Cyclosporin A and its nonimmunosuppressive analogue N‐Me‐Val‐4‐cyclosporin A mitigate glucose/oxygen deprivation‐induced damage to rat cultured hippocampal neurons

Хаспеков, Л. Г.; Friberg, Hans; Halestrap, Andrew P.; Viktorov, I V; Wieloch, Tadeusz

doi:10.1046/j.1460-9568.1999.00743.x

Cited by 107 publications

(70 citation statements)

References 40 publications

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“…Cyclosporin A is problematic as a permeability transition diagnostic with intact cells due to its ability to inhibit calcineurin and hyperphosphorylate proteins (Hallak et al 2001). The more selective methyl-4-valine cyclosporin did not afford convincing protection in our hands (Castilho et al 1999) although others report partial protection against deregulation (Khaspekov et al 1999;Vergun et al 1999;Alano et al 2002).…”

Section: Discussioncontrasting

confidence: 59%

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Vesce

Kirk

Nicholls

2004

Journal of Neurochemistry

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The relationship is investigated between superoxide levels in single cultured rat cerebellar granule neurons exposed continuously to glutamate in low KCl medium and the deregulation of cytoplasmic Ca 2+ . Cells that maintain a regulated cytoplasmic-free Ca 2+ and mitochondrial polarization in the presence of glutamate show no increase in superoxide levels until the onset of cytoplasmic Ca 2+ deregulation. Oxidative stress of mitochondrial origin is readily detectable, as the inhibitors rotenone and antimycin A markedly increase superoxide levels with no effect on cytoplasmic-free Ca 2+ . The potent cell-permeant superoxide dismutase/catalase mimetic manganese tetrakis (N-ethylpyridinium-2yl) porphyrin, MnTE-PyP, abolishes the deregulation-related increase in superoxide but has no effect on deregulation itself. A combination of catalase with the free radical scavenger 4-hydroxy-TEMPO also fails to reduce deregulation. Following the loss of Ca 2+ homeostasis nuclei undergo condensation; this morphological change is not inhibited by MnTE-PyP and cannot account for the increased ethidium fluorescence. Phospholipase A 2 inhibitors decrease the deregulation-related increase in superoxide without protecting against deregulation. In conclusion, our study indicates that deregulation is not caused by NMDA receptor-mediated oxidative stress as NMDA receptor activation does not increase superoxide levels until the onset of deregulation. Furthermore, the majority of superoxide is produced in the cytoplasm rather than in mitochondria.

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Section: Discussioncontrasting

confidence: 59%

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Vesce

Kirk

Nicholls

2004

Journal of Neurochemistry

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“…Treatment with CsA decreases infarct size after cerebral ischemia͞reperfusion injury (32)(33)(34). Furthermore, conditions known to favor activation of the PTP, such as mitochondrial sequestration of calcium, generation of oxidative stress, and depletion of ATP levels, are present during ischemia͞reperfusion.…”

Section: Generation Of Cypd-deficient Micementioning

confidence: 99%

“…In vivo, the inhibitory effect of CsA emphasized the critical importance of PT in cell death induced by ischemia͞reperfusion. In models of ischemic brain injury, treatment with CsA or its analogue, N-methyl-valine-4 CsA, significantly decreases infarct size (32)(33)(34). However, the importance of CypD in vivo and in cell culture remains poorly understood because of the pleiotropic nature of CsA.…”

