Vigabatrin, the GABA‐transaminase inhibitor, damages cone photoreceptors in rats

Abstract

Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase. Subsequently, central visual function was reported to also be irreversibly altered. This visual loss is associated with a decrease in the electroretinogram measurement localizing the deficit to the retina. To investigate its cellular origin, we treated rats daily with vigabatrin for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damages, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from cone cell injury to a more severe disorganization of the photoreceptor layer.

Retinal Function in Rabbits Does Not Improve 4–5 Months after Terminating Treatment with Vigabatrin

“…There seems to be a permanent retinal damage consistent with the irreversible visual field defects seen in patients. The results of Duboc et al [27] suggest there is a probability that vigabatrin medication results in permanent damage to cone photoreceptors, which is in accordance with our observed alterations in the photopic ERG. At the time of analysis we did not have a specific marker for staining of cones.…”

“…Several studies have demonstrated a reduced ERG also after discontinuation of medication [15,17,18,21]. Duboc et al [27] have performed a study in rats, tissue has been confirmed in another investigation by Sills et al [29]. They have also demonstrated a pronounced accumulation of vigabatrin in retina compared to brain tissue, considering this as a plausible cause of the visual field constriction reported in patients.…”

“…In the study by Duboc et al [27] immunohistological examination of sectioned rat retina indicates severe alterations in retinal architecture both immediately after drug withdrawal and after a wash out period of 45 days. PNA staining reveals disorganized cone outer and inner segments and a decrease in cone density throughout the whole retina.…”

Retinal nerve fibre layer characteristics with vigabatrin-associated visual field loss—could scanning laser polarimetry aid diagnosis?

“…14 Rod photoreceptors do not have any GABA receptors unlike cones, ganglion, amacrine, and bipolar cells, and recent animal testing suggests that vigabatrin causes irreversible death of cone photoreceptors and ganglion cells with secondary atrophy of the RNFL. 15 If this does prove to be the mechanism of damage, then RNFL assessment would provide a screening tool that would reveal damage before visual field damage would be evident through formal field testing.…”

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration

“…6,61 In a previous work, we showed that Scones were more sensitive to taurine depletion than other neurons, 6 and we proposed that this could be because S-cones are more sensitive to blue light 45 or to oxidative stress. 6 Taurine depletion could act synergistically with light to induce photoreceptor degeneration 6,[15][16][17] ; however, in a previous study maintaining taurine-depleted mice in darkness slowed, but did not avoid, photoreceptor degeneration, 16 suggesting that there were other intrinsic and/or extrinsic factors involved.…”