Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders - Specificity vs. toxicity.
Morota, Saori LU ; Månsson, Roland LU ; Hansson, Magnus LU
; Kasuya, Kazuhiko
; Shimazu, Motohide
; Hasegawa, Erika
; Yanagi, Shigeru
; Omi, Akibumi
; Uchino, Hiroyuki
and Elmer, Eskil
LU
(2009)
In Experimental Neurology
218.
p.353-362
- Abstract
- Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation,... (More)
- Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation, can also occur independently of the mPT phenomenon. Here, in isolated rodent brain-derived and human liver mitochondria, we re-evaluate drugs promoted as potent mPT inhibitors. We address the definition of an mPT inhibitor and present strategies to reliably detect mPT inhibition in vitro. Surprisingly, none of the 12 compounds tested displayed convincing mPT inhibition or effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla(3)-EtVal(4)-Cyclosporin (Debio 025). Propofol and 2-aminoethoxydiphenyl borate (2-APB) inhibited swelling in de-energized mitochondria but did not increase calcium retention capacity (CRC). Progesterone, trifluoperazine, allopregnanolone and 4-hydroxy-tamoxifen dose-dependently reduced CRC and respiratory control and were thus toxic rather than beneficial to mitochondrial function. Interestingly, topiramate increased CRC at high concentrations likely by a mechanism separate from direct mPT inhibition. We conclude that a clinically relevant mPT inhibitor should have a mitochondrial target and increase mitochondrial calcium retention at concentrations which can be translated to human use. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1392390
- author
- Morota, Saori
LU
; Månsson, Roland
LU
; Hansson, Magnus
LU
; Kasuya, Kazuhiko
; Shimazu, Motohide
; Hasegawa, Erika
; Yanagi, Shigeru
; Omi, Akibumi
; Uchino, Hiroyuki
and Elmer, Eskil
LU
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Experimental Neurology
- volume
- 218
- pages
- 353 - 362
- publisher
- Elsevier
- external identifiers
-
- wos:000268117400022
- pmid:19348797
- scopus:67649771533
- pmid:19348797
- ISSN
- 0014-4886
- DOI
- 10.1016/j.expneurol.2009.03.036
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Laboratory for Experimental Brain Research (013041000)
- id
- 9f202a7c-f3ea-4342-899b-a21847976933 (old id 1392390)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/19348797?dopt=Abstract
- date added to LUP
- 2016-04-04 07:58:46
- date last changed
- 2024-01-12 03:20:46
@article{9f202a7c-f3ea-4342-899b-a21847976933,
abstract = {{Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation, can also occur independently of the mPT phenomenon. Here, in isolated rodent brain-derived and human liver mitochondria, we re-evaluate drugs promoted as potent mPT inhibitors. We address the definition of an mPT inhibitor and present strategies to reliably detect mPT inhibition in vitro. Surprisingly, none of the 12 compounds tested displayed convincing mPT inhibition or effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla(3)-EtVal(4)-Cyclosporin (Debio 025). Propofol and 2-aminoethoxydiphenyl borate (2-APB) inhibited swelling in de-energized mitochondria but did not increase calcium retention capacity (CRC). Progesterone, trifluoperazine, allopregnanolone and 4-hydroxy-tamoxifen dose-dependently reduced CRC and respiratory control and were thus toxic rather than beneficial to mitochondrial function. Interestingly, topiramate increased CRC at high concentrations likely by a mechanism separate from direct mPT inhibition. We conclude that a clinically relevant mPT inhibitor should have a mitochondrial target and increase mitochondrial calcium retention at concentrations which can be translated to human use.}},
author = {{Morota, Saori and Månsson, Roland and Hansson, Magnus and Kasuya, Kazuhiko and Shimazu, Motohide and Hasegawa, Erika and Yanagi, Shigeru and Omi, Akibumi and Uchino, Hiroyuki and Elmer, Eskil}},
issn = {{0014-4886}},
language = {{eng}},
pages = {{353--362}},
publisher = {{Elsevier}},
series = {{Experimental Neurology}},
title = {{Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders - Specificity vs. toxicity.}},
url = {{http://dx.doi.org/10.1016/j.expneurol.2009.03.036}},
doi = {{10.1016/j.expneurol.2009.03.036}},
volume = {{218}},
year = {{2009}},
}