| 1. |
- Friberg, Hans, et al.
(författare)
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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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Ingår i: The Journal of Neuroscience. - 0270-6474. ; 18:14, s. 5151-5159
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability
- 1999
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 72:6, s. 2488-2497
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Tidskriftsartikel (refereegranskat)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. |
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| 4. |
- Friberg, Hans, et al.
(författare)
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Mitochondrial permeability transition in acute neurodegeneration.
- 2002
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Ingår i: Biochimie. - 1638-6183. ; 84:2-3, s. 241-250
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Tidskriftsartikel (refereegranskat)abstract
- Acute neurodegeneration in man is encountered during and following stroke, transient cardiac arrest, brain trauma, insulin-induced hypoglycemia and status epilepticus. All these severe clinical conditions are characterized by neuronal calcium overload, aberrant cell signaling, generation of free radicals and elevation of cellular free fatty acids, conditions that favor activation of the mitochondrial permeability transition pore (mtPTP). Cyclosporin A (CsA) and its analog N-methyl-valine-4-cyclosporin A (MeValCsA) are potent blockers of the mtPTP and protect against neuronal death following excitotoxicity and oxygen glucose deprivation. Also, CsA and MeValCsA diminish cell death following cerebral ischemia, trauma, and hypoglycemia. Here we present data that strongly imply the mtPT in acute neurodegeneration in vivo. Compounds that readily pass the blood-brain-barrier (BBB) and block the mtPT may be neuroprotective in stroke.
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| 5. |
- Friberg, Hans, et al.
(författare)
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Terapeutisk hypotermi efter hjärtstopp : ny länk i kedjan som kan rädda liv
- 2004
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 101:30-31, s. 2412-6
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Tidskriftsartikel (refereegranskat)abstract
- Sudden, unexpected cardiac arrest is a common cause of death. Among patients who are successfully resuscitated, a majority dies without regaining consciousness. Therapeutic hypothermia has recently been shown to improve neurological outcome in two randomized studies and to improve survival in one of them. Based on the two studies, international evidence-based recommendations have been proposed and published (ILCOR). In this review we discuss the theoretical background of hypothermic neuroprotection and therapeutic implications. We propose that victims of cardiac arrest with return of spontaneous circulation and persistent unconsciousness are considered for hypothermia treatment and that data from treated patients are collected in a common website database (see: www.scctg.org) to allow further evaluation of the use of ICU resources, efficacy of hypothermia treatment and potential risks.
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| 6. |
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| 7. |
- Hansson, Magnus, et al.
(författare)
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Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria.
- 2003
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Ingår i: Brain Research. - 1872-6240. ; 960:1-2, s. 99-111
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Khaspekov, Leonid, et al.
(författare)
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Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4-cyclosporin A mitigate glucose/oxygen deprivation-induced damage to rat cultured hippocampal neurons
- 1999
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X. ; 11:9, s. 3194-3198
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Tidskriftsartikel (refereegranskat)abstract
- When mouse hippocampal neuronal cultures, 2-3 weeks in vitro, were transiently exposed to combined glucose and oxygen deprivation (100% argon, 5% CO2, in glucose-free medium) for 90 min, extensive neuronal degeneration had occurred after 24 h of reoxygenation. When these cultures were preincubated with cyclosporin A, a calcineurin inhibitor and a blocker of the mitochondrial permeability transition, neuronal death diminished by 30-50%. Similarly, the cyclosporin A analogue, N-Me-Val-4-cyclosporin A, a potent blocker of the mitochondrial permeability transition with no significant calcineurin blocking activity, decreased cell death by 70-80%. Both cyclosporin A and N-Me-Val-4-cyclosporin A markedly attenuated calcium-induced swelling of isolated mouse brain mitochondria by blocking the mitochondrial permeability transition. The potassium thiocyanate-stabilized binding of cyclophilin D to mouse brain mitochondrial membranes was completely prevented by cyclosporin A and N-Me-Val-4-cyclosporin A. Our results strongly suggest that the mitochondrial permeability transition is involved in oxygen/glucose deprivation-induced cell death in vitro. Cyclophilin D and other components of the mitochondrial permeability transition may be important targets for neuroprotective and anti-ischaemic drugs.
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| 9. |
- Lifshitz, J, et al.
(författare)
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Structural and functional damage sustained by mitochondria after traumatic brain injury in the rat: Evidence for differentially sensitive populations in the cortex and hippocampus
- 2003
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 23:2, s. 219-231
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Tidskriftsartikel (refereegranskat)abstract
- The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid-percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 +/- 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 +/- 36 at 3 hours) compared with uninjured populations (Ctx: 418 +/- 44; Hipp: 393 +/- 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI.
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