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Emily R. Noonan, Tara L. Favazza, Nan Zhang, Alessia Di Nardo, Ronald M. Hansen, James D. Akula, Mustafa Sahin, Anne B. Fulton; Effects of Vigabatrin on Retina in Pigmented Rats. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2457.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate, in pigmented rats, the effects of vigabatrin (VGB) on the retina.
Male Long-Evans rats were administered 250 mg/kg VGB IP for 52 days (n=10). Vehicle treated rats served as controls (n=17). During the injection regimen, intermittent electroretinograms (ERGs) were used to monitor retinal function for toxicity. Scotopic and photopic ERG parameters were recorded and compared. Sensitivity and saturated amplitude of the rod photoresponse (S, RmP3) and postreceptor response (log σ, Vmax), as well as summed oscillatory potentials amplitude (SOPA), were derived from dark-adapted ERGs. Sensitivity and saturated amplitude of the cone-mediated log σcone and Vmaxcone, and the amplitude of the 25 Hz flicker response (A25), were measured in light-adapted ERGs. Side effects, including weight loss and skin lesions began to appear at approximately day 30 and became increasingly severe; thus, final ERGs were obtained after 49-52 days of injections. In an effort to induce VGB toxicity in a shortened duration, a second group of animals (n=12) were injected with 500 mg/kg VGB and ERGs obtained after 29-31 days of injections. Following ERG, a subset of eyes from each group were harvested and sectioned for histology, or retinae were prepared for Western blot analysis. Data were analyzed by one-way (dose) ANOVA.
Of the parameters derived from dark-adapted ERG responses, VGB significantly enhanced RmP3, Vmax and SOPA. To evaluate these parameters for monotonic increase with dosage, planned contrasts were performed on these parameters; all were significant. That is, increased dosage of VGB lead to increased ERG parameter values. None of the key response parameters showed VGB-induced deficits. All cone-mediated responses parameters, log σcone, Vmaxcone, and A25, were also significantly enhanced by VGB, the latter two showing dose dependency. Migration of photoreceptor nuclei toward the retinal pigment epithelium was observed in peripheral retina of VGB-treated animals. In the 500 mg/kg group, significant alterations were noted in ER stress and the Akt signalling pathway.
VGB, an antiepileptic agent that inhibits GABA-transaminase, is associated with retinal and visual dysfunction in some patients. VGB toxicity has been demonstrated in other labs in the albino rat. In these pigmented rats, VGB did not induce deficits in retinal function, but rather enhanced retinal function in a dose dependent manner. Nonetheless, occasional retinal neuronal dysplasia as well as evidence of ER stress were observed.
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