GABA Changes with Vigabatrin in the Developing Human Brain

Abstract

Summary:Purpose: Changes in y-aminobutyric acid (GABA) physiology are important in determining seizure susceptibility in the developing nervous system. Noninvasive measurements of brain GABA in adults with epilepsy have demonstrated important relations among seizure control, brain GABA levels, and changes in brain GABA with drugs designed to alter GABA metabolism. The purpose of this study was to demonstrate the changes in GABA in the occipital lobes of children with epilepsy after treatment with vigabatrin (VGB).Methods: Ten proton nuclear magnetic resonance spectroscopic (NMRS) studies were obtained on four subjects with epilepsy. The subjects were between ages 1 and 5 years. Occipital lobe GABA levels were measured before and after treatment with VGB.Results: Brain GABA levels increased significantly in these subjects after VGB treatment (p < 0.05, paired Student's t test). In one subject, brain GABA was decreased in the region of the epileptic focus compared with the homologous region of the opposite hemisphere. A nearly fivefold increase in GABA occurred in the epileptic region after VGB treatment in this subject.Conclusions: VGB increases brain GABA levels in children with epilepsy. NMRS can be used to monitor the response of brain GABA levels to drugs known to alter GABA physiology and serve as an important tool to understand the role of GABAmediated inhibition in pediatric epilepsies. Key Words: Nuclear magnetic resonance spectroscopy-NMR-GABAEpilepsy-Children-Anticonvulsants. y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human cortex. Extensive studies in animals have shown that changes in GABA release and metabolism have an important role in the origin and spread of seizure activity (1). Recent advances in nuclear magnetic resonance spectroscopy (NMRS) have permitted noninvasive measurements of cerebral GABA in animals and humans (2,3). Novel studies of GABA synthesis and metabolism in animal and human cortex by using NMRS have increased our understanding of the role of this important inhibitory neurotransmitter in human health and disease (43).Recently new antiepileptic agents (AEDs) have been developed that act on GABA-mediated inhibition to provide improved seizure control in complex partial and generalized epilepsies. Proton ('H) NMRS studies of adult subjects treated with vigabatrin (VGB), an irrevers-

Maternal exposure to the antiepileptic drug vigabatrin affects postnatal development in the rat

“…Its action lasts at least for 24 h and causes an increase of the whole brain GABA concentration by about 4-fold in the mouse [2]. Similar effects have been observed also in adult men by [ 1 H] nuclear magnetic resonance spec-troscopy [3] and in children with epilepsy [4]. VGB crosses the placental filter slowly by simple diffusion through a hydrophilic pathway in women [5] and it causes a transient increase of GABA in both placenta and embryo of VGB treated mice [6].…”

Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument

“…The effect of the use of triclofos sodium for sedation on the metabolism of GABA and Glu was unclear. There are several reports that vigabatrin increases the brain GABA level by inhibiting GABA transaminase (Petroff et al 1995(Petroff et al , 1996Weber et al 1999;Novotny et al 1999) although triclofos sodium does not change the activity of this enzyme. Aasly et al (1999) reported that the GABA content did not appear to be correlated with antiepileptic therapy.…”

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

“…However, AEDs that target the GABAergic system are highly effective anticonvulsants (46)(47)(48). Children with infantile spasms have very low GABA and homocarnosine levels (49). TPM and VGB are the two most effective drugs that improve the outcome of children with infantile spasms (9,50,51).…”