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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).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Mutations of CYP46A1 are associated with Alzheimer’s disease. A T-C polymorphism located 151 bases 5′ to exon 3, CYP46AJ*TT, is associated with increased risk of Alzheimer’s disease (Papassotiropoulos et al. 2003). Neuropathologic examination of the patients and controls have shown that brain β-amyloid load and the levels of soluble β-amyloid-42 and phosphorylated tau in cerebrospinal fluid are significantly higher in subjects with the CYP46AJ*TT genotype. It is unknown why CYP46A1 polymorphisms can affect the development of Alzheimer’s disease. It is speculated that functional change of cholesterol 24-hydroxylase may alter cholesterol concentrations in vulnerable neurons, thereby affecting amyloid precursor protein processing and β-amyloid production. In Cyp46a1 knockout mice, hepatic cholesterol and bile acid metabolism remain unchanged compared to wild-type controls, but synthesis of new cholesterol in the brain is reduced by approximately 40%, despite steady-state levels of cholesterol being similar in the knockout mice (Lund et al. 2003).
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Analysis of protein and RNA has demonstrated that cholesterol 24-hydroxylase is expressed predominantly in the brain. In the brain, 24-hydroxylase is expressed in neurons in several regions. The concentrations of 24S-hydroxycholesterol in serum are low in newborn mice, reach a peak between postnatal days 12 and 15, and thereafter decline to baseline levels, whereas the 24-hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate with age. 1.2.4.7.2 26α-Hydroxylase
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.
An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia
Published in Expert Review of Neurotherapeutics, 2021
Siddhartha Dutta, Sayeeda Rahman, Rahnuma Ahmad, Tarun Kumar, Gitashree Dutta, Sudeshna Banerjee, Abdullahi Rabiu Abubakar, Adekunle Babajide Rowaiye, Sameer Dhingra, Velayutham Ravichandiran, Santosh Kumar, Paras Sharma, Mainul Haque, Jaykaran Charan
The liver, not the neurons or the glial cells, is responsible for breaking the brain’s cholesterol. Therefore, it needs to be transported to the periphery for cholesterol clearance, and the presence of BBB intercepts the free passage of cholesterol into the systemic circulation [51]. However, reports show that a minute quantity of cholesterol enters the peripheral circulation each day through the CSF via an APOE-dependent mechanism [51,59]. The excess cholesterol in the brain has several other elimination pathways. The principal route by which the brain eliminates the excess cholesterol through the BBB into the circulation and maintains homeostasis is by forming 24S-OH, synonymously known as cerebrosterol [42,43,60]. Cholesterol 24-hydroxylase converts cholesterol into 24S-OH, making it lipophilic to cross the BBB freely [42,43,61]. It is postulated that approximately 90% of circulating 24S-OH is acquired from the brain. Hence, the blood concentrations of 24S-OH indirectly represent the CNS turnover of cholesterol [44,45,62].
Epilepsy: key experimental therapeutics in early clinical development
Published in Expert Opinion on Investigational Drugs, 2020
Claude Steriade, Jacqueline French, Orrin Devinsky
Cholesterol 24-hydroxylase (CH24 H) metabolizes cholesterol to its end product, 24-hydroxycholesterol (24-HC), which is an endogenous positive allosteric modulator of NMDA receptors. CH24 H inhibition could reduce glutamatergic excitation. TAK-935 was developed as a specific CH24 H inhibitor and has anticonvulsant activity in animal seizure models, including a SCN1A mutation Dravet syndrome mouse model [14].