Development of tolerance to the effects of vigabatrin (γ‐vinyl‐GABA) on GABA release from rat cerebral cortex, spinal cord and retina

Abstract

1 The effects ot acute and chronic vigabatrin (y-vinyl-GABA) (GVG) administration on y-aminobutyric acid (GABA) levels and release in rat cortical slices, spinal cord slices and retinas were studied. 2 GVG (250mgkg-1 i.p.) administered to rats 18h before death (acute administration) produced an almost 3 fold increase in GABA levels of the cortex and spinal cord and a 6 fold increase in retinal GABA. The levels of glutamate, aspartate, glycine and taurine were unaffected. 3 When GVG (250mgkg-' i.p.) was administered daily for 17 days (chronic administration) a similar (almost 3 fold) increase in cortical GABA occurred but the increases in spinal and retinal GABA were reduced by approximately 40%. 4 Acute administration of GVG strikingly increased the potassium-evoked release (KCI 50mM) of GABA from all three tissues. This enhanced evoked release was reduced by about 50% in tissues taken from rats that had been chronically treated with GVG. 5 Acute administration of GVG reduced GABA-transaminase (GABA-T) activity by approximately 80% in cortex and cord and by 98% in the retina. Following the chronic administration of GVG, there was a trend for GABA-T activities to recover (significant only in cortex). Acute administration of GVG had no effect on glutamic acid decarboxylase (GAD) activity in cortex or spinal cord. However, chronic treatment resulted in significant decreases in GAD activity in both the cortex and cord (35% and 50% reduction respectively). 6 The K-evoked release of glutamate, aspartate, glycine and taurine from cortical slices and the Kevoked release of glycine from spinal slices and retinas were not affected by either acute or chronic GVG treatment.7 These experiments indicate that GVG treatment increases specifically the K-evoked release of GABA and that tolerance can develop to this enhancing effect of GVG on central GABA release. This tolerance may result from increased feedback inhibition of GAD with a consequent reduction of presynaptic GABA stores.

Effects of Increased γ‐Aminobutyric Acid Levels on GAD67 Protein and mRNA Levels in Rat Cerebral Cortex

“…There were also minor, statistically significant, decreases in the levels of glutamine (to 86% of control levels) and aspartate (to 88% of control levels). These changes were expected both from our own work in vitro (Rimvall and Martin, 1992) and from other investigators' work in vivo (Perry et al, 1979;Neal and Shah, 1990).…”

“…Although they did not determine whether GABA acted selectively on either of the two GAD proteins, their results are strikingly similar to ours. Several other research groups have previously suggested that GABA plays a role in controlling GAD levels (see Tunnicliff and Ngo, 1986, for review;Haber et al, 1970;Sze, 1970;Sze and Lovell, 1970;Neal and Shah, 1990;De Mello et al, 199 l), but the mechanism for such a regulatory action has never been determined. To investigate the nature of GABA's selective inhibitory action on GAD,,, we used quantitative RNA slot-blotting with RNA from saline-and GVG-treated rats.…”

The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study

“…The decrease in retinal taurine level appears to be inconsistent with previous findings showing no change in multiple taurine tissue levels after 17 days of VGB administration [32]. However, the shorter administration period and animal species difference may account for this discrepancy.…”

Characteristics of a Unique Visual Field Defect Attributed to Vigabatrin

“…The reduced Arden index suggests a direct effect on retinal pigment epithelium, whereas the specific abnormalities of the ERG could be explained by changes in amacrine and Muller cell function (24,25). The increased GABA levels, which result from the irreversible bloclung of GABA metabolism, are greater in the retina than in the cortex (26,27). The possibility therefore remains that visual field loss may not be specific to VGB but may also be seen in association with other AEDs that systemically increase GABA levels (28).…”