The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Joe E. Springer - One of the best experts on this subject based on the ideXlab platform.
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Pretreatment with the Cyclosporin Derivative, NIM811, Improves the Function of Synaptic Mitochondria following Spinal Cord Contusion in Rats
Journal of neurotrauma, 2007Co-Authors: Melanie L. Mcewen, Patrick G. Sullivan, Joe E. SpringerAbstract:Trauma to the spinal cord causes a cascade of secondary events, such as mitochondrial dysfunction, which disrupts cellular functions and ultimately leads to cell death. Cyclosporin A (CsA) is a potent immunosuppressant that promotes mitochondrial function by inhibiting mitochondrial permeability transition (mPT). Clinical trials examining CsA in traumatic brain injury are currently underway, but CsA is potentially neurotoxic. NIM811 is a non-immunosuppressive CsA Derivative that inhibits mPT at nanomolar concentrations and with significantly less cytotoxicity than CsA. In the present study, we investigated the effects of NIM811 treatment on mitochondrial bioenergetics and the production of reactive oxygen species following spinal cord injury (SCI) in rats. Rats were pretreated with NIM811 or vehicle, and after 15 min the rats received a “mild/moderate” spinal cord contusion. After 24 h, the spinal cords were rapidly removed and synaptosomal mitochondria were isolated. NIM811 pretreatment significantly imp...
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Post-treatment with the Cyclosporin Derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion.
Journal of neurotrauma, 2007Co-Authors: Rangaswamyrao Ravikumar, Melanie L. Mcewen, Joe E. SpringerAbstract:Cyclosporin A (CsA) is a potent immunosuppressive drug shown to inhibit mitochondrial permeability transition (mPT). Although the therapeutic efficacy of CsA in traumatic brain injury is being inve...
Melanie L. Mcewen - One of the best experts on this subject based on the ideXlab platform.
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Pretreatment with the Cyclosporin Derivative, NIM811, Improves the Function of Synaptic Mitochondria following Spinal Cord Contusion in Rats
Journal of neurotrauma, 2007Co-Authors: Melanie L. Mcewen, Patrick G. Sullivan, Joe E. SpringerAbstract:Trauma to the spinal cord causes a cascade of secondary events, such as mitochondrial dysfunction, which disrupts cellular functions and ultimately leads to cell death. Cyclosporin A (CsA) is a potent immunosuppressant that promotes mitochondrial function by inhibiting mitochondrial permeability transition (mPT). Clinical trials examining CsA in traumatic brain injury are currently underway, but CsA is potentially neurotoxic. NIM811 is a non-immunosuppressive CsA Derivative that inhibits mPT at nanomolar concentrations and with significantly less cytotoxicity than CsA. In the present study, we investigated the effects of NIM811 treatment on mitochondrial bioenergetics and the production of reactive oxygen species following spinal cord injury (SCI) in rats. Rats were pretreated with NIM811 or vehicle, and after 15 min the rats received a “mild/moderate” spinal cord contusion. After 24 h, the spinal cords were rapidly removed and synaptosomal mitochondria were isolated. NIM811 pretreatment significantly imp...
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Post-treatment with the Cyclosporin Derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion.
Journal of neurotrauma, 2007Co-Authors: Rangaswamyrao Ravikumar, Melanie L. Mcewen, Joe E. SpringerAbstract:Cyclosporin A (CsA) is a potent immunosuppressive drug shown to inhibit mitochondrial permeability transition (mPT). Although the therapeutic efficacy of CsA in traumatic brain injury is being inve...
F. Loor - One of the best experts on this subject based on the ideXlab platform.
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Atypical multi-drug resistance (MDR): low sensitivity of a P-glycoprotein-expressing human T lymphoblastoid MDR cell line to classical P-glycoprotein-directed resistance-modulating agents.
