Taurine deficiency is a cause of vigabatrin‐induced retinal phototoxicity

Abstract

Objective Although vigabatrin irreversibly constricts the visual field, it remains a potent therapy for infantile spasms and a third-line drug for refractory epilepsies. In albino animals, this drug induces a reduction in retinal cell function, retinal disorganisation and cone photoreceptor damage. The objective of this study was to investigate the light dependence of the vigabatrin-elicited retinal toxicity and to screen for molecules preventing this secondary effect of vigabatrin. Methods Rats and mice were treated daily with vigabatrin 40mg and 3mg, respectively. Retinal cell lesions were demonstrated by assessing cell function with electroretinogram measurements, and quantifying retinal disorganization, gliosis and cone cell densities. Results Vigabatrin-elicited retinal lesions were prevented by maintaining animals in darkness during treatment. Different mechanisms including taurine deficiency were reported to produce such phototoxicity; we therefore measured amino acid plasma levels in vigabatrin-treated animals. Taurine levels were 67% lower in vigabatrin-treated animals than in control animals. Taurine supplementation reduced all components of retinal lesions in both rats and mice. Among 6 vigabatrin-treated infants, the taurine plasma level was found to be below normal in three patients and undetectable in two patients. Interpretation These results indicate that vigabatrin generates a taurine deficiency responsible for its retinal phototoxicity. Future studies will investigate whether co-treatment with taurine and vigabatrin can limit epileptic seizures without inducing the constriction of the visual field. Patients on vigabatrin could gain immediate benefit from reduced light exposures and dietetic advice on taurine-rich foods.

Lipoic acid effects on glutamate and taurine concentrations in rat hippocampus after pilocarpine-induced seizures

“…It has been demonstrated that seizures induced by pilocarpine produces changes in oxidative metabolism and interacts with glutamatergic receptors to produced part of its stimulatory action on the central nervous system [24][25][26][27] . The fall in glutamate content, after pretreatment with lipoic acid, is most readily explained as a consequence of inhibiting their release or increasing their metabolization [28][29][30] . Moreover, the lipoic acid can reduce the metabolization rate and/or augment the release and syntheses of neuroprotective taurine, suggesting a protective action of this amino acid against the excitotoxicity mediated by glutamate during seizures.…”

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…One study in rodents showed that vigabatrin-associated retinopathy is associated with light exposure [72]. More recently, it has been suggested that a deficiency of taurine is implicated in the pathogenic process of vigabatrinassociated retinopathy [73,74]. A pharmacogenetic exploration of vigabatrin-induced visual field constriction has also been undertaken, although no clear association has been identified [75].…”

“…These MRI abnormalities may occur as early as 3 months after the initiation of therapy. They may be, in rare cases, accompanied by movement disorders [73]. Susceptibility seems to be restricted to infancy.…”

Vigabatrina aumenta atividade da superóxido dismutase no corpo estriado de ratos após crises convulsivas induzidas pela pilocarpina

“…Estudos sugerem que a vigabatrina produz seus efeitos anticonvulsivantes por meio da diminuição da atividade da enzima GABA-transaminase 28 , pelo aumento da liberação do GABA e pela diminuição da concentração da dopamina e taurina cerebral 29 . A vigabatrina pode exercer efeito neuroprotetor contra o dano neuronal produzido pelo aumento no conteúdo de radicais livres durante as crises convulsivas.…”