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H Yasui - One of the best experts on this subject based on the ideXlab platform.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0 degree C. The working model preparation (n = 7 in each group) showed a better cardiac output (74.6 +/- 25.7 versus 192.7 +/- 19.6 mL/min, P < .0001) and a lower lipid peroxide level (2.1 +/- 1.3 versus 0.6 +/- 0.3 nmol/mL. P < .05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n = 7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69 +/- 24% versus 140 +/- 67%, P < .05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid u74500a prevents vascular and myocardial dysfunction after 24 hour heart preservation a study based on cross circulated blood perfused rabbit hearts
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P<.0001) and a lower lipid peroxide level (2.1±1.3 versus 0.6±0.3 nmol/mL, P<.05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n=7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69±24% versus 140±67%, P<.05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. Conclusions These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P

  • the effect of Lazaroid u74500a a novel inhibitor of lipid peroxidation on 24 hour heart preservation a study based on a working model using cross circulated blood perfused rabbit hearts
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P<0.05) lower than those in group S. The Frank-Starling curve (indicating the left atrial pressure-aortic flow relationship) showed a significant left and upward shift in group L compared with that in group S (P<0.0001). The heart pretreated with U74500A showed less ischemia-reperfusion injury, better ventricular function, and a lower lipid peroxide level. We thus conclude that the inhibition of lipid peroxidation with Lazaroid appears to offer some potential benefits for long-term heart preservation.

  • The effect of Lazaroid (U74500A), a novel inhibitor of lipid peroxidation, on 24-hour heart preservation. A study based on a working model using cross-circulated blood-perfused rabbit hearts.
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P

Patrik Brundin - One of the best experts on this subject based on the ideXlab platform.

  • Comparison between survival of Lazaroid-treated embryonic nigral neurons in cell suspensions, cultures and transplants
    Brain Research, 2002
    Co-Authors: Jenny Karlsson, Mia Emgård, Patrik Brundin
    Abstract:

    Death of transplanted dopaminergic neurons is induced both during preparation of donor tissue and after intrastriatal grafting. Oxidative stress is thought to be partly responsible for this cell death. In the present study we compared the effects of three lipid peroxidation inhibitors, the Lazaroids Tirilazad mesylate, U-83836E and U-101033, on survival of embryonic mesencephalic neurons in different paradigms. The Lazaroids were equally potent in preventing serum deprivation-induced death of cultured dopaminergic neurons. In a second set of experiments, mesencephalic suspensions were pretreated with Lazaroids and cell survival was analyzed immediately after dissociation, after 2 or 24 h in culture or after intrastriatal transplantation. Lazaroid pretreatment failed to protect mesencephalic neurons in the in vitro paradigms and U-101033E did not protect grafted dopaminergic neurons in contrast to the neuroprotective effects previously reported for U-83836E and Tirilazad. Pretreatment with the iron chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic neurons, nor did it improve neuronal survival in the serum deprivation model. U-83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro-oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found that systemic treatment of the graft recipient rat with Tirilazad mesylate (before and during the first 3 days after grafting) improved survival of transplanted dopaminergic neurons to 180% of control values. Our results show that systemic treatment with a lipid peroxidation inhibitor for 3 days can promote graft survival, but also highlights the poor correlation between neuroprotective effect of pharmacological compounds in vitro and in grafts.

  • Interactive report C omparison between survival of Lazaroid-treated embryonic nigral neurons in cell suspensions, cultures and transplants
    2002
    Co-Authors: Jenny Karlsson, Mia Emgård, Patrik Brundin
    Abstract:

    Death of transplanted dopaminergic neurons is induced both during preparation of donor tissue and after intrastriatal grafting. Oxidative stress is thought to be partly responsible for this cell death. In the present study we compared the effects of three lipid peroxidation inhibitors, the Lazaroids Tirilazad mesylate, U-83836E and U-101033, on survival of embryonic mesencephalic neurons in different paradigms. The Lazaroids were equally potent in preventing serum deprivation-induced death of cultured dopaminergic neurons. In a second set of experiments, mesencephalic suspensions were pretreated with Lazaroids and cell survival was analyzed immediately after dissociation, after 2 or 24 h in culture or after intrastriatal transplantation. Lazaroid pretreatment failed to protect mesencephalic neurons in the in vitro paradigms and U-101033E did not protect grafted dopaminergic neurons in contrast to the neuroprotective effects previously reported for U-83836E and Tirilazad. Pretreatment with the iron chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic neurons, nor did it improve neuronal survival in the serum deprivation model. U-83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro-oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found that systemic treatment of the graft recipient rat with Tirilazad mesylate (before and during the first 3 days after grafting) improved survival of transplanted dopaminergic neurons to 180% of control values. Our results show that systemic treatment with a lipid peroxidation inhibitor for 3 days can promote graft survival, but also highlights the poor correlation between neuroprotective effect of pharmacological compounds in vitro and in grafts.  2002 Elsevier Science B.V. All rights reserved.

