Globus pallidus restricted diffusion associated with vigabatrin therapy

Trindade, Regis Augusto Reis; Wainstein, Betina; Campos, Lillian Gonçalves; Pérez, Juliano Adams; Bianchin, Marino Muxfeldt; Vedolin, Leonardo; Duarte, Juliana Davila

doi:10.1590/0004-282x20170192

Cited by 5 publications

(2 citation statements)

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“…The mechanism by which VGB selectively affects the visual system has not been clearly defined (Shields and Pellock 2011;Tugcu et al 2017;Peng et al 2017;Yang et al 2012), while other studies suggest that VGB does not display an increased association with visual field abnormalities (Schwarz et al 2016). More recently, VGB has been associated with white matter spongiosis and restricted globus pallidus diffusion (Pearl et al 2018;Trindade et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Walters

Arning

Jansen

et al. 2019

Neurochemistry International

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The anticonvulsant vigabatrin (VGB; Sabril R) irreversibly inhibits GABA transaminase to increase neural GABA, yet its mechanism of retinal toxicity remains unclear. VGB is suggested to alter several amino acids, including homocarnosine, β-alanine, ornithine, glycine, taurine, and 2aminoadipic acid (AADA), the latter a homologue of glutamic acid. Here, we evaluate the effect of VGB on amino acid concentrations in mice, employing a continuous VGB infusion (subcutaneously implanted osmotic minipumps), dose-escalation paradigm (35-140 mg/kg/d, 12 days), and amino acid quantitation in eye, visual and prefrontal cortex, total brain, liver and plasma. We hypothesized that continuous VGB dosing would reveal numerous hitherto undescribed amino acid disturbances. Consistent amino acid elevations across tissues included GABA, β-alanine, carnosine, ornithine and AADA, as well as neuroactive aspartic and glutamic acids, serine and glycine. Maximal increase of AADA in eye occurred at 35 mg/kg/d (41 ± 2 nmol/g (n=21, vehicle) to 60 ± 8.5 (n=8)), and at 70 mg/kd/d for brain (97 ± 6 (n=21) to 145 ± 6 (n=6)), visual cortex (128 ± 6 to 215 ± 19) and prefrontal cortex (124 ± 11 to 200 ± 13; mean ± SEM; p<0.05), the first demonstration of tissue AADA accumulation with VGB in mammal. VGB effects on basic amino acids, including guanidino-species, suggested the capacity of VGB to alter urea cycle function and nitrogen disposal. The known toxicity of AADA in retinal glial cells highlights new avenues for assessing VGB retinal toxicity and other off-target effects.

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Section: Introductionmentioning

confidence: 99%

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Walters

Arning

Jansen

et al. 2019

Neurochemistry International

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“…25,33 It has been suggested that VGB-induced elevation of ocular/retinal GABA induces excitotoxicity via GABAergic receptors, [34][35][36] resulting in oxidative stress. [37][38][39][40] Other studies have suggested globus pallidi and white matter anomalies associated with chronic VGB intake, [41][42][43] and pathological roles for amino acids (ornithine, taurine) that share structural and biochemical properties of GABA have also been implicated in VGB-associated ocular toxicity. 29,44,45 Thus, there is no clear consensus as to the mechanism(s) of potential VGB ocular toxicity.…”

Section: Discussionmentioning

confidence: 99%

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

Walters

Jansen

Ainslie

et al. 2019

Pharmacology Res & Perspec

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Vigabatrin (VGB; (S)‐(+)/(R)‐(‐) 4‐aminohex‐5‐enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA‐T), manifests use‐limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6‐8 animals/dose) for 12 days. VGB enantiomers, total GABA and β‐alanine (BALA), 4‐guanidinobutyrate (4‐GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC. Plasma VGB concentrations increased linearly by dose (3 ± 0.76 (35 mg/kg/d); 15.1 ± 1.4 (70 mg/kg/d); 34.6 ± 3.2 μmol/L (140 mg/kg/d); mean ± SEM) with an S/R ratio of 0.74 ± 0.02 (n = 14). Steady state S/R ratios (35, 70 mg/kg/d doses) were highest in eye (5.5 ± 0.2; P < 0.0001), followed by VC (3.9 ± 0.4), PFC (3.6 ± 0.3), liver (2.9 ± 0.1), and brain (1.5 ± 0.1; n = 13‐14 each). Total VGB content of eye exceeded that of brain, PFC and VC at all doses. High‐dose VGB diminished endogenous metabolite production, especially in PFC and VC. GABA significantly increased in all tissues (all doses) except brain; BALA increases were confined to liver and VC; and 4‐GBA was prominently increased in brain, PFC and VC (and eye at high dose). Linear correlations between enantiomers and GABA were observed in all tissues, but only in PFC/VC for BALA, 4‐GBA, and creatine. Preferential accumulation of the VGB S isomer in eye and VC may provide new insight into VGB ocular toxicity.

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Globus pallidus restricted diffusion associated with vigabatrin therapy

Cited by 5 publications

References 5 publications

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

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