Acute vigabatrin retinotoxicity in albino rats depends on light but not GABA.
OBJECTIVE
Vigabatrin (VGB) is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase. Its use as an antiepileptic drug (AED) has been limited because it causes retinal dysfunction, leading to visual field defects (VFDs). We performed this study to identify factors contributing to acute VGB retinotoxicity.


METHODS
In ex vivo experiments, Sprague-Dawley rat retinas were isolated and incubated with VGB or GABA in the presence or absence of light. In in vivo experiments, Sprague-Dawley rats were given intraperitoneal injections of VGB and then exposed to light or kept in the dark. The retinas were analyzed histologically by using both light and electron microscopy.


RESULTS
Incubating retinas with 50-500 microM VGB under 20,000 Lux white light for < or = 20 h caused a characteristic time- and dose-dependent degeneration limited to the outer retina. Incubating retinas with 500 microM VGB in darkness for 20 h caused no damage. Five hundred micromolar GABA and 50 microM tiagabine were not toxic in the presence or absence of light. Sprague-Dawley rats exposed to an intense white light for 20 h after a 1,000-mg/kg intraperitoneal injection of VGB showed damage in the outer retina, whereas those kept in the dark did not.


CONCLUSIONS
Direct exposure of the retina to VGB causes acute retinotoxicity that depends on light exposure rather than GABA accumulation.
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA. Izumiy@psychiatry.wustl.edu
Yukitoshi
Y
Izumi
Makoto
M
Ishikawa
Ann M
AM
Benz
Masayo
M
Izumi
Charles F
CF
Zorumski
Liu Lin
LL
Thio
D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D003624:Darkness / Q000009:adverse effects; D008027:Light / Q000009:adverse effects*; D008297:Male; D009557:Nipecotic Acids / Q000633:toxicity; D010775:Photic Stimulation / Q000009:adverse effects; D010786:Photoreceptor Cells / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology; D012607:Scotoma / Q000139:chemically induced / Q000473:pathology; D000078308:Tiagabine; D020888:Vigabatrin / Q000633:toxicity*; D014786:Vision Disorders / Q000139:chemically induced* / Q000473:pathology; D014794:Visual Fields / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000927:Anticonvulsants; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin; D000078308:Tiagabine