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Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina

Neural Regeneration Research 2023年第5期18卷 1004-1008页

作者： Yukitoshi Izumi Makoto Ishikawa Toru Nakazawa Hiroshi Kunikata Kota Sato Douglas F.Covey Charles F.Zorumski Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA Department of Ophthalmic Imaging and Information Analytics Tohoku University Graduate School of MedicineSendaiJapan Department of Ophthalmology Tohoku University Graduate School of MedicineSendaiJapan Department of Retinal Disease Control Tohoku University Graduate School of MedicineSendaiJapan Department of Advanced Ophthalmic Medicine Tohoku University Graduate School of MedicineSendaiJapan Department of Developmental Biology Washington University School of MedicineSt.LouisMOUSA

Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

关键词： allopregnanolone autophagy enantiomers excitotoxicity gamma-aminobutyric acid type A receptors glaucoma optic nerve oxysterols

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The Involvement of Lipids in Alzheimer's Disease

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Journal of Genetics and Genomics 2014年第5期41卷 261-274页

作者： Wei Ling Florence Lim Ian James Martins Ralph Nigel Martins School of Medical Sciences Edith Cowan University Centre of Excellence in Alzheimer's Disease Research and Care McCusker Foundation for Alzheimer's Disease Research Inc. Suite 22 Hollywood Medical Centre School of Psychiatry and Clinical Neurosciences The University of Western Australia

It has been estimated that Alzheimer＇s disease （AD）, the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the e4 variant of apolipoprotein E （APOE）. Evidence suggests that the ApoE protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review ApoE-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.

关键词： Alzheimer's disease Lipids ApoE oxysterols Inflammation

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New insights into the regulation of cholesterol eft from the sperm membrane

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Asian Journal of Andrology 2015年第4期17卷 561-567页

作者： Tamara Leahy Bart M Gadella Faculty of Veterinary Science University of Sydney 2006 Sydney Australia Department of Farm Animal Health and of Biochemistry and Cell Biology Faculty ofVeterinary Medicine Utrecht University Yalelaan 2 3584 CM Utrecht The Netherlands.

Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon＇s preparation for fertilization. Some factors that regulate these events are described （e.g., bicarbonate, calcium） but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings？ This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledlze, sl）erm handlin~ techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization.

关键词： ATP binding cassette transporters albumin high-density lipoprotein lipid rafts membrane fluidity membranemicrodomains membrane packing oxysterols reverse cholesterol transport sterol transporters

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The acidic pathway of bile acid synthesis: Not just an alternative pathway

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Liver Research 2019年第2期3卷 88-98页

作者： William M.Pandak Genta Kakiyama Department of Internal Medicine Virginia Commonwealth UniversityRichmondVAUSA Department of Veterans Affairs RichmondVAUSA

Over the last two decades,the prevalence of obesity,and metabolic syndromes(MS)such as nonalcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus(T2DM),have dramatically *** acids play a major role in the digestion,absorption of nutrients,and the body's redistribution of absorbed lipids as a function of their chemistry and signaling *** a result,a renewed interest has developed in the bile acid metabolic pathways with the challenge of gaining insight into novel treatment approaches for this rapidly growing healthcare *** the two major pathways of bile acid synthesis in the liver,the foremost role of the acidic(alternative)pathway is to generate and control the levels of regulatory oxysterols that help control cellular cholesterol and lipid *** transport to mitochondrial sterol 27-hydroxylase(CYP27A1)by steroidogenic acute regulatory protein(StarD1),and the subsequent 7a-hydroxylation of oxysterols by oxysterol 7a-hydroxylase(CYP7B1)are the key regulatory steps of the *** observations suggest CYP7B1 to be the ultimate controller of cellular oxysterol *** review discusses the acidic pathway and its contribution to lipid,cholesterol,carbohydrate,and energy ***,discussed is how the acidic pathway's dysregulation not only leads to a loss in its ability to control cellular cholesterol and lipid homeostasis,but leads to inflammatory conditions.

关键词： Bile acids Metabolic syndromes(MS) Cardiovascular disease(CVD) Inflammation Insulin resistance oxysterols

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Distribution of cholesterol 24-hydroxylase in the monkey brain

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Neuroscience Bulletin 2010年第3期26卷 197-204页

作者：和欣王维义华茜北京中医药大学基础医学院解剖学教研室北京100029 新加坡国立大学杨璐龄医学院解剖学系新加坡119260 北京中医药大学基础医学院科研实验中心北京100029

Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain *** present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey *** The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron *** High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and *** microscopy revealed that the enzyme was localized in the axon *** the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and *** The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.

