Retinal Function and Morphology of Retina and Brain in Rabbits Treated With Per Oral Topiramate

Abstract

Abstract: : Purpose: Topiramate is an anti–epileptic drug with three different mechanisms of action, two of which affect GABA–activity in retina and brain (similar to vigabatrin). The aim of the study was to evaluate the retinal function and the histopathology of retina and brain, in rabbits treated with topiramate. Methods:Seven rabbits were treated with a daily per oral dose of topiramate during a period of 8 months. Nine rabbits receiving water served as controls. One treated rabbit and three controls died unexpectedly and randomly during the study, and were therefore excluded. Blood samples were analyzed for determination of topiramate serum levels in order to ensure successful drug administration. Standardized full–field electroretinograms (ERGs) were assessed on six occasions prior and during treatment. After terminating treatment the rabbits were sacrificed and the morphology of the sectioned retina (stained with GABA, GFAP and vimentin) and brain (stained with GABA and GFAP), was studied. Results:In all treated rabbits serum topiramate levels were elevated when treatment was tolerated, and low or undetectable when the dose was reduced because of loss of appetite, a known adverse effect of this drug. Before treatment, the full–field ERG results were similar in the six treated rabbits and in the six controls. After 8 months of treatment the full–field ERG demonstrated a normal rod function in the treated rabbits and in the controls, but a statistically significant reduction of the isolated light adapted cone b–wave amplitude in the rabbits treated with topiramate (Wilcoxon signed ranks test, p=0.046). We also compared the treated group before and after treatment finding a significant difference also in the isolated dark adapted cone b–wave amplitude (Wilcoxon signed ranks test, p=0.028). Retinal immunohistology revealed in 4 of 6 treated rabbits a severe accumulation of GABA in amacrine cells and in the inner plexiform layer, compared to the controls. One treated rabbit had an enhanced GFAP–activity and fewer Müller cells (stained with vimentin) compared to the controls. The GABA and GFAP immunostained brain sections did not show any differences to the control animals. Conclusions: Topiramate, orally administrated to rabbits, may cause a significantly reduced cone b–wave amplitude in the full–field ERG, similarly to vigabatrin, which has previously not been reported. Histopathology of the retina correlates to some extent with the reduced retinal function. Brain morphology is not affected by topiramate in rabbits.

Keywords: retina • electroretinography: non-clinical • immunohistochemistry