Cargando…

Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology

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 in...

Descripción completa

Detalles Bibliográficos
Autores principales: Stavrovskaya, Irina G., Narayanan, Malini V., Zhang, Wenhua, Krasnikov, Boris F., Heemskerk, Jill, Young, S. Stanley, Blass, John P., Brown, Abraham M., Beal, M. Flint, Friedlander, Robert M., Kristal, Bruce S.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212009/
https://www.ncbi.nlm.nih.gov/pubmed/15263028
http://dx.doi.org/10.1084/jem.20032053
_version_ 1782148602950320128
author Stavrovskaya, Irina G.
Narayanan, Malini V.
Zhang, Wenhua
Krasnikov, Boris F.
Heemskerk, Jill
Young, S. Stanley
Blass, John P.
Brown, Abraham M.
Beal, M. Flint
Friedlander, Robert M.
Kristal, Bruce S.
author_facet Stavrovskaya, Irina G.
Narayanan, Malini V.
Zhang, Wenhua
Krasnikov, Boris F.
Heemskerk, Jill
Young, S. Stanley
Blass, John P.
Brown, Abraham M.
Beal, M. Flint
Friedlander, Robert M.
Kristal, Bruce S.
author_sort Stavrovskaya, Irina G.
collection PubMed
description 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.
format Text
id pubmed-2212009
institution National Center for Biotechnology Information
language English
publishDate 2004
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-22120092008-03-11 Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology Stavrovskaya, Irina G. Narayanan, Malini V. Zhang, Wenhua Krasnikov, Boris F. Heemskerk, Jill Young, S. Stanley Blass, John P. Brown, Abraham M. Beal, M. Flint Friedlander, Robert M. Kristal, Bruce S. J Exp Med Article 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. The Rockefeller University Press 2004-07-19 /pmc/articles/PMC2212009/ /pubmed/15263028 http://dx.doi.org/10.1084/jem.20032053 Text en Copyright © 2004, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Stavrovskaya, Irina G.
Narayanan, Malini V.
Zhang, Wenhua
Krasnikov, Boris F.
Heemskerk, Jill
Young, S. Stanley
Blass, John P.
Brown, Abraham M.
Beal, M. Flint
Friedlander, Robert M.
Kristal, Bruce S.
Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title_full Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title_fullStr Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title_full_unstemmed Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title_short Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
title_sort clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212009/
https://www.ncbi.nlm.nih.gov/pubmed/15263028
http://dx.doi.org/10.1084/jem.20032053
work_keys_str_mv AT stavrovskayairinag clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT narayananmaliniv clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT zhangwenhua clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT krasnikovborisf clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT heemskerkjill clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT youngsstanley clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT blassjohnp clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT brownabrahamm clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT bealmflint clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT friedlanderrobertm clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology
AT kristalbruces clinicallyapprovedheterocyclicsactonamitochondrialtargetandreducestrokeinducedpathology