Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria.
Hansson, Magnus LU
; Persson, Tanja
; Friberg, Hans
LU
; Keep, Marcus F
; Rees, Anthony
; Wieloch, Tadeusz
LU
and Elmer, Eskil
LU
(2003)
In Brain Research
960(1-2).
p.99-111
- Abstract
- The mitochondrial permeability transition (mPT) is considered to be an important mediator of apoptosis and necrosis, and is specifically blocked by cyclosporin A (CsA). CsA has been shown to exert a potent neuroprotective action in vivo when allowed to cross the blood–brain barrier in various animal models of acute neurological insults and neurodegenerative disease. The neuroprotective effect of CsA is considered to be mediated through specific inhibition of the mitochondrial permeability transition pore (mPTP) and through inhibition of neuronal calcineurin activity. Characterization of mPT has mainly been performed in liver and heart mitochondria, and some brain studies have reported a decreased inhibitory effect of CsA and questioned the... (More)
- The mitochondrial permeability transition (mPT) is considered to be an important mediator of apoptosis and necrosis, and is specifically blocked by cyclosporin A (CsA). CsA has been shown to exert a potent neuroprotective action in vivo when allowed to cross the blood–brain barrier in various animal models of acute neurological insults and neurodegenerative disease. The neuroprotective effect of CsA is considered to be mediated through specific inhibition of the mitochondrial permeability transition pore (mPTP) and through inhibition of neuronal calcineurin activity. Characterization of mPT has mainly been performed in liver and heart mitochondria, and some brain studies have reported a decreased inhibitory effect of CsA and questioned the importance of mPT in brain-derived mitochondria. We have used the de-energized model of swelling to examine the mPT in brain-derived non-synaptosomal mitochondria. Ca2+-induced swelling was evaluated by electron microscopy and by measurement of spectrophotometric alterations in light scattering. Permeability transition was readily induced in a majority of the mitochondria at a wide range of Ca2+ levels and was powerfully inhibited by CsA with a half-maximal effect at not, vert, similar23 nM CsA. The swelling kinetics and CsA effects were comparable to previous findings in de-energized liver and heart mitochondria. Careful characterization of mPT and CsA effects in brain-derived mitochondria is the first step in evaluating newly developed CsA analogues capable of crossing the blood–brain barrier and preferentially entering the brain. The importance of CsA causing a shift of the mitochondrial sensitivity to Ca2+ in neurological disorders is discussed. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/111714
- author
- Hansson, Magnus
LU
; Persson, Tanja
; Friberg, Hans
LU
; Keep, Marcus F
; Rees, Anthony
; Wieloch, Tadeusz
LU
and Elmer, Eskil
LU
- organization
- publishing date
- 2003
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mitochondrial permeability transition, Neuroprotection, Cyclosporin A, Neurodegeneration
- in
- Brain Research
- volume
- 960
- issue
- 1-2
- pages
- 99 - 111
- publisher
- Elsevier
- external identifiers
-
- wos:000180609900012
- pmid:12505662
- scopus:0037449449
- ISSN
- 1872-6240
- DOI
- 10.1016/S0006-8993(02)03798-8
- 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), Anaesthesiology and Intensive Care (013230022)
- id
- 76f20df3-6fc9-48b2-b6d6-146bd25c853f (old id 111714)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12505662&dopt=Abstract
- date added to LUP
- 2016-04-01 11:57:26
- date last changed
- 2024-01-08 02:48:57
@article{76f20df3-6fc9-48b2-b6d6-146bd25c853f,
abstract = {{The mitochondrial permeability transition (mPT) is considered to be an important mediator of apoptosis and necrosis, and is specifically blocked by cyclosporin A (CsA). CsA has been shown to exert a potent neuroprotective action in vivo when allowed to cross the blood–brain barrier in various animal models of acute neurological insults and neurodegenerative disease. The neuroprotective effect of CsA is considered to be mediated through specific inhibition of the mitochondrial permeability transition pore (mPTP) and through inhibition of neuronal calcineurin activity. Characterization of mPT has mainly been performed in liver and heart mitochondria, and some brain studies have reported a decreased inhibitory effect of CsA and questioned the importance of mPT in brain-derived mitochondria. We have used the de-energized model of swelling to examine the mPT in brain-derived non-synaptosomal mitochondria. Ca2+-induced swelling was evaluated by electron microscopy and by measurement of spectrophotometric alterations in light scattering. Permeability transition was readily induced in a majority of the mitochondria at a wide range of Ca2+ levels and was powerfully inhibited by CsA with a half-maximal effect at not, vert, similar23 nM CsA. The swelling kinetics and CsA effects were comparable to previous findings in de-energized liver and heart mitochondria. Careful characterization of mPT and CsA effects in brain-derived mitochondria is the first step in evaluating newly developed CsA analogues capable of crossing the blood–brain barrier and preferentially entering the brain. The importance of CsA causing a shift of the mitochondrial sensitivity to Ca2+ in neurological disorders is discussed.}},
author = {{Hansson, Magnus and Persson, Tanja and Friberg, Hans and Keep, Marcus F and Rees, Anthony and Wieloch, Tadeusz and Elmer, Eskil}},
issn = {{1872-6240}},
keywords = {{Mitochondrial permeability transition; Neuroprotection; Cyclosporin A; Neurodegeneration}},
language = {{eng}},
number = {{1-2}},
pages = {{99--111}},
publisher = {{Elsevier}},
series = {{Brain Research}},
title = {{Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria.}},
url = {{http://dx.doi.org/10.1016/S0006-8993(02)03798-8}},
doi = {{10.1016/S0006-8993(02)03798-8}},
volume = {{960}},
year = {{2003}},
}