更新于：2024-09-19

ASIC3

更新于：2024-09-19

基本信息

别名

ACCN3、acid sensing ion channel subunit 3、acid-sensing (proton-gated) ion channel 3

+ [11]

简介

Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Generates a biphasic current with a fast inactivating and a slow sustained phase. In sensory neurons is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissue. May be involved in hyperalgesia. May play a role in mechanoreception. Heteromeric channel assembly seems to modulate channel properties.

关联

项与 ASIC3 相关的药物

A-317567

靶点

ASIC3

作用机制

ASIC3 modulators

在研机构

Abbott Laboratories

原研机构

Abbott Laboratories

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

THA-902 XL

靶点

ASIC3

作用机制

ASIC3 inhibitors

在研机构-

原研机构

Theralpha S.A.S.

在研适应症-

非在研适应症

疼痛

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

TH-902

靶点

ASIC3 x Nav1.8

作用机制

ASIC3 inhibitors [+1]

在研机构-

原研机构

Theralpha S.A.S.

在研适应症-

非在研适应症

纤维肌痛 [+2]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ASIC3 相关的临床结果

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100 项与 ASIC3 相关的转化医学

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0 项与 ASIC3 相关的专利（医药）

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549

项与 ASIC3 相关的文献（医药）

2024-08-01·European Journal of Pharmacology

Fenofibrate ameliorates nitroglycerin-induced migraine in rats: Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways

Article

作者: Sallam, Nada A ; Ruby, Hassan A ; Kenway, Sanaa A ; Khattab, Mohamed A ; Sayed, Rabab H

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.

2024-06-01·The Kaohsiung Journal of Medical Sciences

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats

Article

作者: Zhou, Hong-Yun ; Deng, Yuan ; Zhan, Yu ; Zhang, Zi-Qi ; Zhao, Qiong

AbstractSlow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate‐induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme‐linked immunosorbent assay, quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism‐related proteins, and acid‐sensitive ion channel 3/extracellular signal‐regulated kinase (ASIC3/ERK) pathway‐related molecules. PF treatment not only attenuated compound diphenoxylate‐induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5‐hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.

2024-06-01·Stroke

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

Article

作者: Xiong, Zhi-Gang ; Leng, Tiandong ; Yang, Tao ; Sun, Huawei ; Simon, Roger

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.

