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The Journal of Neuroscience, November 15, 2000, 20(22):8229-8237
Limitations of Cyclosporin A Inhibition of the Permeability
Transition in CNS Mitochondria
Nickolay
Brustovetsky and
Janet M.
Dubinsky
Department of Neuroscience, University of Minnesota, Minneapolis,
Minnesota 55455
Activation of the mitochondrial permeability transition may
contribute to excitotoxic neuronal death (Ankarcrona et al., 1996; Dubinsky and Levi, 1998). However, cyclosporin A (CsA), a potent inhibitor of the permeability transition in liver mitochondria, only
protects against neuronal injury by limited doses of glutamate and
selected ischemic paradigms. The lack of consistent CsA inhibition of
the mitochondrial permeability transition was analyzed with the use of
isolated brain mitochondria. Changes in the permeability of the inner
mitochondrial membrane were evaluated by monitoring mitochondrial
membrane potential (  ), using the distribution of
tetraphenylphosphonium, and by monitoring mitochondrial swelling, using
light absorbance measurements. Metabolic impairments, large Ca2+ loads, omission of external
Mg2+, or low doses of palmitic acid or the
protonophore FCCP exacerbated Ca2+-induced sustained
depolarizations and swelling and eliminated CsA inhibition. BSA
restored CsA inhibition in mitochondria challenged with 50 µM Ca2+, but not with 100 µM Ca2+. CsA failed to prevent
Ca2+-induced depolarization or to repolarize
mitochondria when mitochondria were depolarized excessively.
Similarly, CsA failed to prevent mitochondrial swelling or PEG-induced
shrinkage after swelling when the Ca2+ challenge
produced a strong, sustained depolarization. Thus in brain mitochondria
CsA may be effective only as an inhibitor of the permeability
transition and the Ca2+-activated low permeability
state under conditions of partial depolarization. In contrast, ADP plus
oligomycin inhibited both permeabilities under all of the conditions
that were tested. In situ, the neuroprotective action of
CsA may be limited to glutamate challenges sufficiently toxic to induce
the permeability transition but not so severe that mitochondrial
depolarization exceeds threshold.
Key words:
permeability transition; cyclosporin A; excitotoxicity; mitochondria; neurodegeneration; cyclophilin
Copyright © 2000 Society for Neuroscience 0270-6474/00/20228229-09$05.00/0
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