| 1. |
- Friberg, Hans, et al.
(author)
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Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death
- 1998
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In: The Journal of Neuroscience. - 0270-6474. ; 18:14, s. 5151-5159
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Journal article (peer-reviewed)abstract
- Induction of the mitochondrial permeability transition (MPT) has been implicated in cellular apoptosis and in ischemia-reperfusion injury. During MPT, a channel in the inner mitochondrial membrane, the mitochondrial megachannel, opens and causes isolated mitochondria to swell. MPT and mitochondrial swelling is inhibited by cyclosporin A (CsA), which may also inhibit apoptosis in some cells. Treatment with CsA (50 mg/kg, i.v.) showed a robust reduction of brain damage when administered 30 min before insulin- induced hypoglycemic isoelectricity of 30 min duration. Ultrastructural examination of the dentate gyrus revealed a marked swelling of dendrites and mitochondria during the hypoglycemic insult. In CsA-treated animals, mitochondria resumed a normal and contracted appearance during and after the hypoglycemic insult. Treatment with FK 506 (2 mg/kg, i.v.), a compound with immunosuppressive action similar to that of CsA, was not protective. Studies on the swelling kinetics of isolated mitochondria from the hippocampus showed that CsA, but not FK 506, inhibits calcium ion-induced MPT. We conclude that CsA treatment during hypoglycemic coma inhibits the MPT and reduces damage and that mitochondria and the MPT are likely to be involved in the development of hypoglycemic brain damage in the rat.
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| 2. |
- Friberg, Hans, et al.
(author)
-
Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability
- 1999
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 72:6, s. 2488-2497
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Journal article (peer-reviewed)abstract
- Mitochondria from different regions of the brain were prepared, and the activation of the mitochondrial permeability transition (MPT) by calcium was investigated by monitoring the associated mitochondrial swelling. In general, the properties of the MPT in brain mitochondria were found to be qualitatively similar to those observed in liver and heart mitochondria. Thus, swelling was inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents and alkalosis facilitated swelling. Cyclosporin A and its nonimmunosuppressive analogue N-methyl-Val-4-cyclosporin A (PKF 220- 384.) both inhibited swelling and prevented the translocation of cyclophilin D from the matrix to the membranes of cortical mitochondria. However, the calcium sensitivity of the MPT differed in mitochondria from three brain regions (hippocampus > cortex > cerebellum) and is correlated with the susceptibility of these regions to ischemic damage. Depleting mitochondria of AdNs by treatment with pyrophosphate ions sensitized the MPT to [Ca2+] and abolished regional differences, implying regional differences in mitochondrial AdN content. This was confirmed by measurements showing significant differences in AdN content among regions (cerebellum > cortex > hippocampus). Our data add to recent evidence that the MPT may be involved in neuronal death.
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| 3. |
- Hansson, Magnus, et al.
(author)
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Differences in the profile of protection afforded by TRO40303 and mild hypothermia in models of cardiac ischemia/reperfusion injury.
- 2015
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 760:Apr 17, s. 7-19
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Journal article (peer-reviewed)abstract
- The mode of protection against cardiac reperfusion injury by mild hypothermia and TRO40303 was investigated in various experimental models and compared to MitoQ in vitro. In isolated cardiomyocytes subjected to hypoxia/reoxygenation, TRO40303, MitoQ and mild hypothermia delayed mPTP opening, inhibited generation of mitochondrial superoxide anions at reoxygenation and improved cell survival. Mild hypothermia, but not MitoQ and TRO40303, provided protection in a metabolic starvation model in H9c2 cells and preserved respiratory function in isolated rat heart mitochondria submitted to anoxia/reoxygenation. In the Langendorff-perfused rat heart, only mild hypothermia provided protection of hemodynamic function and reduced infarct size following ischemia/reperfusion. In biopsies from the left ventricle of pigs subjected to in vivo occlusion/reperfusion, TRO40303 specifically preserved respiratory functions in the peri-infarct zone whereas mild hypothermia preserved both the ischemic core area and the peri-infarct zones. Additionally in this pig model, only hypothermia reduced infarct size. We conclude that mild hypothermia provided protection in all models by reducing the detrimental effects of ischemia, and when initiated before occlusion, reduced subsequent reperfusion damage leading to a smaller infarct. By contrast, although TRO40303 provided similar protection to MitoQ in vitro and offered specific protection against some aspects of reperfusion injury in vivo, this was insufficient to reduce infarct size.
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