Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin‐associated ocular toxicity?

Abstract

Vigabatrin (VGB; γ‐vinylGABA) is a unique antiepileptic directly elevating CNS GABA via inactivation of the GABA metabolic enzyme GABA‐transaminase. VGB is effective in treating infantile spasms, a rare seizure disorder associated with significant morbidity. The potential for unexplained bilateral constriction of the visual field associated with VGB intervention can severely limit its temporal utility. Removal of this potential adverse effect with adjuvant intervention(s) would represent a significant advance in epilepsy therapeutics.

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme‐replacement therapeutic strategies

“…A major advance came in 1999 with the development of a murine knockout model, so-called aldehyde dehydrogenase 5a1 ( aldh5a1 −/− ) mice (Hogema et al 2000). While the phenotype of this animal model is severe, with early lethality at 3 weeks of life, it has provided insights into GABAergic, glutamatergic, GHBergic, metabolic, oxidative stress, and other parameters otherwise unavailable (Gupta et al 2002; Cortez et al 2004; Buzzi et al 2006; Wu et al 2006; Jansen et al 2008; Pearl et al 2009; Vogel et al 2015, 2016, 2017a–f). Thus far, therapeutics that rescue this model from premature lethality include GABA B and GHB receptor antagonists, the non-physiological amino acid taurine, the antiepileptic agent vigabatrin, the ketogenic diet, and rapalog agents such as Torin 2, the latter an mTOR inhibitor.…”

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

“…The role(s) of GABA, β‐alanine and 4‐GBA in the ocular toxicity of VGB remain unknown. Conversely, we and others have demonstrated that supraphysiological GABA impacts the mTOR pathway of autophagy, leading to mitochondrial accumulation and enhanced oxidative stress . β‐Alanine, the structural homologue of GABA, has GABAergic and glycinergic roles that are well‐described, but its role in VGB‐mediated toxicity has not been investigated.…”

“…Conversely, we and others have demonstrated that supraphysiological GABA impacts the mTOR pathway of autophagy, leading to mitochondrial accumulation and enhanced oxidative stress. 10,11,[50][51][52] β-Alanine, the structural homologue of GABA, has GABAergic and glycinergic roles that are well-described, 53 F I G U R E 1 2 Tissue pools of VGB enantiomers as a function of VGB dose. ND, Not Determined -Prefrontal cortex samples from animals treated with the 35 mg/kg/d dose were used for RNA isolation and thus were unavailable for enantiomer analysis.…”

“…Although GABA, and GABAergic mechanisms, have been implicated in VGB-related ocular toxicity, the potential mechanistic role for other metabolites remains unclear. [9][10][11] VGB formulations are racemic mixtures of the (S)-(+) and (R)-(-) enantiomers (equal ratio), with only the (S)-(+) enantiomer responsible for GABA-transaminase inactivation and therapeutic activity 1,12 .…”

Clinical Pharmacology & Therapeutics: Past, Present, and Future

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