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Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline.

Månsson, Roland LU ; Hansson, Magnus LU ; Morota, Saori; Uchino, Hiroyuki; Ekdahl Clementson, Christine LU and Elmer, Eskil LU (2007) In Neurobiology of Disease 25. p.198-205
Abstract
Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further,... (More)
Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further, minocycline did not inhibit calcium- or tBid-induced cyt c release. We conclude that the neuroprotective mechanism of minocycline is likely not related to direct inhibition of mPT and propose that the mitochondrial effects of minocycline may contribute to toxicity rather than tissue protection at high dosing in animals and humans. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Neurobiology of Disease
volume
25
pages
198 - 205
publisher
Elsevier
external identifiers
  • wos:000242665200021
  • scopus:33751093803
ISSN
0969-9961
DOI
10.1016/j.nbd.2006.09.008
language
English
LU publication?
yes
id
c3d35e14-773b-4d7e-92eb-41bb7d163fd5 (old id 162110)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17067803&dopt=Abstract
date added to LUP
2007-07-16 12:14:26
date last changed
2017-05-28 03:35:22
@article{c3d35e14-773b-4d7e-92eb-41bb7d163fd5,
  abstract     = {Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further, minocycline did not inhibit calcium- or tBid-induced cyt c release. We conclude that the neuroprotective mechanism of minocycline is likely not related to direct inhibition of mPT and propose that the mitochondrial effects of minocycline may contribute to toxicity rather than tissue protection at high dosing in animals and humans.},
  author       = {Månsson, Roland and Hansson, Magnus and Morota, Saori and Uchino, Hiroyuki and Ekdahl Clementson, Christine and Elmer, Eskil},
  issn         = {0969-9961},
  language     = {eng},
  pages        = {198--205},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2006.09.008},
  volume       = {25},
  year         = {2007},
}