Ketogenic diet exerted anti-seizure function related with alteration of lipid metabolism via pparγ signaling pathway
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315058 | GEO | 2026/06/11
REPOSITORIES: GEO
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Project description:Epilepsy affects between 1-2% of people worldwide and is defined symptomatically by the appearance of spontaneous, recurrent seizures. The ketogenic diet (KD) is an anticonvulsant treatment that has been used to manage medically-intractable epilepsies. Both clinical and experimental reports show that the KD can be used to treat a variety of seizure types. During KD treatment, ketone bodies, rather than glucose, become the major energy substrate for the brain; somehow, metabolic conversion confers a potent anticonvulsant effect. The KD requires 10-12 days to become maximally effective, suggesting that changes in gene expression are involved in its anticonvulsant action. Despite its use for over 80 years, the mechanism of the diet remains unknown. It is expected that this work will help elucidate the underlying anticonvulsant action of the KD and contribute to future, rationale-based drug development. We propose to identify sets of genes activated/repressed within hippocampus after treatment with a KD. We hypothesize that gene expression patterns induced by alterations in metabolic pathways are critically involved with the anticonvulsant effects of the KD in mice. Mice (n=44, 129svJ) will be used for these experiments. Animals will be fed either a KD (n=22) or control diet (n=22) for 14 days. After this time, ten animals from each group will be subjected to flurothyl seizure testing to confirm seizure threshold elevation. Of the remaining KD- (n=12) or control-fed (n=12) animals, two left hippocampi will be pooled together such that six arrays from each treatment group can be tested. This is expected to reduce biological variability. Right hippocampi (n=12/group) will be maintained in our lab for corroborative analysis via RT-PCR and immunohistochemistry. All tissue samples will be rapidly dissected, frozen in liquid nitrogen, and stored at -80C until shipping/corroborative testing. Data analysis will be completed with Significance of Array Measurement (SAM) program using ANOVA from protection for multiple comparisons. Please use the Affy chip with known genes in lieu of the chip containing mostly EST's.
2008-06-11 | E-GEOD-1829 | biostudies-arrayexpress
Project description:Epilepsy is characterized by hypersynchronous neuronal discharges, which are associated with an increased cerebral metabolic rate of oxygen and ATP demand. Uncontrolled seizure activity (status epilepticus) results in mitochondrial exhaustion and ATP depletion, which potentially generate energy mismatch and neuronal loss. Many cells can adapt to increased energy demand by increasing metabolic capacities. However, acute metabolic adaptation during epileptic activity and its relationship to chronic epilepsy remains poorly understood. We elicited seizure-like events (SLEs) in an in vitro model of status epilepticus for eight hours. Electrophysiological recording and tissue oxygen partial pressure recordings were performed. After eight hours of ongoing SLEs, we used proteomics-based kinetic modeling to evaluate changes in metabolic capacities. We compared our findings regarding acute metabolic adaptation to published proteomic and transcriptomic data from chronic epilepsy patients. Epileptic tissue acutely responded to uninterrupted SLEs by upregulating ATP production capacity. This was achieved by a coordinated increase in the abundance of proteins from the respiratory chain and oxidative phosphorylation system. In contrast, chronic epileptic tissue shows a 25-40% decrease in ATP production capacity. In summary, our study reveals that epilepsy leads to dynamic metabolic changes. Acute epileptic activity boosts ATP production, while chronic epilepsy reduces it significantly.
2024-09-12 | PXD055090 | Pride
Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients 4 Control sibling samples (sample= 10 pooled larvae) and 4 Nav1.1 mutants (sample= 10 pooled larvae) were collected at 6 dpf (days post fertilization). The Nav1.1 mutants were selected based on phenotype (dark color).
2014-01-04 | E-GEOD-43312 | biostudies-arrayexpress
Project description:<h4><strong>INTRODUCTION: </strong>Approximately 1% of the world's population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD's success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.</h4><h4><strong>OBJECTIVES: </strong>The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.</h4><h4><strong>METHODS: </strong>FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).</h4><h4><strong>RESULTS: </strong>Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1-/-. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.</h4><h4><strong>CONCLUSION: </strong>Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.</h4>
2022-01-06 | MTBLS1432 | MetaboLights
Project description:The ketogenic diet (KD) is an anticonvulsant treatment that has been used to manage medically-intractable epilepsies. The KD requires 10-12 days to become maximally effective, suggesting that changes in gene expression are involved in its anticonvulsant action. Using the Affymetrix rat arrays (RAE230A), 6 control samples and 5 KD samples were run.
