Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Walters, Dana C.; Arning, Erland; Jansen, Erwin E.W.; Salomons, Gajja S.; Brown, Madalyn; Schmidt, Michelle; Ainslie, Garrett R.; Roullet, Jean Baptiste; Gibson, K. Michael

doi:10.1016/j.neuint.2019.02.015

Cited by 15 publications

(14 citation statements)

References 56 publications

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“…Benzodiazepines (such as clobazam diazepam, lorazepam, clonazepam) phenobarbital and stiripentol enhance the inhibitory transmission of GABA by allosteric activation of the GABA A receptor thus increasing the frequency of chloride (Cl − ) channel openings [53,54]. Vigabatrin, instead, is an inhibitor of GABA transaminase, the enzyme responsible for the catabolism of GABA [55]. In addition to enhancing the inhibitory transmission of GABA, other drugs exert their antiepileptic action, also exploiting the blockage of the Ca 2+ and Na + channels.…”

Section: Common Antiepileptic Drugsmentioning

confidence: 99%

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials

et al. 2019

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Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.

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Section: Common Antiepileptic Drugsmentioning

confidence: 99%

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials

et al. 2019

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“…Moreover, VGB given for 3-7 days lowered GAD activity in the mouse's brain. It is well documented that the anticonvulsive activity of VGB is related to an increase in the central nervous system GABA level [38,39]. Except for GABA-AT inhibition, stimulation of GABA release from synaptosomes is also considered as VGB's mechanism of action [40].…”

Section: Discussionmentioning

confidence: 99%

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration

Świąder

Zakrocka

et al. 2019

Pharmacol. Rep

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Background The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. Methods VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. Results After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. Conclusions The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.

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“…Lys was significantly increased (∼20%) in R6/2 plasma. It is not clear whether there is any relation between high plasma level of Lys and elevated AADA content in brain tissues, the elevation of the latter in the brain tissues could exert its toxicity via enhanced release or transport of excitatory Glu 50, 51 . Undeniably, the increase of these amino acids along with the decreased levels of three BH 4 -dependent neurotransmitter synthases (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice

Hung

Zhu

Kittur

et al. 2022

Preprint

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Pathophysiology associated with Huntington’s disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the polyQ-induced early pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants, which lack an Htt ortholog to avoid any associated effects from endogenous Htt. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and that mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most impaired protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolisms. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and contribute to a better understanding of mHtt-altered C1 metabolism and C1 interconnected BH4 metabolism leading to the pathogenesis of HD.

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Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

Cited by 15 publications

References 56 publications

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration

Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice

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