Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.
Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.
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DOI：
10.1084/jem.20032053
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发表时间：
2004-07-19
期刊：
影响因子：
--
通讯作者：
Kristal BS
中科院分区：
文献类型：
--
作者：
Stavrovskaya IG;Narayanan MV;Zhang W;Krasnikov BF;Heemskerk J;Young SS;Blass JP;Brown AM;Beal MF;Friedlander RM;Kristal BS
大量证据表明，线粒体是导致神经元细胞死亡的几个途径中的一个主要检查点，但从下游后果中区分关键的繁殖阶段一直很困难。线粒体通透性转变（mPT）可能在卒中相关损伤中起关键作用。为了解决这一假设，确定潜在的治疗方法，并筛选已知毒性的既定药物的新用途，1,040种fda批准的药物和其他生物活性化合物被测试为潜在的mPT抑制剂。我们报告了28种结构相关药物的鉴定，包括三环抗抑郁药和抗精神病药，能够延缓mPT。临床上可达到的一种抑制mPT的药物，异丙嗪，在体外和小鼠中风模型中都具有保护作用。具体来说，异丙嗪可以保护缺氧-葡萄糖剥夺小鼠的原代神经元培养物，减少大脑中动脉闭塞/再灌注小鼠的梗死面积和神经功能损伤。这些结果，结合对旧研究的新见解，(a)提示了一类安全、耐受的中风和神经退行性疾病药物；(b)为理解线粒体在神经元细胞死亡中的作用提供新工具；(c)证明富含临床可用药物的生物活性化合物筛选集合的临床/实验价值；(d)提供基于发现的证据，证明mPT是卒中相关损伤的重要致病事件。
Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.
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影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
DOI：
10.1073/pnas.94.5.2007
发表时间：
1997-03-04
影响因子：
11.1
作者：
Hara, H;Friedlander, RM;Moskowitz, MA
通讯作者：
Moskowitz, MA
影响因子：
25
作者：
Heemskerk, J;Tobin, AJ;Ravina, B
通讯作者：
Ravina, B
影响因子：
5.3
作者：
Friberg, H;Ferrand-Drake, M;Wieloch, T
通讯作者：
Wieloch, T
影响因子：
11.2
作者：
Arvin, KL;Han, BH;Holtzman, DM
通讯作者：
Holtzman, DM