The ketogenic diet metabolite beta-hydroxybutyrate (β-HB) reduces incidence of seizure-like activity (SLA) in a K atp - and GABA b -dependent manner in a whole-animal Drosophila melanogaster model

Li, Jinglu; O’Leary, Emma I.; Tanner, Geoffrey R.

doi:10.1016/j.eplepsyres.2017.04.003

Cited by 29 publications

(29 citation statements)

References 20 publications

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“…Preprandial and postprandial blood BHB concentrations were both significantly elevated in this trial, when dogs consumed the MCT‐DS in comparison to the control‐DS, which is in accordance with dogs fed an MCT‐enriched kibble diet 24 . In a Drosophila invitro model, BHB reduces seizure‐like neuronal activity, which is thought to be mediated via K ATP channel activity and GABA B signaling inhibition 69 . In a kainic acid rat seizure model intraperitoneal BHB administration prolonged the onset of induced seizures.…”

Section: Discussionsupporting

confidence: 81%

A multicenter randomized controlled trial of medium‐chain triglyceride dietary supplementation on epilepsy in dogs

Berk

Law

Packer

et al. 2020

Veterinary Internal Medicne

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Background: Medium-chain triglyceride (MCT) enriched diet has a positive effect on seizure control and behavior in some dogs with idiopathic epilepsy (IE).Objective: To evaluate the short-term efficacy of MCTs administered as an add-on dietary supplement (DS) to a variable base diet to assess seizure control and antiseizure drug's (ASD) adverse effect profiles.Animals: Twenty-eight dogs with International Veterinary Epilepsy Task Force Tier II (IVETF) level diagnosis of treated IE with 3 or more seizures in the last 3 months were used.Methods: A 6-month multicenter, prospective, randomized, double-blinded, placebocontrolled crossover trial was completed, comparing an MCT-DS with a control-DS.A 9% metabolic energy-based amount of MCT or control oil was supplemented to the dogs' diet for 3 months, followed by a control oil or MCT for another 3 months, respectively. Dogs enrolled in this study satisfied most requirements of IE diagnosis stated by the IVETF II level. If they received an oil DS or drugs that could influence the metabolism of the investigated DS or chronic ASD, the chronic ASD medication was adjusted, or other causes of epilepsy were found, the dogs were excluded from the study.Abbreviations: ASD, antiseizure drug; BHB, beta hydroxybutyric acid; C10, decanoic acid = capric acid; C8, octanoic acid = caprylic acid; DS, dietary supplement; IE, idiopathic epilepsy; ITTA, intention to treat analysis; IVETF II, International Veterinary Epilepsy Task Force Tier II; KBr, potassium bromide; LEV, levetiracetam; MBW, metabolic body weight; MCT, medium-chain triacylglyceride; ME, metabolic energy; PB, phenobarbital; QoL, quality of life; RER, resting energy requirement; RVC, Royal Veterinary College; VAS, visual analog score.

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Section: Discussionsupporting

confidence: 81%

A multicenter randomized controlled trial of medium‐chain triglyceride dietary supplementation on epilepsy in dogs

Berk

Law

Packer

et al. 2020

Veterinary Internal Medicne

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“…This pathway is highly conserved because fasting enhances long-term memory formation in multiple tasks in Drosophila melanogaster by a mechanism requiring CREB activation in mushroom body neurons 40 . Ketones, particularly BHB, upregulate GABAergic tone, which can protect against seizures 41,42 , and may mediate adaptive responses of neuronal circuits to IMS. The monoamine neurotransmitters serotonin, noradrenaline and dopamine may also play important roles in the effects of IMS on neuronal network activity 43,44 .…”

Section: Signalling Pathways Impacted By Imsmentioning

confidence: 99%

Intermittent metabolic switching, neuroplasticity and brain health

et al. 2018

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During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

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“…However, the antiepileptic mechanisms of this diet are multiple and still remain ill-defined (Rho, 2017;Simeone et al, 2017). Importantly, experimental studies have demonstrated that the ketone body BHB reduces seizure-like activity in a drosophila melanogaster model (Li et al, 2017). In the same study, it was shown that a K ATP blocker or a GABA B receptor antagonist (CGP-55845) reversed BHB effects, providing conclusive evidence that the beneficial effects of the ketogenic diet are likely mediated by K ATP channels and GABA B receptors.…”

Section: Discussionmentioning

confidence: 99%

Paroxysmal Discharges in Tissue Slices From Pediatric Epilepsy Surgery Patients: Critical Role of GABAB Receptors in the Generation of Ictal Activity

Levinson

Tran

Barry

et al. 2020

Front. Cell. Neurosci.

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In the present study, we characterized the effects of bath application of the proconvulsant drug 4-aminopyridine (4-AP) alone or in combination with GABA A and/or GABA B receptor antagonists, in cortical dysplasia (CD type I and CD type IIa/b), tuberous sclerosis complex (TSC), and non-CD cortical tissue samples from pediatric epilepsy surgery patients. Whole-cell patch clamp recordings in current and voltage clamp modes were obtained from cortical pyramidal neurons (CPNs), interneurons, and balloon/giant cells. In pyramidal neurons, bath application of 4-AP produced an increase in spontaneous synaptic activity as well as rhythmic membrane oscillations. In current clamp mode, these oscillations were generally depolarizing or biphasic and were accompanied by increased membrane conductance. In interneurons, membrane oscillations were consistently depolarizing and accompanied by bursts of action potentials. In a subset of balloon/giant cells from CD type IIb and TSC cases, respectively, 4-AP induced very low-amplitude, slow membrane oscillations that echoed the rhythmic oscillations from pyramidal neurons and interneurons. Bicuculline reduced the amplitude of membrane oscillations induced by 4-AP, indicating that they were mediated principally by GABA A receptors. 4-AP alone or in combination with bicuculline increased cortical excitability but did not induce seizure-like discharges. Ictal activity was observed in pyramidal neurons and interneurons from CD and TSC cases only when phaclofen, a GABA B receptor antagonist, was added to the 4-AP and bicuculline solution. These results emphasize the critical and permissive role of GABA B receptors in the transition to an ictal state in pediatric CD tissue and highlight the importance of these receptors as a potential therapeutic target in pediatric epilepsy.

show abstract

The ketogenic diet metabolite beta-hydroxybutyrate (β-HB) reduces incidence of seizure-like activity (SLA) in a K atp - and GABA b -dependent manner in a whole-animal Drosophila melanogaster model

Cited by 29 publications

References 20 publications

A multicenter randomized controlled trial of medium‐chain triglyceride dietary supplementation on epilepsy in dogs

A multicenter randomized controlled trial of medium‐chain triglyceride dietary supplementation on epilepsy in dogs

Intermittent metabolic switching, neuroplasticity and brain health

Paroxysmal Discharges in Tissue Slices From Pediatric Epilepsy Surgery Patients: Critical Role of GABAB Receptors in the Generation of Ictal Activity

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