项与 ASIC3 相关的新闻（医药）

2024-04-30

·CPHI制药在线

青藤碱镇痛作用机制研究进展

关注并星标CPHI制药在线青藤碱是一种从防几科植物青风藤的根和茎中提取分离出的生物碱，结构上属于吗啡烷类。青藤碱在中西医临床上应用广泛，中医认为，青风藤有祛风止痛、通络活血的作用，常用水煎剂治疗疼痛和风湿及类风湿性关节炎。西医则通过青风藤的提取物青藤碱来发挥作用，临床上主要用于治疗风湿病及神经痛等，代表药有正清风痛宁缓释片。青藤碱镇痛效果显著、应用广泛、不良反应少、无成瘾性等优点，具备成为能够广泛应用于临床疼痛治疗中新镇痛药物的潜力。青藤碱对于多种类型的疼痛均可发挥镇痛作用，如炎性疼痛、神经病理性疼痛、伤害刺激性疼痛等。目前研究报道主要认为青藤碱可以通过调控p38丝裂原活化蛋白激酶(p38MAPK)、钙/钙调素依赖性蛋白激酶Ⅱ(Ca/ CaMKII)、环磷酸腺苷(cAMP)-蛋白激酶A(PKA)、Janus激酶2/信号传导与转录激活因子3(JAK2/ STAT3)等信号通路来减少致痛因子的释放，降低神经元的兴奋性，阻碍疼痛信号的传递，进而发挥其镇痛作用。另外，也有报道指出，青藤碱可以通过激活γ-氨基丁酸A型(GABAA)受体，降低谷氨酸水平等方式抑制伤害性信息的传递。以及通过调控参与疼痛信号传递的离子通道，抑制痛觉传导途径达到降低疼痛的目的。 ①基于p38MAPK 信号通路的镇痛机制 p38丝裂原活化蛋白激酶 (p38MAPK)是一类保守的丝氨酸-苏氨酸蛋白激酶，参与细胞生长、细胞凋亡、炎症反应等多种生理和病理过程，同时也参与病理性疼痛的外周敏化及中枢敏化。青藤碱可通过抑制p38MAPK 的激活阻断痛觉传导通路，从而提高疼痛阈值。研究发现，给完全弗氏佐剂诱导的炎性疼痛大鼠鞘内注射p38MAPK的特异性阻断剂可抑制外周敏化，使大鼠的热痛阈明显提高，但对炎症反应无影响，说明p38MAPK在疼痛信号传递中发挥重要作用。另有研究发现，p38MAPK可激活磷脂酶A2，促进花生四烯酸的生成，诱导前列腺素(prostaglandin，PG) 的合成，进一步加重疼痛。而青藤碱可通过抑制p38MAPK 的表达，并且抑制促炎因子的释放，既可以缓解疼痛也可以减轻炎症反应。对胶原诱导的关节炎大鼠模型采用青藤碱联合针刺治疗，观察到大鼠血清及滑膜中TNF-α、IL-6、IL-1β和IL-8 水平及COX-2和诱导型一氧化氮合酶 ( iNOS) 蛋白表达均降低，p38MAPK 蛋白表达也受到抑制。青藤碱能抑制小胶质细胞中 p38MAPK 磷酸化，并降低活化小胶质细胞中TNF-α、IL-1β、iNOS 及 ROS 的水平，阻碍胶质细胞活化诱导的疼痛发生。另外，神经损伤后，机体释放大量的 ATP，可激活嘌呤能受体 P2X3，使Ca2+的通透性显著增加，参与疼痛的形成和维持，而青藤碱可减少背根神经节中嘌呤能受体 P2X3 白和在 mRNA 的表达水平，从而抑制 p38MAPK 的磷酸化和激活，进而缓解疼痛。 ②基于Ca/ CaMKII 信号通路的镇痛机制青藤碱可降低细胞内Ca2 +水平，抑制p-CaMKII/ CaMKII的表达，抑制c-fos和COX-2的转录活性，即青藤碱可以通过阻碍CaMKII/ CREB信号途径来减轻疼痛。在炎性疼痛中，青藤碱既可以通过抑制脊髓和背根神经节组织中CaMK2α的表达来抑制CaMKII 的激活，又可以通过抑制 CaMKII 的磷酸化增加去甲肾上腺素5-羟色胺(具有镇痛作用的神经递质)的表达水平产生强效的镇痛作用。研究证实，青藤碱的抗吗啡依赖作用与CaMKII/ CREB 途径有关，青藤碱可降低cAMP和细胞内Ca2+水平，从而抑制CaMKII和CREB的激活，减轻疼痛。青藤碱还可显著下调背根神经节细胞和神经性疼痛大鼠脊髓组织中磷酸化p38 MAPK、CREB、c-fos、磷酸化CaMKII、COX-2、IL-1β和IL-17α 的体内和体外表达水平，减轻背根神经节炎症以抑制神经痛。表明青藤碱可以通过降低细胞内Ca2+的水平、抑制CaMKII 的活化、抑制CREB 磷酸化等来调控Ca/CaMKII 信号通路，对神经病理性疼痛产生镇痛作用。 ③基于JAK2 / STAT3信号通路的镇痛机制非受体型酪氨酸激酶2/信号转导和转录激活因子3(JAK2 / STAT3)信号通路是由细胞因子刺激的信号转导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程，也是慢性疼痛中重要的信号转导途径之一。