Effects of Vigabatrin (γ‐vinyl GAB A) on Neuro transmission‐Related Amino Acids and on GAB A nd Benzodiazepine Receptor Binding in Rats

Abstract

The effect of 12-day intraperitoneal i.p. administration of vigabatrin (GVG, gamma-vinyl GABA) to rats on the neurotransmission-related amino acids in various brain regions (cortex, hippocampus, cerebellum, and spinal cord), cisternal fluid (CSF) and blood was studied. Results showed that GVG administration increased the levels of GABA in cortical and subcortical regions of the brain and CSF without affecting GABA and benzodiazepine receptors in the cortex. In addition, a dose-dependent decrease was noted in the concentration of glutamate in the hippocampus and in the concentrations of aspartate and glutamine in the cortex, hippocampus, and cerebellum. The changes in the levels of amino acids in the brain, except for that of GABA, were not reflected in the CSF, however, and the levels of amino acids in discrete brain regions did not show any correlation with those in the serum or in the CSF. The results suggest that GVG administration might suppress development and spread of seizures not only by elevating the level of the inhibitory amino acid GABA, but also by decreasing the levels of excitatory amino acids in the brain.

Neuropharmacological and Neurobiological Relevance of In vivo 1H-MRS of GABA and Glutamate for Preclinical Drug Discovery in Mental Disorders

“…For example, vigabatrin elicited a stronger change in GABA in the prefrontal cortex than in the striatum whereas for 3-MP and tiagabine this preference was reversed. Such region-specific responses are in concordance with previous studies (Halonen et al, 1991;Sheikh and Martin, 1998) and, although their basis is not fully explored, they may be rationalized by the intrinsic differential target expression, target occupancy, metabolic flux rates, and feedback regulation in the striatum and the prefrontal cortex. GABA-T and GAD65/67 have been reported to be more expressed in the striatum than in the prefrontal cortex whereas for GAD1 this preference is reversed (Durkin et al, 1995;Gale et al, 1984;Laprade and Soghomonian, 1999).…”

GABA Changes with Vigabatrin in the Developing Human Brain

“…VGB increases brain GABA levels in both animals and humans by irreversibly inhibiting GABAtransaminase (4,17,18). Our results suggest that occipital lobe GABA levels are increased in children with epilepsy after treatment with VGB.…”

In vivo monitoring of rat brain metabolites during vigabatrin treatment using localized 2D‐COSY

“…Like GABA, taurine can act as an inhibitory neurotransmitter or neuromodulator, and it has been shown that GABA can stimulate taurine release. [19][20][21][22][23][24][25]36 Based on this and other data, it has been suggested that there is a functional and metabolic interrelationship between GABA and taurine, 37 and this may underlie the observed increase in taurine.…”

“…This latter finding is at odds with the majority of vigabatrin studies in animals, in which decreases in brain glutamine have been found both acutely and chronically. 19,20,22,28 However, one study by Bernasconi et al 29 demonstrated that following a single dose (150 mg/kg) of vigabatrin in mice an acute decrease in cerebral glutamine was followed by an increase above control values at 20 h. Similarly, a study of patients treated with vigabatrin to control epilepsy demonstrated an increase in cerebral glutamine. 26 There is substantial evidence that glutamine is a major precursor of GABA 30,31 and, consequently, if GABA continues to be synthesized but not catabolized then a decrease in this precursor pool might be expected.…”

“…The effects of vigabatrin on brain metabolism have been widely studied both in animals [19][20][21][22][23][24][25] and humans. 2,26,27 In animal models both invasive methods (e.g.…”