly lower than the values obtained 24 h post-SE despite similarities in their plasma osmolality values. BGT1 mRNA was not altered by lipopolysaccharide-induced inflammation while the transcription factor tonicity-responsive enhancer binding protein and the GABA transporters 1 and 3 were. These results suggest that neither plasma osmolality nor inflammation fully account for the changes seen in BGT1 mRNA expression post-SE. However, it is evident that BGT1 mRNA expression is altered by SE and displays a temporal pattern with similarities to both GABA and osmolyte transporters. Further investigation of BGT1 regulation in the brain is warranted.

Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: Correlation with other seizure and epilepsy models.

Chronic electrical stimulation via corneal electrodes can rapidly yield large numbers of kindled mice with a seizure phenotype reflective of secondarily generalized partial seizures. The corneal kindled mouse model has been found to be a highly sensitive and efficient screening model for antiepileptic drug (AED) discovery. The present study further evaluates the utility of the corneal kindled mouse model as a tool for rapid screening of investigational AEDs. Results obtained with nine AEDs (valproic acid, lamotrigine, phenytoin, carbamazepine, levetiracetam, vigabatrin, topiramate, tiagabine, and ezogabine) with varying mechanisms of action and clinical spectrums, as well as six investigational compounds were evaluated in the corneal kindled mouse. ED(50) values are compared to those obtained in the hippocampal kindled rat, the mouse maximal electroshock (MES) model, the 6Hz partial psychomotor seizure model, and the subcutaneous pentylenetetrazol (scPTZ) test. The results obtained in the corneal kindled mouse demonstrate a positive correlation with those attained employing established preclinical models: MES (r² = 0.9511), scPTZ (r² = 0.9697), 6Hz (r² = 0.9519), and hippocampal kindling (r² = 0.9037). The demonstrated predictive ability of the corneal kindled mouse model supports its use in the early evaluation of investigational AEDs.