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

Autor:	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.
Jazyk:	angličtina
Zdroj:	Stroke [Stroke] 2024 Jun; Vol. 55 (6), pp. 1660-1671. Date of Electronic Publication: 2024 Apr 25.
DOI:	10.1161/STROKEAHA.124.046963
Abstrakt:	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.
Databáze:	MEDLINE
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