  • Additive effects of caspase inhibitor and Lazaroid on the survival of transplanted rat and human embryonic dopamine neurons
    Experimental neurology, 2000
    Co-Authors: Oskar Hansson, Jenny Karlsson, Roger F. Castilho, Gabriele S. Kaminski Schierle, Pierluigi Nicotera, Marcel Leist, Patrik Brundin
    Abstract:

    Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by Lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a Lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.

  • tirilazad mesylate improves survival of rat and human embryonic mesencephalic neurons in vitro
    Experimental Neurology, 1997
    Co-Authors: Agneta Othberg, Marcus F Keep, Patrik Brundin, Olle Lindvall
    Abstract:

    Abstract The survival rate of embryonic dopamine (DA) neurons after transplantation to the striatum is only 5–20%. Therefore, mesencephalic tissue from several donors needs to be implanted in a parkinsonian patient to induce a therapeutic improvement. Lazaroids are a group of neuroprotective compounds which inhibit lipid peroxidation. Previously, two Lazaroids (U-74389G and U-83836F) have been found to improve the survival of both cultured and grafted rat DA neurons. The only Lazaroid approved for human use is tirilazad mesylate. The objective of the present study was to explore the effects of tirilazad mesylate on DA neuron survival in cultures of rat ventral mesencephalon and its capacity to promote the in vitro cell viability of embryonic rat and human mesencephalic tissue, treated and dissociated in the same way as in clinical trials. After 7 days in vitro, the number of tyrosine hydroxylase-immunopositive, presumed DA neurons was 140% higher in rat cultures treated with 0.3 μ M tirilazad mesylate than that in control cultures. Rat and human cell suspensions supplemented with tirilazad mesylate maintained a high degree of viability for several hours longer than control suspensions. These results indicate that tirilazad mesylate promotes the survival of both rat and human embryonic mesencephalic neurons in vitro. Tirilazad mesylate can be administered clinically and may become a useful tool for increasing survival of grafted DA neurons in patients, thereby reducing the needed quantity of human donor tissue.

  • The Lazaroid U-83836E improves the survival of rat embryonic mesencephalic tissue stored at 4°C and subsequently used for cultures or intracerebral transplantation
    Brain research bulletin, 1996
    Co-Authors: Eva Maria Grasbon-frodl, Naoyuki Nakao, Patrik Brundin
    Abstract:

    Abstract We assessed the effects of addition of the Lazaroid U-83836E to a preservation medium on the survival of rat dopamine neurons stored before culturing or intracerebral transplantation. Embryonic ventral mesencephalic tissue was preserved at 4°C for 8 days with or without the addition of 0.3 μM of U-83836E to a chemically defined “hibernation” medium. Freshly dissected mesencephalic tissue was used in control groups. For culture experiments, the mesencephalic tissue was dissociated and grown in serum-containing medium. Following 24–48 h in vitro, the number of dopamine neurons in cultures derived from tissue hibernated without the Lazaroid was 40% of fresh control, compared with 67% of control in cultures prepared from tissue stored in the presence of U-83836E. When mesencephalic tissue was transplanted to the dopamine-depleted striatum of hemiparkinsonian rats following 8 days storage at 4°C in a medium without U-83836E, the mean number of surviving dopamine neurons in the grafts was significantly reduced to 40% of control. In contrast, grafts of tissue which had been hibernated in U-83836E-containing medium contained as many dopamine neurons as transplants of freshly dissected tissue. High yields of surviving grafted dopamine neurons were correlated to a significantly faster onset of functional recovery of amphetamine-induced motor asymmetry. We conclude that the storage period for rat mesencephalic tissue can be prolonged up to 8 days when using Lazaroid-supplemented hibernation medium. As Lazaroids have undergone clinical safety testing, the application of Lazaroids for tissue storage in clinical transplantation trials can be envisaged.

