N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E(2) to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice.
N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E(2) to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice.
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DOI：
10.1002/ana.25356
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发表时间：
2018-12
影响因子：
11.2
通讯作者：
Ratan RR
中科院分区：
文献类型：
--
作者：
Karuppagounder SS;Alin L;Chen Y;Brand D;Bourassa MW;Dietrich K;Wilkinson CM;Nadeau CA;Kumar A;Perry S;Pinto JT;Darley-Usmar V;Sanchez S;Milne GL;Pratico D;Holman TR;Carmichael ST;Coppola G;Colbourne F;Ratan RR
N-乙酰半胱氨酸（NAC）是一种临床批准的含巯基氧化还原调节化合物，目前正用于许多神经和精神疾病的试验。虽然一般被标记为“抗氧化剂”，但对其作用部位的理解不足是其在神经学实践中使用的障碍。在这里，我们检查了NAC在啮齿动物出血性中风模型中的功效和作用机制。氯化血红素用于在培养的神经元中建立铁下垂和出血性中风的模型。采用胶原酶纹状体灌注法建立小鼠和大鼠脑出血模型。化学生物学、靶向脂质组学、花生四烯酸5-脂氧合酶（ALOX 5）敲除小鼠和病毒基因转移用于深入了解NAC的药理学靶点和作用机制。NAC通过中和花生四烯酸依赖性ALOX 5活性产生的毒性脂质来预防氯化血红素诱导的铁凋亡。NAC的疗效需要增加谷胱甘肽，并与谷胱甘肽依赖性酶（如谷胱甘肽S-转移酶）抑制反应性脂质相关。因此，其保护作用被化学或分子脂质过氧化抑制剂模仿。损伤后递送的NAC减少了小鼠脑出血后至少7天的神经元死亡并改善了功能恢复，并且可以与临床批准的前列腺素E2（PGE 2）协同作用。NAC是一种很有前途的ICH保护性治疗方法，其作用是抑制核ALOX 5的毒性花生四烯酸产物，该产物在体外和体内与外源性递送的保护性PGE 2协同作用。这些发现为NAC的靶点提供了新的见解，超越了作为抗氧化剂的一般特征，导致神经保护，并提供了一种可行的组合策略，以优化NAC治疗涉及铁凋亡的神经系统疾病（如ICH）的疗效和安全性。神经学年鉴2018;84：854-872
N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5‐lipoxygenase (ALOX5) knockout mice, and viral‐gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC. NAC prevented hemin‐induced ferroptosis by neutralizing toxic lipids generated by arachidonate‐dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione‐dependent enzymes such as glutathione S‐transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E2 (PGE2). NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854–872
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影响因子：
3.7
作者：
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通讯作者：
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脑部出血疏散（Mistie）中微创手术加上高度的安全性和功效：一项随机，控制，开放标签，第2期试验。
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Hanley, Daniel F.;Thompson, Richard E.;Muschelli, John;Rosenblum, Michael;McBee, Nichol;Lane, Karen;Bistran-Hall, Amanda J.;Mayo, Steven W.;Keyl, Penelope;Gandhi, Dheeraj;Morgan, Tim C.;Ullman, Natalie;Mould, W. Andrew;Carhuapoma, J. Ricardo;Kase, Carlos;Ziai, Wendy;Thompson, Carol B.;Yenokyan, Gayane;Huang, Emily;Broaddus, William C.;Graham, R. Scott;Aldrich, E. Francois;Dodd, Robert;Wijman, Cristanne;Caron, Jean-Louis;Huang, Judy;Camarata, Paul;Mendelow, A. David;Gregson, Barbara;Janis, Scott;Vespa, Paul;Martin, Neil;Awad, Issam;Zuccarello, Mario
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Zuccarello, Mario
影响因子：
17.1
作者：
Karuppagounder SS;Alim I;Khim SJ;Bourassa MW;Sleiman SF;John R;Thinnes CC;Yeh TL;Demetriades M;Neitemeier S;Cruz D;Gazaryan I;Killilea DW;Morgenstern L;Xi G;Keep RF;Schallert T;Tappero RV;Zhong J;Cho S;Maxfield FR;Holman TR;Culmsee C;Fong GH;Su Y;Ming GL;Song H;Cave JW;Schofield CJ;Colbourne F;Coppola G;Ratan RR
通讯作者：
Ratan RR