Anti-cancer drugs, 1993Co-Authors: B Jachez, F. LoorAbstract:Verapamil, Cyclosporin A (CsA), the Cyclosporin Derivative SDZ PSC 833 and the novel cyclopeptolide SDZ 280-446 were tested for their capacity to chemosensitize a P-glycoprotein (Pgp)-expressing multi-drug resistant (MDR) variant of the CEM human T lymphoblastoid cell subline (CCRF ACTD 400+). That MDR-CEM cell subline had been previously selected for MDR by actinomycin D and displayed a very high resistance phenotype: 3700-fold for actinomycin D, 3900-fold for vincristine, 1200-fold for taxol, 1000-fold for daunomycin (DAU) and 400-fold for colchicine. Interestingly, these MDR-CEM cells displayed little chemosensitization by resistance-modulating agents (RMA) which presumably work by inhibiting Pgp function. These MDR-CEM cells displayed virtually no chemosensitization by 1 microM verapamil or 1 microgram/ml (about 0.8 microM) CsA, whereas their chemosensitization for different anti-cancer drugs (ACD) was rather stable (from 51- to 82-fold) with 1 microgram/ml (about 0.8 microM) SDZ 280-446, while being very unbalanced (from 5- to 38-fold) with 1 microgram/ml (about 0.8 microM) SDZ PSC 833. Exposure of the MDR-CEM cells to Pgp-directed RMAs, during their loading with DAU (DAU-loading phase), hardly restored DAU retention: SDZ 280-446 being as poorly active as SDZ PSC 833, and about only 3- and 4-fold more active than CsA and verapamil. In contrast, SDZ PSC 833 treatment of human MDR-KB and MDR-LoVo cell lines under the same conditions could restore most or all the DAU retention shown by the parental (Par) cells, in spite of their high level of resistance. By keeping the MDR-CEM cells in the presence of RMA throughout the experiment (both DAU-loading and DAU-efflux phases), a better DAU retention could be restored by the different RMAs used, their order of relative restoration activity being SDZ 280-446 3- to 4-fold > SDZ PSC 833 3- to 10-fold > CsA 2- to 4-fold > verapamil. Nevertheless, the level of DAU retention restored in the MDR-CEM cells reached a plateau at 50% of the Par-CEM cell level. Therefore, although the MDR-CEM cells expressed easily detectable membranous Pgp molecules and probably used them for DAU efflux, they displayed an additional efflux mechanism that was not sensitive to the Pgp inhibitors.
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SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance
British Journal of Cancer, 1992Co-Authors: F. Loor, D. Boesch, A. Pourtier-manzanedo, C Gavériaux, B Jachez, G EmmerAbstract:SDZ 280-446 is a semi-synthetic Derivative of a natural cyclic peptolide. Its ability to sensitise in vitro tumour cells whose resistance is due to P-glycoprotein-mediated anticancer-drug efflux was shown using four different pairs of parental drug-sensitive (Par-) and multidrug-resistant (MDR-) cell lines, from three different species (mouse, human, Chinese hamster) representing four different cell lineages (monocytic leukaemia, nasopharyngeal epithelial carcinoma, colon epithelial carcinoma, ovary fibroblastoid carcinoma), and using four different drug classes (colchicine, vincristine, daunomycin/doxorubicin and etoposide). By measuring its capacity to restore normal drug sensitivity of MDR-cells in culture in vitro, it appeared that SDZ 280-446 belongs to the same class of very potent chemosensitisers as the Cyclosporin Derivative SDZ PSC 833: both are about one order of magnitude more active than Cyclosporin A (CsA), which is itself about one order of magnitude more active than other known chemosensitisers (including verapamil, quinidine and amiodarone which have already entered clinical trials in MDR reversal). Low concentrations of SDZ 280-446 could also restore cellular daunomycin retention in MDR-P388 cells to the levels found in the Par-P388 cells. SDZ 280-446 was also effective as a chemosensitiser when given orally in vivo. In a syngeneic mouse model, combined therapy with vinca alkaloids given i.p. and SDZ 280-446 given per os for 5 consecutive days significantly prolonged the survival of MDR-P388 tumour-bearing mice, when compared with mice receiving vinca alkaloids alone. Another protocol, using three cycles of i.p. doxorubicin at 4 day intervals, could also not increase MDR-P388 tumour-bearing mouse survival unless the mice received SDZ 280-446 orally 4 h before each doxorubicin injection. Though only very few combined therapy treatment protocols have been tested so far, clear increases in survival time of MDR-tumour-bearing mice were regularly obtained, leaving hope for major improvement of the therapy using other dosing schedules.
