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.

mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…The current report expands the link between supraphysiological GABA and mTOR signaling described in earlier studies (Lakhani et al 2014; Vogel et al 2015). Until now, drugs that have extended the lifespan of aldh5a1 −/− mice have included taurine, vigabatrin (an irreversible inhibitor of GABA-transaminase), CGP-35348 (a GABA B receptor antagonist), NCS-382 (a GHB receptor antagonist), and the ketogenic diet (Hogema et al 2001; Gupta et al 2002; Nylen et al 2008b).…”

“… Recent studies have identified a role for supraphysiological GABA in the regulation of mTOR (mechanistic target of rapamycin), a protein kinase with pleiotropic roles in cellular development and homeostasis, including integration of growth factors and nutrient sensing, and synaptic input in neurons (Lakhani et al 2014; Vogel et al 2015). Aldehyde dehydrogenase 5a1-deficient ( aldh5a1 −/− ) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA that disrupts mitophagy and increases mitochondria number with enhanced oxidant stress.…”

Increased Skeletal Muscle GLUT4 Expression in Obese Mice After Voluntary Wheel Running Exercise Is Posttranscriptional

“…Mice in the Torin 1 study were given intraperitoneal injections of either 5 mg/kg Torin 1 or vehicle treatment every day of the running period (18). Rapamycin and Torin 1 treatments were prepared in a vehicle PBS solution containing 5% polyethylene glycol 400/5% Tween 80 as described previously (17).…”

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

“…Further, long-term treatment with VGB is contraindicated due to marked and permanent visual-field impairments (Singh et al 2013; Froger et al 2014; Good et al 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). Of further concern is the predicted expectation that VGB will augment brain GABA (Ergezinger et al 2003; Pearl et al 2014a; 2014b), which is a relevant observation in light of recent studies (described above) highlighting GABA-induced impairment of autophagic processes (Vogel et al 2015). The potential use of mTOR inhibitors (e.g., rapamycin, Torin 1 or 2) along with VGB might be an effective intervention, since this would both decrease production of GHB and clear the oxidative-damaging effects of further-enhanced GABA levels.…”