title: Torin 1 partially corrects vigabatrin-induced mitochondrial increase in mouse.
abstract: 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.
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, Washington.
authors.forename: Kara R
authors.initials: KR
authors.lastname: Vogel
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, Washington.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Ainslie
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Erwin E W
authors.initials: EE
authors.lastname: Jansen
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, Washington.
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson