A novel dietary therapy for epilepsy: potential mechanisms of action
一种新型癫痫饮食疗法:潜在的作用机制
基本信息
- 批准号:9813521
- 负责人:
- 金额:$ 3.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-17 至 2022-09-16
- 项目状态:已结题
- 来源:
- 关键词:AffectAmygdaloid structureAnticonvulsantsAntiepileptic AgentsApneaBathingBehaviorBrainBreathingCarbohydratesCessation of lifeChildChildhoodClinical TrialsDataDefectDetectionDevelopmentDietDrosophila genusDrug resistanceElectrocardiogramElectroencephalographyElectrophysiology (science)EpilepsyFatty acid glycerol estersFoodFrequenciesFunctional disorderFutureGenesGlucoseHigh Pressure Liquid ChromatographyHippocampus (Brain)HumanIncidenceInduced HyperthermiaInterneuronsIonsKetone BodiesKetonesKetosisLeadLinkLiteratureMeasuresMediatingMicrodialysisMilkModelingMusNeuronsNutritionalOutcome StudyPalatePatientsPharmacologyPhenotypePhysiciansPlayPreventionPrevention strategyProductionPropertyRattusRefractoryResearchRiskRoleScientistSeizuresSerotonergic SystemSerotoninSeveritiesSignal TransductionSliceSupplementationTechniquesTestingTonic - clonic seizuresTrainingTryptophanWorkbaseblood glucose regulationcareerdravet syndromeexperimental studyextracellularfeedingflyhigh riskhippocampal pyramidal neuronin vivoinhibitory neuronketogenic dietmortalitymouse modelmutantneurochemistrynon-compliancenovelnutritional guidelinepatch clamppre-clinicalpreventrespiratorysudden unexpected death in epilepsyvoltage
项目摘要
Project Summary/Abstract
More than one-third of people with epilepsy have inadequate control of seizures even when taking
multiple antiepileptic drugs (AEDs). Uncontrolled tonic-clonic seizures place patients at high risk
of sudden unexpected death in epilepsy (SUDEP), a major cause of mortality in patients with
drug-resistant epilepsy. The high-fat, very low-carbohydrate ketogenic diets (KDs) help some
patients with uncontrolled epilepsy, especially children, but have been described as unpalatable
and are often not tolerated by patients, leading to high rates of non-compliance.
We have obtained preliminary data from a mouse model of Dravet Syndrome (DS), a devastating
childhood-onset epilepsy with refractory seizures and a high incidence of SUDEP, and found
seizure-induced death is greatly reduced by supplementing their diet with milk whey (WD). This
WD was just as protective as two different KDs, but did not require an increase in ketone bodies.
Moreover, our preliminary studies suggest that a WD and KDs increase 5-HT levels and 5-HT
release in the brain of mice. This is important, as 5-HT is known to inhibit seizures and also plays
a critical role in control of breathing. Defects in the 5-HT system have been linked to both
respiratory dysfunction and SUDEP. In this proposed project, we will test the hypotheses that 1)
whey prevents seizure-induced death by reducing seizure frequency and/or stimulating postictal
breathing via increased brain 5-HT, and 2) whey prevents postictal death by reversing the basic
underlying defect in DS mice, which is thought to be a decrease in excitability of GABAergic fast-
spiking interneurons. To determine how a WD affects seizures, breathing and neurochemistry,
we will use video-EEG/EKG to evaluate the anticonvulsant effects of a WD on spontaneous and
hyperthermia-induced seizures, and in vivo microdialysis with high performance liquid
chromatography to measure extracellular 5-HT in the amygdala, a region implicated in seizure
propagation and postictal apnea. We will perform patch clamp recordings on hippocampal brain
slices from WD-fed DS mice to evaluate intrinsic electrophysiological properties of interneurons
and pyramidal neurons, and will determine if changes in excitability due to the WD are mediated
by increased 5-HT signaling. These studies will provide preclinical data that may guide future
clinical trials to evaluate milk whey supplementation as a safe and healthy dietary therapy for
drug-resistant epilepsy that is more palatable and effective than the KD. These experiments may
also lead to new avenues of treatment targeted at the serotonergic mechanisms engaged by milk
whey.
项目总结/文摘
项目成果
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Frida Angelina Teran其他文献
Frida Angelina Teran的其他文献
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{{ truncateString('Frida Angelina Teran', 18)}}的其他基金
A novel dietary therapy for epilepsy: potential mechanisms of action
一种新型癫痫饮食疗法:潜在的作用机制
- 批准号:
10238919 - 财政年份:2018
- 资助金额:
$ 3.24万 - 项目类别: