ArticleThe European journal of neuroscience2015
Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus.
Article in The European journal of neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Efficacy and safety of efavirenz in Niemann-Pick disease type C.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Trial
- The Impact of the Natural Level of Blood Biochemicals on Electroencephalographic Markers in Healthy People.Sensors (Basel, Switzerland) · 2024Article
- Neuropathology of New-Onset Refractory Status Epilepticus (NORSE).Journal of neurology · 2023Review
- Clinico-biological markers for the prognosis of status epilepticus in adults.Journal of neurology · 2022Article
- Characterization of three naturally occurring lignans, sesamol, sesamolin, and sesamin, as potent inhibitors of human cytochrome P450 46A1: Implications for treating excitatory neurotoxicity.Frontiers in pharmacology · 2022Article
- Gene Expression Analysis Identifies Cholesterol Metabolism Dysregulation in Hippocampus of Phenytoin-Resistant Pentylenetetrazol-Kindled Epileptic Mice.Neuromolecular medicine · 2021Article
- Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications.Frontiers in aging neuroscience · 2021Review
- Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice.Scientific reports · 2020Article
- In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.Journal of medicinal chemistry · 2020Article
- Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes.Brain communications · 2020Article
- Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Can a hypercholesterolemic diet change the basal brain electrical activity and during status epilepticus in rats?Metabolic brain disease · 2019Article
- Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease.Neuropharmacology · 2017Article
- Article
- Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis.Frontiers in molecular neuroscience · 2017Article
- Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity.The Journal of biological chemistry · 2016Article
- Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices.Journal of neurophysiology · 2016Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Elevations in neuronal cholesterol have been associated with several degenerative diseases. An enhanced excitability and synchronous firing in surviving neurons are among the sequels of neuronal death in these diseases and also in some epileptic syndromes. Here, we attempted to increase neuronal cholesterol levels, using a short hairpin RNA to suppress expression of the enzyme cytochrome P450 family 46, subfamily A, polypeptide 1 gene (CYP46A1). This protein hydroxylates cholesterol and so facilitates transmembrane extrusion. A short hairpin RNA CYP46A1construction coupled to the adeno-associated virus type 5 was injected focally and unilaterally into mouse hippocampus. It was selectively expressed first in neurons of the cornu ammonis (hippocampus) (CA)3a region. Cytoplasmic and membrane cholesterol increased, and the neuronal soma volume increased and then decreased before pyramidal cells died. As CA3a pyramidal cells died, interictal electroencephalographic (EEG) events occurred during exploration and non-rapid eye movement sleep. With time, neuronal death spread to involve pyramidal cells and interneurons of the CA1 region. CA1 neuronal death was correlated with a delayed local expression of phosphorylated tau. Astrocytes were activated throughout the hippocampus and microglial activation was specific to regions of neuronal death. CA1 neuronal death was correlated with distinct aberrant EEG activity. During exploratory behaviour and rapid eye movement sleep, EEG oscillations at 7-10 Hz (theta) could accelerate to 14-21 Hz (beta) waves. They were accompanied by low-amplitude, high-frequency oscillations of peak power at ~300 Hz and a range of 250-350 Hz. Although episodes of EEG acceleration were not correlated with changes in exploratory behaviour, they were followed in some animals by structured seizure-like discharges. These data strengthen links between increased cholesterol, neuronal sclerosis and epileptic behaviour.
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