Vigabatrin, but not Gabapentin or Topiramate, Produces Concentration‐related Effects on Enzymes and Intermediates of the GABA Shunt in Rat Brain and Retina

Sills, Graeme J.; Butler, Elaine; Forrest, Gerard; Ratnaraj, Neville; Patsalos, Philip N.; Brodie, Martin J.

doi:10.1046/j.1528-1157.2003.04203.x

Cited by 57 publications

(39 citation statements)

References 46 publications

(71 reference statements)

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“…Although another study found no retinal lesions after administering VGB orally for 1 year to CD[SD]BR (albino) rats, this study also hypothesized that light has a critical role in VGB retinotoxicity (28). Finally, because GABA can be toxic to neurons (29,30), VGB retinotoxicity may stem from higher retinal GABA levels (25,26).…”

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confidence: 68%

“…We selected this VGB dose because it results in high VGB levels, significant decreases in GABA transaminase activity, and significant increases in GABA levels in the retinas of Sprague-Dawley rats (25,26). Rats exposed to the standard light cycle after receiving VGB were less active than the saline controls.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

“…The ex vivo preparation provides better control over experimental variables, whereas the in vivo studies allow extrapolation to an intact system (24). We investigated whether VGB produces acute retinotoxicity because retinal VGB and GABA levels increase 2 to 4 h after intraperitoneal injections of VGB in Sprague-Dawley rats (25,26). We examined the role of light because oral administration of VGB for 90 days produced disorganization of the outer nuclear layer of the retinas in Sprague-Dawley (albino) but not in Lister-Hooded (pigmented) rats (27).…”

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confidence: 99%

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Acute Vigabatrin Retinotoxicity in Albino Rats Depends on Light But Not GABA

Izumi¹,

Ishikawa

Benz³

et al. 2004

Epilepsia

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Summary:Purpose: Vigabatrin (VGB) is an irreversible inhibitor of γ -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 µM VGB under 20,000 Lux white light for ≤20 h caused a characteristic time-and dose-dependent degeneration limited to the outer retina. Incubating retinas with 500 µM VGB in darkness for 20 h caused no damage. Five hundred micromolar GABA and 50 µM 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.

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confidence: 68%

Section: In Vivo Experimentsmentioning

confidence: 99%

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confidence: 99%

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Acute Vigabatrin Retinotoxicity in Albino Rats Depends on Light But Not GABA

Izumi¹,

Ishikawa

Benz³

et al. 2004

Epilepsia

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“…Several studies have demonstrated a reduced ERG also after discontinuation of medication [15,17,18,21]. Duboc et al [27] have performed a study in rats, tissue has been confirmed in another investigation by Sills et al [29]. They have also demonstrated a pronounced accumulation of vigabatrin in retina compared to brain tissue, considering this as a plausible cause of the visual field constriction reported in patients.…”

Section: Discussionmentioning

confidence: 90%

Retinal Function in Rabbits Does Not Improve 4–5 Months after Terminating Treatment with Vigabatrin

Kjellström

Bruun

et al. 2006

Doc Ophthalmol

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Kjellström 2Keywords: Vigabatrin, electroretinogram, immunohistochemistry, drug toxicity. AbstractPurpose: We have previously reported changes in retinal function and histopathology in rabbits treated with vigabatrin. The purpose of the present study was to evaluate retinal function and histopathology of retina in rabbits 4-5 months after terminating vigabatrin medication. Methods: Five rabbits were treated with a daily per oral dose of vigabatrin during 12-13 months. After terminating treatment an observation period of 4-5 months followed. Six rabbits receiving water served as controls. Standardized full-field electroretinograms were performed every 6-8 weeks, using a Burian-Allen bipolar contact lens. After 18 months the rabbits were sacrificed and the morphology of the sectioned retina was studied. The antibodies used for staining were GABA, GFAP, GAD, and vimentin. Results: After 12-13 months of treatment full-field ERG was reduced in all rabbits treated with vigabatrin. There was a statistically significant difference in the dark adapted cone b-wave amplitude between treated animals and controls (Wilcoxon signed ranks test, p=0.043). This difference was consistent also 4-5 months after terminating treatment. Immunohistology of the sectioned retina demonstrated no significant difference in immunoreactivity between treated animals and controls. All treated rabbits demonstrated elevated serum concentration of the drug during medication. Conclusion: Four to five months after terminating treatment with vigabatrin the rabbit full-field ERG remains reduced in isolated cone bwave amplitude indicating that vigabatrin induced retinal dysfunction may be irreversible. However, immunohistology is normal after a period without treatment, implying that the previously described changes in retinal morphology and glial cell activity are reversible, and probably exist only during treatment.

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“…If GABA-T inhibition were relevant to the anticonvulsant activity of gabapentin or pregabalin, the drugs should increase brain GABA levels, as is the case for the anticonvulsant drug vigabatrin. In the rat, neither gabapentin nor pregabalin increases GABA levels (Sills et al, 2003;Errante and Petroff, 2003), although small increases have been reported with gabapentin in human brain tissue slices (Errante et al, 2002). [Increases in GABA also were seen in human neocortex with topiramate (Petroff et al, 2001) and lamotrigine (Kuzniecky et al, 2002) which are not known to alter the synthesis or metabolism of GABA.]…”

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confidence: 99%