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Selected Correction of Vigabatrin‐Related Toxicity in Mice with Adjuvant Rapalog Intervention
Author(s) -
Vogel Kara,
Jansen Erwin,
Salomons Gajja,
Gibson K. Michael
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb518
Subject(s) - vigabatrin , oxidative stress , glutathione , gaba transaminase , toxicity , malondialdehyde , chemistry , endocrinology , mitochondrion , medicine , pharmacology , biochemistry , biology , anticonvulsant , enzyme , epilepsy , glutamate decarboxylase , neuroscience
Vigabatrin (γ‐vinyl GABA; Sabril R ), an antiepileptic drug that irreversibly inhibits GABA‐transaminase, enhances central nervous system GABA. VGB is employed therapeutically for infantile spasms, secondary generalized and complex partial seizures. However, VGB has a well‐defined retinal toxicity that significantly impacts its long‐term use. We administered VGB (35 and 250 mg/kg/d) to mice for 7 days. GABA was quantified by isotope dilution mass spectrometry, and redox parameters (malondialdehyde (MDA), glutathione (GSH)) determined using spectrometric assays. Transmission electron microscopy (TEM) was employed to quantify mitochondrial abundance. VGB induced a dose‐dependent increase in GABA in the brain (1,717.5 + 109.7 nmol/mg vehicle; 5,236.9 + 1,223.4 VGB (35 mg/kg); 10,559.0 + 968.9 VGB (250 mg/kg)) and eye (158.5 + 21.9 vehicle; 680.6 + 63.1 VGB (35 mg/kg); 939.0 + 161.3, VGB (250 mg/kg); ANOVA, p<0.0001). TEM micrographs revealed significantly increased mitochondrial abundance along the retinal pigmented epithelium (vehicle 60 + 20 mitochondria/micrograph; VGB (35 mg/kg) 73 + 18; p<0.01), hippocampus and liver. MDA levels were 3.1‐fold elevated with VGB intervention (p<0.05) and total GSH levels showed a trend toward depletion in eye, indicative of oxidative stress associated with enhanced mitochondrial number. Torin 1 application (5mg/kg) for 7 days corrected mitochondrial accumulation in hippocampus (figure 1). Our data highlight the potential of adjuvant rapalog intervention with VGB. Support NIH R21 NS 85369.