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Restoration of daunomycin retention in multidrug-resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive Cyclosporin Derivative
Experimental cell research, 1991Co-Authors: D. Boesch, K. Muller, A. Pourtier-manzanedo, F. LoorAbstract:Overexpression of P-glycoprotein may cause increased efflux of a variety of anticancer drugs (ACD) leading to multidrug resistance (MDR) of tumor cells. Two sublines of murine monocytic leukemia P388 cells were used, one parental (Par-P388) and one multidrug resistant (MDR-P388). In cell growth inhibition assays in vitro, the Par-P388 cells showed a normal sensitivity to daunomycin (DAU) while the MDR-P388 cells were 200-fold resistant. In cellular fluorescence assays, DAU retention in MDR-P388 cells reached only 5% of the level achieved in Par-P388 cells. This cell line pair was used to compare the nonimmunosuppressive Cyclosporin analog PSC 833 with several resistance-modifying agents (RMAs) for their in vitro chemosensitizing activity and for their restoration of DAU retention. PSC 833 sensitized the MDR-P388 cells 60- and 140-fold when used at 0.1 and 0.3 μg/ml (0.08 and 0.25 μM), respectively, a complete restoration of sensitivity being obtained at 1.0 μg/ml PSC 833. Similarly as little as 0.1 μg/ml (0.08 μM) PSC 833 was sufficient to restore intracellular DAU retention to 60% of the level found in Par-P388 cells, a 3-fold higher concentration restoring virtually the whole DAU retention. For both these activities, PSC 833 was at least one order of magnitude more active than CsA, which was itself an order of magnitude stronger than verapamil, another RMA already used in clinic. Since PSC 833 had no effect on the Par-P388 cells, neither on chemosensitization nor on drug retention, it is assumed that it acts on the P-glycoprotein, which is highly expressed on the membrane of the MDR-P388 cells, by inhibiting the function of the P-glycoprotein pump and thus restoring a normal ACD-sensitivity of the MDR-P388 cells.
John J Lemasters - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the mitochondrial permeability transition by the nonimmunosuppressive Cyclosporin Derivative nim811
Molecular Pharmacology, 2002Co-Authors: Peter C. Waldmeier, T Qian, J J Feldtrauer, John J LemastersAbstract:Cyclosporin A (CsA) shows cytoprotective properties in many cellular and in vivo models that may depend on interference of the interaction of cyclophilin A with calcineurin or of cyclophilin D with the mitochondrial permeability transition (PT) pore. The nonimmunosuppressive Cyclosporin Derivative N -methyl-4-valine-Cyclosporin (PKF220-384) inhibits the mitochondrial permeability transition (MPT) like CsA but without calcineurin inactivation. PKF220-384 has been used to discriminate between PT pore- and calcineurin mediated effects but is no longer available. Here, we evaluated the effects of another nonimmunosuppressive Cyclosporin Derivative, N -methyl-4-isoleucine-Cyclosporin (NIM811) on the MPT. Using two newly developed microtiter plate assays, one measuring mitochondrial swelling from absorbance and the other measuring mitochondrial membrane potential from changes in safranin fluorescence, we show that NIM811 blocks the MPT induced by calcium and inorganic phosphate, alone or in combination with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the complex I inhibitor rotenone, and the prooxidant t -butylhydroperoxide. NIM811 was equipotent to CsA and half as potent as PKF220-384. Additionally, we show that NIM811 blocks cell killing and prevents in situ mitochondrial inner membrane permeabilization and depolarization during tumor necrosis factor-α–induced apoptosis to cultured rat hepatocytes. NIM811 inhibition of apoptosis was equipotent with CsA except at higher concentrations: CsA lost efficacy but NIM 811 did not. We conclude that NIM811 is a useful alternative to PKF220-384 to investigate the role of the mitochondrial permeability transition in apoptotic and necrotic cell death.
