Drug library screen identifies inhibitors of toxic astrogliosis.
Drug library screen identifies inhibitors of toxic astrogliosis.
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DOI：
10.1016/j.msard.2022.103499
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发表时间：
2022-03
影响因子：
4
通讯作者：
Bielekova B
中科院分区：
文献类型：
--
作者：
Masvekar R;Kosa P;Barbour C;Milstein JL;Bielekova B
多发性硬化（MS）是一种慢性神经炎性疾病，其中活化的免疫细胞直接或间接地诱导脱髓鞘和轴突降解。炎症刺激也会改变星形胶质细胞的表型，使其具有神经毒性。在神经炎症动物模型和MS病变中观察到了由此产生的“毒性星形胶质细胞”表型。由毒性星形胶质细胞分泌的蛋白质在MS患者的脑脊液（CSF）中升高，并且可再现地与神经功能障碍和脑萎缩的累积率相关。这表明神经毒性星形胶质细胞在MS中的致病作用。在这里，我们将市售的食品和药物管理局批准的或临床开发中的小分子文库应用于毒性星形胶质细胞增生的体外模型，以鉴定抑制星形胶质细胞向神经毒性表型的炎性转化的药物和信号通路。与内质网应激相关的三种途径的抑制剂：1）蛋白酶体，2）热休克蛋白90和3）雷帕霉素的哺乳动物靶标可重复地降低炎症诱导的星形胶质细胞向毒性表型的转化。丹曲林是一种抑制钙通过中枢神经系统细胞内质网中表达的兰尼碱受体释放的抗痉挛药物，在体内可达到的浓度下也发挥了抑制作用。最后，我们在临床试验中将CSF SERPINA3确定为抑制毒性星形胶质细胞的相关药效学标志物。药物库筛选为毒性星形胶质细胞的产生提供了机制上的见解，并为立即进行的原理验证临床试验确定了候选药物。
Multiple sclerosis (MS) is a chronic neuroinflammatory disorder, in which activated immune cells directly or indirectly induce demyelination and axonal degradation. Inflammatory stimuli also change the phenotype of astrocytes, making them neurotoxic. The resulting ‘toxic astrocyte’ phenotype has been observed in animal models of neuroinflammation and in MS lesions. Proteins secreted by toxic astrocytes are elevated in the cerebrospinal fluid (CSF) of MS patients and reproducibly correlate with the rates of accumulation of neurological disability and brain atrophy. This suggests a pathogenic role for neurotoxic astrocytes in MS. Here, we applied a commercially available library of small molecules that are either Food and Drug Administration-approved or in clinical development to an in vitro model of toxic astrogliosis to identify drugs and signaling pathways that inhibit inflammatory transformation of astrocytes to a neurotoxic phenotype. Inhibitors of three pathways related to the endoplasmic reticulum stress: 1) proteasome, 2) heat shock protein 90 and 3) mammalian target of rapamycin reproducibly decreased inflammation-induced conversion of astrocytes to toxic phenotype. Dantrolene, an anti-spasticity drug that inhibits calcium release through ryanodine receptors expressed in the endoplasmic reticulum of central nervous system cells, also exerted inhibitory effect at in vivo achievable concentrations. Finally, we established CSF SERPINA3 as a relevant pharmacodynamic marker for inhibiting toxic astrocytes in clinical trials. Drug library screening provides mechanistic insight into the generation of toxic astrocytes and identifies candidates for immediate proof-of-principle clinical trial(s).
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影响因子：
3.7
作者：
Gold L;Ayers D;Bertino J;Bock C;Bock A;Brody EN;Carter J;Dalby AB;Eaton BE;Fitzwater T;Flather D;Forbes A;Foreman T;Fowler C;Gawande B;Goss M;Gunn M;Gupta S;Halladay D;Heil J;Heilig J;Hicke B;Husar G;Janjic N;Jarvis T;Jennings S;Katilius E;Keeney TR;Kim N;Koch TH;Kraemer S;Kroiss L;Le N;Levine D;Lindsey W;Lollo B;Mayfield W;Mehan M;Mehler R;Nelson SK;Nelson M;Nieuwlandt D;Nikrad M;Ochsner U;Ostroff RM;Otis M;Parker T;Pietrasiewicz S;Resnicow DI;Rohloff J;Sanders G;Sattin S;Schneider D;Singer B;Stanton M;Sterkel A;Stewart A;Stratford S;Vaught JD;Vrkljan M;Walker JJ;Watrobka M;Waugh S;Weiss A;Wilcox SK;Wolfson A;Wolk SK;Zhang C;Zichi D
通讯作者：
Zichi D
影响因子：
11.2
作者：
Barbour, Christopher;Kosa, Peter;Bielekova, Bibiana
通讯作者：
Bielekova, Bibiana
脑脊液标记物显示出进行性多发性硬化症的鞘内炎症。
影响因子：
11.2
作者：
Komori M;Blake A;Greenwood M;Lin YC;Kosa P;Ghazali D;Winokur P;Natrajan M;Wuest SC;Romm E;Panackal AA;Williamson PR;Wu T;Bielekova B
通讯作者：
Bielekova B
冠状动脉疾病患者的单核细胞促炎症反应需要 mTOR 的激活。
影响因子：
6
作者：
Gao, Shanshan;Liu, Weimin;Wu, Yue
通讯作者：
Wu, Yue
影响因子：
7.3
作者：
Kirk, J;Plumb, J;McQuaid, S
通讯作者：
McQuaid, S