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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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Effects of docosahexaenoic acid or arachidonic acid supplementation on the behavior of cardiomyocytes derived from human pluripotent stem cells

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BIOCELL 2023年第5期47卷 1095-1106页

作者： MIZUNA YANO kota HIROI TETSUYA YUASA KENJI INOUE OSAMU YAMAMOTO TAKAO NAKAMURA DAISUKE sato ZHONGGANG FENG Graduate School of Science and Engineering Yamagata UniversityYonezawa9928510Japan Faculty of Health Sciences Japan Healthcare UniversitySapporo0620053Japan

Background:Human heart changes its energetic substrates from lactate and glucose to fatty acids during the neonatal *** the lack of fatty acids in media for the culture of cardiomyocytes derived from human pluripotent stem cells(hiPS-CM),researchers have supplemented mixtures of fatty acids to hiPS-CM and reported the enhancement in the maturation of *** our previous studies,we separately supplemented two polyunsaturated fatty acids(PUFAs),docosahexaenoic acid(DHA)or arachidonic acid(AA),to rat fetal cardiomyocytes and found that the supplementations upregulated the expressions of mRNAs for cardiomyocyte differentiation,fatty acid metabolism,and cellular *** enhancement in cellular contractility was attributed to the improvement in intercellular connection rather than a direct enhancement of the contractile ***:This study reports the successive results of the effects of DHA or AA supplementation on *** addition to the contractile force and mRNA measurements used in the previous study,we further investigated the effect of different cellular aggregations on the contractile force output by means of finite element analysis,measured glucose and fatty acids metabolites,and assessed cTNT and MLC2v expressions through immunofluorecsence ***:It showed that the sole supplementation of albumin-conjugated DHA or AA can be taken up by hiPS-CM without other uptake-enhancing factors,and the supplementations may activate the CD36_ERRγmetabolic *** or AA supplementation increased the cellular contractile ratio on collagen gels and AA supplementation stimulated hiPS-CM aggregation to form cellular *** enhancement effect on the hiPS-CM contractile force was modest since the increase in contractile force was not *** supplementation was more effective than DHA supplementation because it significantly upregulated mRNA expressions of P300 and ***,finite element analysis showed that the formati

关键词： Human iPS cells Cardiomyocytes Polyunsaturated fatty acid mRNA expression Contractility Fatty acid metabolism

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