Open AccessTorin 1 partially corrects vigabatrin‐induced mitochondrial increase in mouse
Author(s) -
Vogel Kara R.,
Ainslie Garrett R.,
Jansen Erwin E. W.,
Salomons Gajja S.,
Gibson K. Michael
Publication year - 2015
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.200
Subject(s) - vigabatrin , mitophagy , mitochondrion , pi3k/akt/mtor pathway , medicine , phosphorylation , pharmacology , central nervous system , endogeny , glutamate receptor , apoptosis , neuroscience , microbiology and biotechnology , biology , anticonvulsant , biochemistry , epilepsy , receptor , autophagy
Recent findings in mice with targeted deletion of the GABA ‐metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4‐aminobutyric acid) in the activation of the mechanistic target of rapamycin ( mTOR ) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short‐term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death.