Suk-joon Hyung - One of the best experts on this subject based on the ideXlab platform.
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Detection of conformation types of Cyclosporin retaining intramolecular hydrogen bonds by mass spectrometry
Analytical and Bioanalytical Chemistry, 2014Co-Authors: Suk-joon Hyung, Xidong Feng, Ye Che, Justin G. Stroh, Michael ShapiroAbstract:Cyclosporin is a family of neutral cyclic undecapeptides widely used for the prevention of organ transplant rejection and controlling viral infection. The equilibrium of conformations assumed by Cyclosporin A in response to the solvent environment is thought to play a critical role in enabling good membrane penetration, which improves upon shielding the polarity of the molecule through forming intramolecular hydrogen bonds. However, the distribution of structures and their internal hydrogen bond geometries have not been elucidated thus far across the series of Cyclosporins. Herein, we elucidate the conformational heterogeneity of Cyclosporins using a set of analytical approaches including ion mobility mass spectrometry, hydrogen–deuterium exchange, and molecular dynamics simulation. Ion mobility measurements reveal a specific conformational distribution for each Cyclosporin Derivative in a structure-dependent manner. In general, we observe that the more compact conformer is associated with a greater frequency of intramolecular hydrogen bonds. Cyclosporin A is populated by structures with an extensive hydrogen bond network that is lacking in Cyclosporin H, which is composed predominantly of a single compact conformation. The slower dynamics of Cyclosporin H backbone is also consistent with the lack of hydrogen bonds. Furthermore, we find a strong correlation between the steric bulk of the side chain at position 2 of Cyclosporin and the distribution of conformers due to differential accommodation of side chains within the macrocycle, and also report a wide range of conformational dynamics in solution. Fig Cyclosporin analogues display distinct conformation types with different hydrogen bonding arrangements
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Detection of conformation types of Cyclosporin retaining intramolecular hydrogen bonds by mass spectrometry
Analytical and bioanalytical chemistry, 2014Co-Authors: Suk-joon Hyung, Xidong Feng, Ye Che, Justin G. Stroh, Michael J. ShapiroAbstract:Cyclosporin is a family of neutral cyclic undecapeptides widely used for the prevention of organ transplant rejection and controlling viral infection. The equilibrium of conformations assumed by Cyclosporin A in response to the solvent environment is thought to play a critical role in enabling good membrane penetration, which improves upon shielding the polarity of the molecule through forming intramolecular hydrogen bonds. However, the distribution of structures and their internal hydrogen bond geometries have not been elucidated thus far across the series of Cyclosporins. Herein, we elucidate the conformational heterogeneity of Cyclosporins using a set of analytical approaches including ion mobility mass spectrometry, hydrogen-deuterium exchange, and molecular dynamics simulation. Ion mobility measurements reveal a specific conformational distribution for each Cyclosporin Derivative in a structure-dependent manner. In general, we observe that the more compact conformer is associated with a greater frequency of intramolecular hydrogen bonds. Cyclosporin A is populated by structures with an extensive hydrogen bond network that is lacking in Cyclosporin H, which is composed predominantly of a single compact conformation. The slower dynamics of Cyclosporin H backbone is also consistent with the lack of hydrogen bonds. Furthermore, we find a strong correlation between the steric bulk of the side chain at position 2 of Cyclosporin and the distribution of conformers due to differential accommodation of side chains within the macrocycle, and also report a wide range of conformational dynamics in solution.