关键词： axon cholesterol cholesterol 24-hydroxylase oxysterols

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Cytotoxicity of Cholesterol Oxides and the Consequences of Relative Molecular Similarity to cGMP Nucleotide

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Journal of Biosciences and Medicines 2023年第11期11卷 190-207页

作者： Wynford Robert Williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. Abnormal levels of cholesterol oxides and steroids in cancerous tissues promote interest in steroid receptor cross-talk during cell-signalling and the steroid metabolome of cancer patients. The research literature links the cytotoxic properties of oxysterols to interference with the NO/cGMP pathway. cGMP participates in cell-signalling and has a molecular structure that relates to cancer-inducing and cancer-preventing agents. This study uses a molecular modelling approach to compare the structures of cholesterol oxides to cGMP. Cholesterol and cholesterol oxide structures fit to a cGMP structural template in several ways, some of which are replicated by corticosteroids and gonadal steroid hormones. The results of this study support the concept that cholesterol oxides modulate cell apoptosis and autophagy via the NO/cGMP pathway and in conjunction with steroid hormones participate in modulating regulation of cell function by cGMP.

关键词： Cholesterol Oxides cGMP oxysterols Molecular Similarity Apoptosis Autophagy Cancer

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Oligomerized Amyloid-<i>β</i><sub>1-40</sub>Peptide Favors Cholesterol, Oxysterol, and Fatty Acid Accumulation in Human Neuronal SK-N-BE Cells

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International Journal of Clinical Medicine 2015年第11期6卷 813-824页

作者： Amira Zarrouk Thomas Nury Mohamed Hammami Gérard Lizard Laboratoire de Biochimie (LR12ES05)-Lab-NAFS “Nutrition Aliments Fonctionnels et Santé Vasculaire” Faculté de Médecine Université de Monastir Monastir Tunisie Equipe “Biochimie du Peroxysome Inflammation et Métabolisme Lipidique” (EA 7270) Université de Bourgogne-Franche Comté/INSERM Dijon France

Amyloid peptide, the main component of senile plaques, is a major biological characteristic of Alzheimer’s disease (AD). The aim of the present study conducted on human neuronal SK-N-BE cells was to evaluate whether oligomerized Aβ1-40-induced cell damages was associated with lipid modifications. Under treatment with Aβ1-40 (10 - 100 μM;24 - 48 h), cell viability was recorded with the MTT test and by measuring LDH activity. Mitochondrial transmembrane potential and ATP production were assessed using flow cytometry and a luciferase-based ATP bioluminescence assay, respectively. Annexin V-CF647 staining assay for cell apoptosis detection was performed using flow cytometry. Potentially intracellular cytotoxic lipids (oxysterols: 7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), and 7-ketocholesterol (7KC), 24(S)-hydroxycholesterol;arachidonic acid (C20:4 n-6);VLCFAs (C22:0, C24:0, C24:6 and C26:0)) were measured using gas chromatography coupled with mass spectrometry. The cellular level of docosahexaenoic acid (C22:6 n-3), often altered in AD, was also quantified. In the presence of Aβ1-40, the percentage of MTT-positive cells decreased and was associated with an increase in LDH activity. In addition, treatment with oligomerized Aβ1-40 induced a decrease of mitochondrial transmembrane potential as well as an apoptotic cell death. Sterol analysis revealed a higher cholesterol level and a significant increase of cytotoxic oxysterols per cell (7KC + 7β-OHC), and of the [(7β-OHC + 7KC)/cholesterol] ratio, considered as a lipid peroxidation index, in Aβ1-40-treated cells. An enhancement of C20:4 n-6, C22:6 n-3 and saturated VLCFAs was also observed. Therefore, Aβ1-40-induced side effects are associated with intracellular accumulation of lipids, especially cholesterol, oxysterols (7β-OHC, 7KC), C20:4 n-6, and saturated VLCFAs, which could in turn contribute to neurotoxicity.

关键词： SK-N-BE Cells Oligomerized Aβ1-40 Cholesterol oxysterols Very Long Chain Fatty Acids

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