神经损伤后，炎性介质的释放诱发神经炎症反应，炎症因子(如 IL-6 等) 可以激活JAK2激酶，激活的JAK2磷酸化STAT3，STAT3 活化后形成二聚体，进入核内与相应的靶基因启动子结合，参与调节炎症因子基因的转录，作用于神经元的 N-甲基-D-天冬氨酸受体，引起中枢敏化。在神经病理性疼痛大鼠脊髓背角中p-JAK2 和p-STAT3 的表达水平均升高，小胶质细胞中p-STAT3 水平升高。而JAK2的抑制剂AG490可下调体内外p-JAK2和p-STAT3，缓解疼痛。研究发现，青藤碱腹腔注射可抑制癌性骨痛大鼠小胶质细胞的激活，下调脊髓背角JAK2及STAT3的表达，进而减轻癌症诱导的骨痛。在缺血性脑卒中的小鼠模型中，青藤碱可通过抑制星形胶质细胞中STAT3的激活及促炎因子的产生减轻神经炎症损伤。另有研究表明，青藤碱可通过抑制炎症反应，抑制 IL-6 / JAK2 / STAT3 级联反应来降低 Bcl-2 的表达，从而减缓浆细胞乳腺炎的发生发展。因此青藤碱可能通过抑制JAK2/STST3通路的激活，发挥其镇痛作用。 ④基于其他信号的镇痛机理研究表明cAMP-PKA 信号通路的异常激活可能与疼痛有关，而既往研究也证实青藤碱可呈剂量依赖性降低吗啡精神依赖小鼠大脑皮质中cAMP含量。不过，青藤碱具体如何通过调控 cAMP-PKA信号通路来发挥镇痛作用的机制尚不明晰，仍需进一步研究。研究发现，抑制哺乳动物雷帕霉素靶蛋白(mTOR) 信号转导，可降低 α-痛觉感受器的反应，从而缓解神经性疼痛。而青藤碱可下调完全弗氏佐剂诱导的炎性疼痛小鼠前扣带回皮层中磷酸化哺乳动物雷帕霉素靶蛋白、磷酸化的4E 结合蛋白、磷酸化S6核糖体蛋白等的表达，表明青藤碱可能通过调节mTOR信号通路发挥镇痛作用。另有研究指出，对于大鼠慢性压迫性损伤所致的坐骨神经痛，青藤碱不仅可以减轻疼痛症状，还可减弱神经性疼痛大鼠的抑郁样症状。青藤碱的镇痛作用可被γ-氨基丁酸A(GABAA) 受体拮抗剂所阻断，表明青藤碱的镇痛作用可能与激动GABAA受体有关。当机体受到伤害性刺激时，在脊髓背角中，神经元释放过量谷氨酸，谷氨酸与突触后膜上的 N-甲基-D-天冬氨酸受体和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体结合，使疼痛传递神经元持续活化，增强中枢敏化，加剧疼痛。青藤碱可降低痛觉环路中兴奋性神经递质-谷氨酸的水平，阻止神经元放电，阻碍伤害性信息的传递，同时可减少 N-甲基-D-天冬氨酸受体和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的表达，共同抑制中枢敏化。此外，研究表明青藤碱可抑制参与痛觉神经元传递信号的电压门控钠通道(VGSCs)，抑制炎性疼痛小鼠脊髓中酸敏感离子通道 (ASICs) 的表达，从而抑制疼痛信号的传递，降低伤害性神经元的细胞兴奋性，产生镇痛作用，故 VGSCs 和ASIC3 也可能是青藤碱发挥镇痛作用的靶点。在研究盐酸青藤碱(SH)对偏头痛大鼠的行为、中脑PAG区NF-κB、环氧化酶-2( COX-2) 表达的干预以及PAG 区的5-HT 表达和镇痛之间关系中发现，SH可能通过抑制 PAG 区 NF-κB和 COX-2 诱导的神经源性炎症反应，上调 5-HT 活性而起到镇痛作用。参考资料 [1]阮珍，寇久社，王东，等.青藤碱镇痛机制的近年研究回顾[J].环球中医药，2021，14(12):2286-2291. [2]李修政，董家潇，许晓东.青藤碱抗炎镇痛作用及机制的研究新进展[J].河北医药，2020，42(20):3148-3153. [3]王玺,张智勇,仇萍,等.青风藤、青藤碱及其相关制剂的研究进展[J].中国药学杂志,2021,56(02):85-93. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。【智药研习社近期线下课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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