Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
نویسندگان
چکیده
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.
منابع مشابه
A Mitochondrial Disorder in a Middle Age Iranian Patient: Report of a Rare Case
Introduction: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) can involve multiple systems and cause stroke-like episodes and status epilepticus. Case Presentation: A 48-year-old female with history of early fatigability, migraine-type headaches, and bilateral sensory-neural hearing loss presented 3 episodes of serial seizures. On admission she was affected by W...
متن کاملHistochemical And Electron Microscopic Diagnosis Of Mitochondrial Myopathy: The First Case Report From Iran
Muscle tissue, skeletal muscle as well as cardiac muscle, is commonly affected in mitochondrial disorders. One explanation for this observation is that muscle tissue has a high-energy demand and therefore is more sensitive to a deficiency of mitochondrial energy production than some other tissues. In mitochondrial disorders, skeletal muscle tissue may be affected primarily by defective respi...
متن کاملEvaluation of Cardiac Mitochondrial Function by a Nuclear Imaging Technique using Technetium-99m-MIBI Uptake Kinetics
Mitochondria play an important role in energy production for the cell. The proper function of a myocardial cell largely depends on the functional capacity of the mitochondria. Therefore it is necessary to establish a novel and reliable method for a non-invasive assessment of mitochondrial function and metabolism in humans. Although originally designed for evaluating myocardial perfusion, 99mTc...
متن کاملA journey in doxorubicin-induced cardiotoxicity with emphasizing on the role of Connexin 43 and Sirtuin-3
Cancer has become a major health problem worldwide. The reported incidence of new cancer cases is estimated at 19.3 million, with a mortality rate of 10 million in the world in 2020. There are some approaches for cancer treatment such as chemotherapy, neoadjuant surgery, hormone therapy, and radiotherapy. Chemotherapy is an aggressive form of chemical drug therapy meant to destroy rapidly growi...
متن کاملEffects of quercetin on bisphenol A-induced mitochondrial toxicity in rat liver
Objective(s): Recognized as a distinguished environmental and global toxicant, Bisphenol A (BPA) affects the liver, which is a vital body organ, by the induction of oxidative stress. The present study was designed to investigate the protective effect of quercetin against BPA in hepatotoxicity in Wistar rats and also, the activity of mitochondrial enzymes were evaluated...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The Journal of Experimental Medicine
دوره 200 شماره
صفحات -
تاریخ انتشار 2004