Personalized medicine: Vinpocetine to reverse effects of <i>GABRB3</i> mutation

Billakota, Santoshi; Andresen, J. Michael; Stewart, Gregory R.; Fedorov, N. A.; Gerlach, Aaron C.; Devinsky, Orrin

doi:10.1111/epi.16394

Cited by 22 publications

(31 citation statements)

References 13 publications

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“…Electrophysiological recordings were performed, using standard methods in the field [70, 71], on HEK-293T cell line transfected with full-length cDNAs for the human GABAA receptor subtypes (α1β3γ2, α2β3γ2, α3β3γ2, α4β3γ2 or α5β3γ2). Holding potential was −70mV.…”

Section: Methodsmentioning

confidence: 99%

Symptomatic and Neurotrophic Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

Bernardo

Marcotte

et al. 2021

Preprint

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Chronic stress is a major risk factor for developing depressive disorders and animal models of stress recapitulate behavioral, cellular and molecular changes that are observed in human depression. Individuals exposed to chronic stress, or patients with MDD experience mood and cognitive dysfunctions. This is in part due to neuronal shrinkage in brain regions involved in several cognitive functions such as the prefrontal cortex (PFC) and the hippocampus (HPC). Also in the context of depression and chronic stress, expression levels and function of the main inhibitory neurotransmitter GABA are reduced. Thus far, drugs targeting this GABA deficit have failed to produce beneficial effects due to broad activity at various GABA receptor subunits, including the α1-subunit, resulting in broad side effects. However, refined and selective activity at the α2/3/5-subunit is hypothesized to exert beneficial effect, devoid of side effects.Here, we show that GL-II-73 and GL-I-54 exert positive allosteric modulation at the α5, and α2/3/5-contianing GABAA receptors respectively, and that they are effective both independently and in combination. Using unpredictable chronic mild stress (UCMS) experiments in male and female C57BL/6 mice (n=12 per group), we showed that acute and chronic administration of a GL-II-73/GL-I-54 racemic mixture (termed “GL-RM”) reduced anxiety-like phenotypes and reversed a working memory deficit in UCMS exposed mice. Brains from animals receiving chronic treatment were collected and stained using a Golgi staining technique. Using stereological approaches, neuronal morphology was reconstructed and dendritic length, spine count and spine density were assessed in pyramidal neurons of the PFC and hippocampus. Chronic GL-RM rescued spine density depletions caused by UCMS at apical and basal dendrites (PFC and CA1). Interestingly, spine densities in both brain regions were correlated to cognitive performance, confirming ameliorative benefits of GL-RM.Together, results support the value of selectively targeting GABAA receptors, excluding the α1-subunit, to overcome chronic stress-induced mood symptoms and cognitive deficits, as well as detriments in neuronal morphology. This study confirm results that were observed in old mice, using a α5-selective positive allosteric modulator, and reinforce the concept that the α2/3/5-containing GABAA receptor are suitable targets for the treatment of stress-induced disorders.

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Section: Methodsmentioning

confidence: 99%

Symptomatic and Neurotrophic Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

Bernardo

Marcotte

et al. 2021

Preprint

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“…A woman with Lennox-Gastaut syndrome (LGS) from a disease-causing variant in GABRB3 experienced a sustained, dose-dependent decrease in epileptiform activity on EEG after starting vinpocetine, a synthetic derivative of vincamine which is an alkaloid derived from the periwinkle plant. Its antiepileptic properties are likely from a combination of sodium channel modulation and GABA-A activity potentiation—future studies will be needed to determine its efficacy and pharmacokinetics in epilepsy ( 68 ).…”

Section: Therapies For Genetic Epilepsiesmentioning

confidence: 99%

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

2022

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Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

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“…120 A single patient with Lennox-Gastaut syndrome carrying a GABRB3 (c.905A>G; Y302C) missense variant was supplemented with vinpocetine leading to a reduction of the epileptiform activity on EEG recordings and improvement of cognitive, behavioural and language functions. 58 Vinpocetine crosses the blood-brain barrier and inhibits voltage-gated calcium channels, glutamate receptors and voltage-dependent Na channels. 121 Antiepileptiform effects of vinpocetine could derive from the above mechanisms of action, plus its inhibition of sodium channels and potentiation of GABAA activity (Table 2).…”

Section: Function-based Therapiesmentioning

confidence: 99%

Novel treatments in epilepsy guided by genetic diagnosis

Marini¹,

Giardino²

2021

Brit J Clinical Pharma

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In recent years, precision medicine has emerged as a new paradigm for improved and more individualized patient care. Its key objective is to provide the right treatment, to the right patient at the right time, by basing medical decisions on individual characteristics, including specific genetic biomarkers. In order to realize this objective researchers and physicians must first identify the underlying genetic cause; over the last 10 years, advances in genetics have made this possible for several monogenic epilepsies. Through next generation techniques, a precise genetic aetiology is attainable in 30–50% of genetic epilepsies beginning in the paediatric age. While committed in such search for novel genes carrying disease‐causing variants, progress in the study of experimental models of epilepsy has also provided a better understanding of the mechanisms underlying the condition. Such advances are already being translated into improving care, management and treatment of some patients. Identification of a precise genetic aetiology can already direct physicians to prescribe treatments correcting specific metabolic defects, avoid antiseizure medicines that might aggravate functional consequences of the disease‐causing variant or select the drugs that counteract the underlying, genetically determined, functional disturbance. Personalized, tailored treatments should not just focus on how to stop seizures but possibly prevent their onset and cure the disorder, often consisting of seizures and its comorbidities including cognitive, motor and behaviour deficiencies. This review discusses the therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanisms and tailored seizure treatment, emphasizing the impact on current clinical practice.

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Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation

Cited by 22 publications

References 13 publications

Symptomatic and Neurotrophic Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

Symptomatic and Neurotrophic Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

Novel treatments in epilepsy guided by genetic diagnosis

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