mentioning

confidence: 99%

Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

Schinzel

Takeuchi²,

Huang³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

756

650

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Mitochondrial permeability transition (PT) is a phenomenon induced by high levels of matrix calcium and is characterized by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochondrial membrane potential, expansion of the matrix, and rupture of the mitochondrial outer membrane. Consequently, PT has been implicated in both apoptotic and necrotic cell death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell death, we created a CypD-deficient mouse. In vitro, CypD-deficient mitochondria showed an increased capacity to retain calcium and were no longer susceptible to PT induced by the addition of calcium. CypD-deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell death in response to these specific death stimuli. However, CypD-deficient MEFs were significantly less susceptible than their WT counterparts to cell death induced by hydrogen peroxide, implicating CypD in oxidative stress-induced cell death. Importantly, CypD-deficient mice displayed a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion, strongly supporting an essential role for CypD in an ischemic injury model in which calcium overload and oxidative stress have been implicated. mitochondria ͉ oxidative stress ͉ calcium homeostasis N umerous toxic stimuli convert mitochondria from a lifesustaining organelle to an inducer of cell death (1-3). In response to cell death stimuli, prodeath proteins sequestered in the inner mitochondrial membrane space are released into the cytosol upon disruption of the mitochondrial outer membrane (MOM) (4-6). The proapoptotic BCL-2 family members BAX and BAK constitute a ''gateway'' to the apoptotic program by regulating events leading to disruption of the MOM (7). BCL-2 family members not only function at the MOM but also are located at the endoplasmic reticulum (ER), where they regulate calcium fluxes. By controlling steady-state calcium levels in the ER, BCL-2 family members regulate the amount of calcium released from the ER to transmit a death signal mediated by mitochondrial calcium uptake (8-11).Sequestration of high levels of calcium by mitochondria can also lead to disruption of the MOM, which, mechanistically, is thought to occur by means of the phenomenon of permeability transition (PT). PT is described as an abrupt increase of inner membrane permeability to solutes with molecular masses of Ͻ1,500 Da. These events are caused by the opening of a highly regulated channel [PT pore (PTP)], which leads to dissipation of the mitochondrial transmembrane potential and an influx of solutes, causing expansion of the matrix (reviewed in ref. 12). The latter event may result in sufficient swelling to rupture the MOM and cause cytochrome c release and subsequent caspase activation, resulting in apoptosis. However, dissipation of the membrane potential can also lead to a sudden d...

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“…16,48 When immobilized on a column, purified recombinant cyclophilin D specifically retains ANT among triton-solubilized IM preparations 49 and ANT plus VDAC among whole mitochondrial membrane extracts. 50 Binding of cyclophilin D to purified mitochondrial IM is inhibited by CsA and enhanced by treatment with tert-butylhydroperoxide and by diamide, 51 suggesting that the cyclophilin-D-ANT interaction favors mitochondrial membrane permeabilization.…”

Section: Cyclophilin Dmentioning

confidence: 99%

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

et al. 2000

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Mitochondrial membrane permeabilization can be a rate limiting step of apoptotic as well as necrotic cell death. Permeabilization of the outer mitochondrial membrane (OM) and/or inner membrane (IM) is, at least in part, mediated by the permeability transition pore complex (PTPC). The PTPC is formed in the IM/OM contact site and contains the two most abundant IM and OM proteins, adenine nucleotide translocator (ANT, in the IM) and voltage-dependent anion channel (VDAC, in the OM), the matrix protein cyclophilin D, which can interact with ANT, as well as apoptosis-regulatory proteins from the Bax/Bcl-2 family. Here we discuss that ANT has two opposite functions. On the one hand, ANT is a vital, specific antiporter which accounts for the exchange of ATP and ADP on IM. On the other hand, ANT can form a non-specific pore, as this has been shown by electrophysiological characterization of purified ANT reconstituted into synthetic lipid bilayers or by measuring the permeabilization of proteoliposomes containing ANT. Pore formation by ANT is induced by a variety of different agents (e.g. Ca 2+ , atractyloside, thiol oxidation, the pro-apoptotic HIV-1 protein Vpr, etc.) and is enhanced by Bax and inhibited by Bcl-2, as well as by ADP. In isolated mitochondria, pore formation by ANT leads to an increase in IM permeability to solutes up to 1500 Da, swelling of the mitochondrial matrix, and OM permeabilization, presumably due to physical rupture of OM. Although alternative mechanisms of mitochondrial membrane permeabilization may exist, ANT emerges as a major player in the regulation of cell death.

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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

Cited by 107 publications

References 40 publications

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

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