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The Role of Oxidative Stress in Neurodegeneration and Protection by Antioxidants
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
The proteins and lipids in the brain are known to get oxidized, and their oxidative products may further lead to ROS production. Cholesterol-related substances have also been reported to cause nerve cell damage. Approximately 25% of the cholesterol in the body is in the brain. As cholesterol is unable to cross the brain barrier, cholesterol in the brain is not food-derived and is, therefore, synthesized in the brain. Cholesterol synthesized in the brain is converted to 24S hydroxycholesterol (24S-OHC) by the enzyme cholesterol 24 hydroxylase (CYP46A1) and then excreted out of the brain. The 24S-OHC has been known to cause neuronal cell death (Yamanaka et al. 2011, Noguchi et al. 2015).
Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
In the brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the BBB. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes have demonstrated that pericytes express LXR nuclear receptors and their target gene ATP-binding cassette, subfamily A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Furthermore, pericytes are able to internalize the amyloid-β peptides which accumulate in the brain of AD patients (Saint-Pol et al. 2012).
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
The turnover of cholesterol in the brain is thought to occur via conversion of excess cholesterol into 24S-hydroxycholesterol. This compound, an oxysterol, is readily secreted from the central nervous system (CNS) into the plasma. Recent cloning of human and mouse cDNA sequences has shown that both proteins are localized to the endoplasmic reticulum, share 95% identity, and represent a new cytochrome P450 subfamily (CYP46).125 Transfection studies have revealed that the proteins encoded by the cDNAs convert cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol. The cholesterol 24-hydroxylase gene contains 15 exons and is located on human chromosome 14q32.1.
Investigational new drugs for the treatment of Dravet syndrome: an update
Published in Expert Opinion on Investigational Drugs, 2023
Slobodan M. Janković, Snežana V. Janković, Radiša Vojinović, Snežana Lukić
In the last year, the results of a clinical study with soticlestat [34], a selective inhibitor of cholesterol 24-hydroxylase that converts cholesterol into 24S-hydroxycholesterol, were published. Decreasing 24S-hydroxycholesterol in the brain reduces the level of glutamate and the sensitivity of its receptors, thus reducing hyperexcitability. In the Phase 2 ELEKTRA clinical study conducted in 139 children with Dravet (n = 51) or Lennox-Gastaut (n = 88) syndrome, it was shown that after 20 weeks of treatment with soticlestat, there was a 50% reduction in the frequency of seizures in children with Dravet syndrome and for 17.08% in children with Lennox-Gastaut syndrome. The frequency of side effects and their severity were very similar to that of placebo, only constipation and lethargy were about 5% more common with soticlestat. The clinical study of the third phase ‘A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome’ (acronym SKYLINE) [35] is currently underway, the completion of which is expected in the first half of 2023; if its results confirm the good results of the ELEKTRA study, we can expect a soon marketing authorization of soticlestat for the treatment of children with Dravet syndrome.
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
In an effort to address the importance of CYP46A1 to AD, Djelti and coworkers used an amyloid precursor protein (APP) transgenic mice (transgenic model for β-amyloid pathology) and inhibited Cyp46a1 expression in the hippocampus through the RNA interference methodology. In normal mice, Cyp46a1 inhibition caused a 2- to 2.5-fold cholesterol content increase in hippocampal neurons and a 1.3-fold increase in hippocampal-isolated lipid rafts. In addition, 24S-hydroxycholesterol content was decreased by approximately 50% in the hippocampus (Djelti et al. 2015). Also, Cyp46a1 downregulation and the consequent accumulation of cholesterol led to hippocampal neuronal death by apoptosis, which promoted cognitive deficits and hippocampal atrophy. Cholesterol accumulation also enhanced recruitment of APP to the lipid rafts and triggered the production of amyloid-β peptides. The observed effects were substantially higher in the APP transgenic mice model (Djelti et al. 2015). Altogether, these results highlight the potential therapeutic value of CYP46A1 for AD.