Vigabatrin-Induced Retinal Toxicity Is Partially Mediated by Signaling in Rod and Cone Photoreceptors

Abstract

Vigabatrin (VGB) is a commonly prescribed antiepileptic drug designed to inhibit GABA-transaminase, effectively halting seizures. Unfortunately, VGB treatment is also associated with the highest frequencies of peripheral visual field constriction of any of the antiepileptic drugs and the mechanisms that lead to these visual field defects are uncertain. Recent studies have demonstrated light exposure exacerbates vigabatrin-induced retinal toxicity. We further assessed this relationship by examining the effects of vigabatrin treatment on the retinal structures of mice with genetically altered photoreception. In keeping with previous studies, we detected increased toxicity in mice exposed to continuous light. To study whether cone or rod photoreceptor function was involved in the pathway to toxicity, we tested mice with mutations in the cone-specific Gnat2 or rod-specific Pde6g genes, and found the mutations significantly reduced VGB toxicity. Our results confirm light is a significant enhancer of vigabatrin toxicity and that a portion of this is mediated, directly or indirectly, by phototransduction signaling in rod and cone photoreceptors.

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

“…Variations in caging and light intensities of animal rooms in the different laboratories would affect the outcome of VGB induced retinopathy [11]. Moreover, prolonged light exposure would exacerbate the VGB-induced retinal toxicity [30].The illumination level of the animal facility in that study (approximately 40 lx for 42days) was considerably lower than the present study (approximately 80 lx for 60days). (3) VGB dose and length of administration: there is a positive trend that the doses and treatment periods are correlated with the severity of VGB induced visual function damage [27,31].…”

“…The difference of species should give rise to the relatively different number and distribution of photoreceptor populations across mammalian retinas, as different photoreceptor subtypes show variable susceptibilities to VGB toxicity [29]. (2) Illumination levels: light is a significant enhancer of VGB toxicity and this is mediated, directly or indirectly, by phototransduction signaling in rod and cone photoreceptors [30]. Variations in caging and light intensities of animal rooms in the different laboratories would affect the outcome of VGB induced retinopathy [11].…”

Vigabatrin Retinal Toxicity First Detected with Electroretinographic Changes: A Case Report

“…Moreover, other groups have demonstrated the role of phototransduction in enhancing vigabatrin toxicity. In this study, mice with altered phototransduction pathways-thus a decreased ability to perceive light-have decreased incidence of VGB retinal toxicity [1]. This observation suggests decreasing light exposure i.e by wearing sunglasses or avoiding excess light might help treat and/or prevent VGB retinal toxicity.…”

“…Despite awareness of its occurrence we have yet to fully elucidate the pathophysiological mechanism. Interestingly, most evidence indicates that the retinal damage associated with VGB is due to the therapeutic effects of the drug specific to its accumulation in the retina [1,6]. Increasing retinal GABA levels leads to unwarranted and prolonged retinal cellular membrane depolarization, subsequent influx of Cl - , Na + and water leading to homeostatic imbalance and cellular demise [10].…”

“…Vigabatrin (VGB) produces its antiepileptic effects by irreversibly inhibiting GABA transaminase, an enzyme responsible for GABA degradation. This inhibition leads to decreased breakdown of endogenous GABA, higher GABA levels and decreased neuronal activity [1]. Clinically, VGB is often used in combination with other antiepileptic drugs as third or fourth line efforts to address pharmacoresistant complex partial seizures and first line for infantile spams.…”