2007-10-27 | E-GEOD-1155 | biostudies-arrayexpress
Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients
2014-01-04 | GSE43312 | GEO
Project description:The ketogenic diet (KD) is an anticonvulsant treatment that has been used to manage medically-intractable epilepsies. The KD requires 10-12 days to become maximally effective, suggesting that changes in gene expression are involved in its anticonvulsant action. Using the Affymetrix rat arrays (RAE230A), 6 control samples and 5 KD samples were run. Keywords: other
2004-03-29 | GSE1155 | GEO
Project description:Traumatic brain injury occasionally causes posttraumatic epilepsy. To elucidate the molecular events responsible for posttraumatic epilepsy, we established a rodent model that involved the injection of microliter quantities of FeCl3 solution into the amygdalar nuclear complex. We previously compared hippocampal gene expression profiles in the traumatic epilepsy model and normal rats at 5 days after brain injury (acute phase) and observed the role of inflammation. In this study, we focused on later stages of epileptogenesis. We compared gene expression profiles at 5, 15 (sub-chronic phase), and 30 days (chronic phase) after brain injury to identify temporal changes in molecular networks involved in epileptogenesis. A total of 81 genes was significantly (at least 2-fold) up- or downregulated over the course of disease progression. We found that genes related to lipid metabolism, namely, Apoa1, Gh, Mc4r, Oprk1, and Pdk4, were temporarily upregulated in the sub-chronic phase. Changes in lipid metabolism regulation might be related to seizure propagation during epileptogenesis. This temporal description of hippocampal gene expression profiles throughout epileptogenesis provides clues to potential markers of disease phases and new therapeutic targets. We employed amygdalar FeCl3 injection to induce chronic, recurrent limbic-type partial seizures with spontaneous secondarily generalized seizures in rats . Sixteen male Wistar rats were kept in hanging cages with unlimited access to food and water and 12-h light-dark cycles. Surgical procedures were conducted following anesthesia with intraperitoneal (i.p.) sodium pentobarbital injections (37.5 mg/kg) at 5 weeks of age. Stereotaxic coordinates were determined with the rat brain atlas. The incisor bar was set 3.3 mm below the interaural line. While under anesthesia, a polyethylene tube containing a stylet to serve as an external guide cannula (1.09-mm outer diameter (o.d.), 0.55-mm inner diameter (i.d.), 2.5 cm in length) was stereotaxically implanted and anchored to the skull with miniature screws and dental cement. The cannula was fixed 5.6 mm anterior and 4.8 mm to the right of the lambda and 8.5 mm below the surface of the skull, positioning it at the right amygdaloid body. Randomly selected rats for in vivo microdialysis to estimate redox had guide cannula placed but were prepared without dental cement on the skull where the microdialysis guide cannula was to be placed. Five days later, the stylet was replaced with an internal delivery cannula (0.5 mm o.d., 0.25 mm i.d.). FeCl3 was dissolved in saline solution (100 mM, pH 2.2). FeCl3 solution (1.0 M-NM-<l) was injected through the inner cannula by means of a microinfusion pump (EP-60; Eicom, Tokyo, Japan) set at a rate of 1.0 M-NM-<l/min (Fe group; n = 12). The external guide cannula was used for electroencephalogram (EEG) recording with an electroencephalograph (type 1A63; SAN-EI, Tokyo, Japan). Rats in the control group (n = 4) were each injected with 1.0 M-NM-<l saline (pH 2.2). Both EEG and behavior were observed for at least 6 h after the injection. While we did not measure the rate or frequency of seizures, we did confirm that the animals had recurrent seizures. These observations and the acute recording confirmed the accuracy of the amygdalar injection. No seizure activity was observed in control group rats. Animals in the control group were sacrificed by cervical dislocation 15 days after amygdalar injection. Animals in the Fe group were subdivided into 3 groups and were sacrificed at 5 (acute phase), 15 (sub-chronic phase of injury), and 30 days (chronic phase of injury) after amygdalar injection. The stages of disease development were categorized according to the EEGs of the model rats; within 5 days after amygdalar injection, epileptiform discharges were recorded in the contralateral and ipsilateral amygdalae; by 15 days after injection, interictal spike discharges were more consistently observed in the contralateral uninjected amygdala; at 30 days after injection bilateral interictal spike discharges continued to be observed. After sacrifice, the right hippocampi were immediately removed and placed in ice-cold phosphate-buffered saline and homogenized (Polytron PT 3000; Brinkmann Instruments, Inc., Westbury, NY, USA) for RNA extraction.
2012-12-31 | E-GEOD-40490 | biostudies-arrayexpress
Project description:Lipid-accumulated reactive astrocytes promote seizure activity in epilepsy
| PRJNA787216 | ENA
Project description:The non-psychotomimetic phytocannabinoid cannabidiol (CBD) has shown anticonvulsant effects in several seizure models in rats and mice. However, the mechanisms by which CBD exerts its antiepileptic effects are not fully elucidated. MicroRNAs (miRNA) are short non-coding RNAs which regulate protein expression. Dysregulation of miRNAs can contribute to the pathology of various diseases, including epilepsy. This could indicate that the modulation of miRNAs is a potential mechanism of action for the therapeutic effects of CBD. Therefore, we sequenced hippocampal samples from CBD or vehicle treated naive mice to see the effects of CBD on miRNA expression.
2023-07-06 | GSE214761 | GEO