Kara R Vogel1, Garrett R Ainslie1, Michelle A Schmidt2, Jonathan P Wisor2, K Michael Gibson3. 1. Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington. 2. Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington. 3. Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington. Electronic address: mike.gibson@wsu.edu.
Abstract
BACKGROUND: Gamma-vinyl-γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss. METHODS: Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels. Visual evoked potentials were examined, eye samples were collected, and gene expression was measured by quantitative reverse transcription-polymerase chain reaction. Similarly, human retinal pigment epithelial cells (ARPE19) were exposed to vigabatrin and treated with mTOR inhibitors for mTOR pathway analysis and to assess alterations in organelle accumulation by microscopy. RESULTS: Dysregulated expression of transcripts in the mTOR pathway, GABAA/B receptors, metabotropic glutamate (Glu) receptors 1/6, and GABA/glutamate transporters in the eye were found in association with visual evoked potential changes during vigabatrin administration. Rrag genes were upregulated in both mouse eye and ARPE19 cells. Immunoblot of whole eye revealed greater than three fold upregulation of a 200 kDa band when immunoblotted for ras-related guanosine triphosphate binding D. Microscopy of ARPE19 cells revealed selective reversal of vigabatrin-induced organelle accumulation by autophagy-inducing drugs, notably Torin 2. Changes in the mTOR pathway gene expression, including Rrag genes, were corrected by Torin 2 in ARPE19 cells. CONCLUSIONS: Our studies, indicating GABA-associated augmentation of RRAG and mTOR signaling, support further preclinical evaluation of mTOR inhibitors as a therapeutic strategy to potentially mitigate vigabatrin-induced ocular toxicity.
BACKGROUND: Gamma-vinyl-γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss. METHODS:Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels. Visual evoked potentials were examined, eye samples were collected, and gene expression was measured by quantitative reverse transcription-polymerase chain reaction. Similarly, human retinal pigment epithelial cells (ARPE19) were exposed to vigabatrin and treated with mTOR inhibitors for mTOR pathway analysis and to assess alterations in organelle accumulation by microscopy. RESULTS: Dysregulated expression of transcripts in the mTOR pathway, GABAA/B receptors, metabotropic glutamate (Glu) receptors 1/6, and GABA/glutamate transporters in the eye were found in association with visual evoked potential changes during vigabatrin administration. Rrag genes were upregulated in both mouse eye and ARPE19 cells. Immunoblot of whole eye revealed greater than three fold upregulation of a 200 kDa band when immunoblotted for ras-related guanosine triphosphate binding D. Microscopy of ARPE19 cells revealed selective reversal of vigabatrin-induced organelle accumulation by autophagy-inducing drugs, notably Torin 2. Changes in the mTOR pathway gene expression, including Rrag genes, were corrected by Torin 2 in ARPE19 cells. CONCLUSIONS: Our studies, indicating GABA-associated augmentation of RRAG and mTOR signaling, support further preclinical evaluation of mTOR inhibitors as a therapeutic strategy to potentially mitigate vigabatrin-induced ocular toxicity.
Authors: Darius Ebrahimi-Fakhari; Afshin Saffari; Lara Wahlster; Jenny Lu; Susan Byrne; Georg F Hoffmann; Heinz Jungbluth; Mustafa Sahin Journal: Brain Date: 2015-12-29 Impact factor: 13.501
Authors: Kara R Vogel; Garrett R Ainslie; Erwin E W Jansen; Gajja S Salomons; K Michael Gibson Journal: Ann Clin Transl Neurol Date: 2015-04-17 Impact factor: 4.511
Authors: Ronak Lakhani; Kara R Vogel; Andreas Till; Jingjing Liu; Sarah F Burnett; K Michael Gibson; Suresh Subramani Journal: EMBO Mol Med Date: 2014-02-27 Impact factor: 12.137
Authors: Kara R Vogel; Garrett R Ainslie; Dana C Walters; Alice McConnell; Sameer C Dhamne; Alexander Rotenberg; Jean-Baptiste Roullet; K Michael Gibson Journal: J Inherit Metab Dis Date: 2018-02-19 Impact factor: 4.982
Authors: Dana C Walters; Erland Arning; Teodoro Bottiglieri; Erwin E W Jansen; Gajja S Salomons; Madalyn N Brown; Michelle A Schmidt; Garrett R Ainslie; Jean-Baptiste Roullet; K Michael Gibson Journal: Neurochem Int Date: 2019-02-26 Impact factor: 3.921
Authors: Dana Walters; Kara R Vogel; Madalyn Brown; Xutong Shi; Jean-Baptiste Roullet; K Michael Gibson Journal: Epilepsy Res Date: 2020-06-20 Impact factor: 3.045
Authors: Dana C Walters; Erwin E W Jansen; Garrett R Ainslie; Gajja S Salomons; Madalyn N Brown; Michelle A Schmidt; Jean-Baptiste Roullet; K M Gibson Journal: Pharmacol Res Perspect Date: 2019-01-07
Authors: Marwa Abd El-Kader; Eman Hamza; Randa El-Gamal; Amira Sobhy Rashed Eladl; Eman Mohamad El Nashar; Mansour A Alghamdi; Omnia S Erfan Journal: J Mol Histol Date: 2021-05-27 Impact factor: 2.611
Authors: Kara R Vogel; Garrett R Ainslie; Erwin E Jansen; Gajja S Salomons; Jean-Baptiste Roullet; K Michael Gibson Journal: PLoS One Date: 2017-10-20 Impact factor: 3.240