Taurine: the comeback of a neutraceutical in the prevention of retinal degenerations.

Taurine is the most abundant amino acid in the retina. In the 1970s, it was thought to be involved in retinal diseases with photoreceptor degeneration, because cats on a taurine-free diet presented photoreceptor loss. However, with the exception of its introduction into baby milk and parenteral nutrition, taurine has not yet been incorporated into any commercial treatment with the aim of slowing photoreceptor degeneration. Our recent discovery that taurine depletion is involved in the retinal toxicity of the antiepileptic drug vigabatrin has returned taurine to the limelight in the field of neuroprotection. However, although the retinal toxicity of vigabatrin principally involves a deleterious effect on photoreceptors, retinal ganglion cells (RGCs) are also affected. These findings led us to investigate the possible role of taurine depletion in retinal diseases with RGC degeneration, such as glaucoma and diabetic retinopathy. The major antioxidant properties of taurine may influence disease processes. In addition, the efficacy of taurine is dependent on its uptake into retinal cells, microvascular endothelial cells and the retinal pigment epithelium. Disturbances of retinal vascular perfusion in these retinal diseases may therefore affect the retinal uptake of taurine, resulting in local depletion. The low plasma taurine concentrations observed in diabetic patients may further enhance such local decreases in taurine concentration. We here review the evidence for a role of taurine in retinal ganglion cell survival and studies suggesting that this compound may be involved in the pathophysiology of glaucoma or diabetic retinopathy. Along with other antioxidant molecules, taurine should therefore be seriously reconsidered as a potential treatment for such retinal diseases.

Taurine is a crucial factor to preserve retinal ganglion cell survival.

Retinal ganglion cells (RGCs) are spiking neurons, which send visual information to the brain, through the optic nerve. RGC degeneration occurs in retinal diseases, either as a primary process or secondary to photoreceptor loss. Mechanisms involved in this neuronal degeneration are still unclear and no drugs directly targeting RGC neuroprotection are yet available. Here, we show that taurine is one factor involved in preserving the RGC survival. Indeed, a taurine depletion induced by the antiepileptic drug, vigabatrin, was incriminated in its retinal toxicity leading to the RGC loss. Similarly, we showed that RGC degeneration can be induced by pharmacologically blocking the taurine-transporter with the chronic administration of a selective inhibitor, which results in a decrease in the taurine levels both in the plasma and in the retinal tissue. Finally, we found that taurine can directly prevent RGC degeneration, occurring either in serum-deprived pure RGC cultures or in animal models presenting an RGC loss (glaucomatous rats and the P23H rats, a model for retinitis pigmentosa). These data suggest that the retinal taurine level is a crucial marker to prevent RGC damage in major retinal diseases.

Taurine provides neuroprotection against retinal ganglion cell degeneration.

Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

Taurine deficiency damages photoreceptors and retinal ganglion cells in vigabatrin-treated neonatal rats.

The anti-epileptic drug vigabatrin induces an irreversible constriction of the visual field, but is still widely used to treat infantile spasms and some forms of epilepsy. We recently reported that vigabatrin-induced cone damage is due to a taurine deficiency. However, optic atrophy and thus retinal ganglion cell degeneration was also reported in children treated for infantile spasms. We here show in neonatal rats treated from postnatal days 4 to 29 that the vigabatrin treatment triggers not only cone photoreceptor damage, disorganisation of the photoreceptor layer and gliosis but also retinal ganglion cell loss. Furthermore, we demonstrate in these neonatal rats that taurine supplementation partially prevents these retinal lesions and in particular the retinal ganglion cell loss. These results provide the first evidence of retinal ganglion cell neuroprotection by taurine. They further confirm that taurine supplementation should be administered with the vigabatrin treatment for infantile spasms or epilepsy.

Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity.

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 disorganization, 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 40 and 3mg vigabatrin, 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 six 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 cotreatment with taurine and vigabatrin can limit epileptic seizures without inducing the constriction of the visual field. Patients taking vigabatrin could gain immediate benefit from reduced light exposures and dietetic advice on taurine-rich foods.

Treatment of epilepsy: the GABA-transaminase inhibitor, vigabatrin, induces neuronal plasticity in the mouse retina.

Vigabatrin was a major drug in the treatment of epilepsy until the discovery that it was associated with an irreversible constriction of the visual field. Nevertheless, the drug is still prescribed for infantile spasms and refractory epilepsy. Disorganization of the photoreceptor nuclear layer and cone photoreceptor damage have been described in albino rats. To investigate the vigabatrin-elicited retinal toxicity further, we examined the retinal tissue of albino mice treated with two vigabatrin doses. The higher dose did not always cause the photoreceptor layer disorganization after 1 month of treatment. However, it triggered a massive synaptic plasticity in retinal areas showing a normal layering of the retina. This plasticity was shown by the withdrawal of rod but not cone photoreceptor terminals from the outer plexiform layers towards their cell bodies. Furthermore, both rod bipolar cells and horizontal cells exhibited dendritic sprouting into the photoreceptor nuclear layer. Withdrawing rod photoreceptors appeared to form ectopic contacts with growing postsynaptic dendrites. Indeed, contacts between rods and bipolar cells, and between bipolar cells and horizontal cells were observed deep inside the outer nuclear layer. This neuronal plasticity is highly suggestive of an impaired glutamate release by photoreceptors because similar observations have been reported in different genetically modified mice with deficient synaptic transmission. Such a synaptic deficit is consistent with the decrease in glutamate concentration induced by vigabatrin. This description of the neuronal plasticity associated with vigabatrin provides new insights into its retinal toxicity in epileptic patients.