Dose-related changes in retinal function and PKC-alpha expression in rabbits on vigabatrin medication. Effect of vigabatrin in the rabbit eye.
BACKGROUND
To investigate, in a rabbit model, the effect of two different doses of vigabatrin (VGB) on retinal function and morphology.


METHODS
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.


RESULTS
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 Müller 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.


CONCLUSIONS
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 Müller 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.
Department of Ophthalmology, University of Lund, 221 85, Lund, Sweden. ulrika.kjellstrom@med.lu.se
Ulrika
U
Kjellström
Anitha
A
Bruun
Fredrik
F
Ghosh
Sten
S
Andréasson
Vesna
V
Ponjavic
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008856:Microscopy, Fluorescence; D019887:Peanut Agglutinin / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011817:Rabbits; D011963:Receptors, GABA-A / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D020888:Vigabatrin / Q000008:administration & dosage / Q000633:toxicity*; D014746:Vimentin / Q000378:metabolism
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D019887:Peanut Agglutinin; D011963:Receptors, GABA-A; D014746:Vimentin; D051571:Protein Kinase C-alpha; D020888:Vigabatrin