Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria

N. Brustovetsky, J. M. Dubinsky

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Abstract

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 (Δψ), 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.

Original languageEnglish (US)
Pages (from-to)8229-8237
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number22
StatePublished - Nov 15 2000

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Keywords

  • Cyclophilin
  • Cyclosporin A
  • Excitotoxicity
  • Mitochondria
  • Neurodegeneration
  • Permeability transition

ASJC Scopus subject areas

  • Neuroscience(all)

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