Dose-related changes in retinal function and PKC-alpha expression in rabbits on vigabatrin medication

作者：Kjellstrom Ulrika^*; Bruun Anitha; Ghosh Fredrik; Andreasson Sten; Ponjavic Vesna

来源：Graefes Archive for Clinical and Experimental Ophthalmology, 2009, 247(8): 1057-1067.

DOI：10.1007/s00417-009-1093-7

• Drug toxicity
• Electroretinography
• Antiepileptic drug
• Immunohistochemistry
• Rabbit retina
• Vigabatrin
• Visual field defect
• GABA A receptor
• Vimentin
• Peanaut agglutinin (PNA)
• Glial fibrillary acidic protein (GFAP)
• Protein kinase C-alpha (PKC-alpha)

To investigate, in a rabbit model, the effect of two different doses of vigabatrin (VGB) on retinal function and morphology.
Twenty-nine rabbits of mixed strain were divided into two groups, receiving either high-dose (n = 15) or low-dose (n = 14) oral VGB treatment (cumulative dose 29.8 +/- 2.9 g and 14.2 +/- 0.6 g respectively). Ten rabbits receiving water served as control animals. The rabbits underwent three baseline ff-ERG measurements before initiation of VGB medication and two ff-ERG registrations during treatment, after 8 and 12-14 weeks respectively. At the end of the study, the expression of protein kinase C-alpha (PKC-alpha), gamma amino butyric acid (GABA) A receptors, vimentin, glial fibrillary acidic protein (GFAP) and peanut agglutinin (PNA) was examined in retinal sections from all rabbits.
In animals of the high-dose group, the ff-ERG measurements revealed a significant decrease of isolated rod b-wave amplitudes, combined rod-cone b-wave amplitudes and amplitudes of oscillatory potentials (OPs); OP1, OP2 and OP3. In the low-dose group, the b-wave amplitudes of combined rod-cone responses as well as OP2 and OP3 were significantly reduced. PKC-alpha labeling demonstrated a dose-related translocation of the enzyme in rod bipolar cells, also revealing a significant decline of the number of PKC-alpha labeled rod bipolar cells in treated animals. Vimentin labeling showed a dose-related deviant labeling pattern of Muller cells, with strikingly low labeling intensity in the outer parts of the cells; in the outer limiting membrane (OLM) as well as the outer nuclear layer (ONL). Labeling with antibodies against GABA A receptors and GFAP, as well as PNA staining, revealed no differences between treated animals and controls.
In this study, VGB medication was associated, in a dose-related manner, with a decrease of ff-ERG amplitudes as well as with altered protein expression in rod bipolar cells and Muller cells, suggesting alterations of inner retinal function. The dose-related morphological and electrophysiological changes indicate a retinal pathology that may explain the constricted visual fields seen in some patients treated with VGB.

• 出版日期2009-8