دورية أكاديمية
أعرض في EDS

Cholestane-3β,5α,6β-Triol Inhibits Acid-Sensing Ion Channels and Reduces Acidosis-Mediated Ischemic Brain Injury.

التفاصيل البيبلوغرافية
العنوان: Cholestane-3β,5α,6β-Triol Inhibits Acid-Sensing Ion Channels and Reduces Acidosis-Mediated Ischemic Brain Injury.
المؤلفون: Sun H; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Yang T; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Simon R; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Xiong ZG; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Leng T; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA.
المصدر: Stroke [Stroke] 2024 Jun; Vol. 55 (6), pp. 1660-1671. Date of Electronic Publication: 2024 Apr 25.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0235266 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4628 (Electronic) Linking ISSN: 00392499 NLM ISO Abbreviation: Stroke Subsets: MEDLINE
أسماء مطبوعة: Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas : American Heart Association
مواضيع طبية MeSH: Acid Sensing Ion Channels*/metabolism , Acid Sensing Ion Channels*/genetics , Cricetulus* , Acidosis*/metabolism , Acidosis*/drug therapy , Mice, Knockout*, Animals ; Mice ; CHO Cells ; Brain Ischemia/metabolism ; Brain Ischemia/drug therapy ; Neurons/drug effects ; Neurons/metabolism ; Cricetinae ; Neuroprotective Agents/pharmacology ; Cholestanols/pharmacology ; Mice, Inbred C57BL ; Acid Sensing Ion Channel Blockers/pharmacology ; Male ; Cells, Cultured
مستخلص: Background: Activation of the acid-sensing ion channels (ASICs) by tissue acidosis, a common feature of brain ischemia, contributes to ischemic brain injury, while blockade of ASICs results in protection. Cholestane-3β,5α,6β-triol (Triol), a major cholesterol metabolite, has been demonstrated as an endogenous neuroprotectant; however, the mechanism underlying its neuroprotective activity remains elusive. In this study, we tested the hypothesis that inhibition of ASICs is a potential mechanism.
Methods: The whole-cell patch-clamp technique was used to examine the effect of Triol on ASICs heterogeneously expressed in Chinese hamster ovary cells and ASICs endogenously expressed in primary cultured mouse cortical neurons. Acid-induced injury of cultured mouse cortical neurons and middle cerebral artery occlusion-induced ischemic brain injury in wild-type and ASIC1 and ASIC2 knockout mice were studied to examine the protective effect of Triol.
Results: Triol inhibits ASICs in a subunit-dependent manner. In Chinese hamster ovary cells, it inhibits homomeric ASIC1a and ASIC3 without affecting ASIC1β and ASIC2a. In cultured mouse cortical neurons, it inhibits homomeric ASIC1a and heteromeric ASIC1a-containing channels. The inhibition is use-dependent but voltage- and pH-independent. Structure-activity relationship analysis suggests that hydroxyls at the 5 and 6 positions of the A/B ring are critical functional groups. Triol alleviates acidosis-mediated injury of cultured mouse cortical neurons and protects against middle cerebral artery occlusion-induced brain injury in an ASIC1a-dependent manner.
Conclusions: Our study identifies Triol as a novel ASIC inhibitor, which may serve as a new pharmacological tool for studying ASICs and may also be developed as a potential drug for treating stroke.
Competing Interests: Disclosures Dr Leng discloses the pending patent No. 63/381 970.
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معلومات مُعتمدة: R01 NS104349 United States NS NINDS NIH HHS; R01 NS128018 United States NS NINDS NIH HHS; SC3 GM122593 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: acid-sensing ion channels; epithelial sodium channels; ischemia; neuroprotective agents; stroke
المشرفين على المادة: 0 (Acid Sensing Ion Channels)
115510-05-9 (cholestane-3,5,6-triol)
0 (Neuroprotective Agents)
0 (Cholestanols)
0 (Acid Sensing Ion Channel Blockers)
تواريخ الأحداث: Date Created: 20240425 Date Completed: 20240524 Latest Revision: 20240526
رمز التحديث: 20240526
مُعرف محوري في PubMed: PMC11126354
DOI: 10.1161/STROKEAHA.124.046963
PMID: 38660789
قاعدة البيانات: MEDLINE
الوصف
تدمد:1524-4628
DOI:10.1161/STROKEAHA.124.046963