Journal article
Torin 1 partially corrects vigabatrin-induced mitochondrial increase in mouse
Annals of clinical and translational neurology, Vol.2(6), pp.699-706
06/2015
Handle:
https://hdl.handle.net/2376/116762
PMCID: PMC4479529
PMID: 26125044
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.
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Details
- Title
- Torin 1 partially corrects vigabatrin-induced mitochondrial increase in mouse
- Creators
- Kara R Vogel - Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, WashingtonGarrett R Ainslie - Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, WashingtonErwin E W Jansen - Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Neuroscience Campus, Amsterdam, The NetherlandsGajja S Salomons - Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Neuroscience Campus, Amsterdam, The NetherlandsK Michael Gibson - Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, Washington
- Publication Details
- Annals of clinical and translational neurology, Vol.2(6), pp.699-706
- Academic Unit
- Pharmacotherapy, Department of
- Publisher
- United States
- Grant note
- R21 NS085369 / NINDS NIH HHS
- Identifiers
- 99900547527101842
- Language
- English
- Resource Type
- Journal article