T Nishida - One of the best experts on this subject based on the ideXlab platform.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0 degree C. The working model preparation (n = 7 in each group) showed a better cardiac output (74.6 +/- 25.7 versus 192.7 +/- 19.6 mL/min, P < .0001) and a lower lipid peroxide level (2.1 +/- 1.3 versus 0.6 +/- 0.3 nmol/mL. P < .05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n = 7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69 +/- 24% versus 140 +/- 67%, P < .05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid u74500a prevents vascular and myocardial dysfunction after 24 hour heart preservation a study based on cross circulated blood perfused rabbit hearts
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P<.0001) and a lower lipid peroxide level (2.1±1.3 versus 0.6±0.3 nmol/mL, P<.05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n=7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69±24% versus 140±67%, P<.05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. Conclusions These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P

  • the effect of Lazaroid u74500a a novel inhibitor of lipid peroxidation on 24 hour heart preservation a study based on a working model using cross circulated blood perfused rabbit hearts
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P<0.05) lower than those in group S. The Frank-Starling curve (indicating the left atrial pressure-aortic flow relationship) showed a significant left and upward shift in group L compared with that in group S (P<0.0001). The heart pretreated with U74500A showed less ischemia-reperfusion injury, better ventricular function, and a lower lipid peroxide level. We thus conclude that the inhibition of lipid peroxidation with Lazaroid appears to offer some potential benefits for long-term heart preservation.

  • The effect of Lazaroid (U74500A), a novel inhibitor of lipid peroxidation, on 24-hour heart preservation. A study based on a working model using cross-circulated blood-perfused rabbit hearts.
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P

Jenny Karlsson - One of the best experts on this subject based on the ideXlab platform.

  • Comparison between survival of Lazaroid-treated embryonic nigral neurons in cell suspensions, cultures and transplants
    Brain Research, 2002
    Co-Authors: Jenny Karlsson, Mia Emgård, Patrik Brundin
    Abstract:

    Death of transplanted dopaminergic neurons is induced both during preparation of donor tissue and after intrastriatal grafting. Oxidative stress is thought to be partly responsible for this cell death. In the present study we compared the effects of three lipid peroxidation inhibitors, the Lazaroids Tirilazad mesylate, U-83836E and U-101033, on survival of embryonic mesencephalic neurons in different paradigms. The Lazaroids were equally potent in preventing serum deprivation-induced death of cultured dopaminergic neurons. In a second set of experiments, mesencephalic suspensions were pretreated with Lazaroids and cell survival was analyzed immediately after dissociation, after 2 or 24 h in culture or after intrastriatal transplantation. Lazaroid pretreatment failed to protect mesencephalic neurons in the in vitro paradigms and U-101033E did not protect grafted dopaminergic neurons in contrast to the neuroprotective effects previously reported for U-83836E and Tirilazad. Pretreatment with the iron chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic neurons, nor did it improve neuronal survival in the serum deprivation model. U-83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro-oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found that systemic treatment of the graft recipient rat with Tirilazad mesylate (before and during the first 3 days after grafting) improved survival of transplanted dopaminergic neurons to 180% of control values. Our results show that systemic treatment with a lipid peroxidation inhibitor for 3 days can promote graft survival, but also highlights the poor correlation between neuroprotective effect of pharmacological compounds in vitro and in grafts.

  • Interactive report C omparison between survival of Lazaroid-treated embryonic nigral neurons in cell suspensions, cultures and transplants
    2002
    Co-Authors: Jenny Karlsson, Mia Emgård, Patrik Brundin
    Abstract:

    Death of transplanted dopaminergic neurons is induced both during preparation of donor tissue and after intrastriatal grafting. Oxidative stress is thought to be partly responsible for this cell death. In the present study we compared the effects of three lipid peroxidation inhibitors, the Lazaroids Tirilazad mesylate, U-83836E and U-101033, on survival of embryonic mesencephalic neurons in different paradigms. The Lazaroids were equally potent in preventing serum deprivation-induced death of cultured dopaminergic neurons. In a second set of experiments, mesencephalic suspensions were pretreated with Lazaroids and cell survival was analyzed immediately after dissociation, after 2 or 24 h in culture or after intrastriatal transplantation. Lazaroid pretreatment failed to protect mesencephalic neurons in the in vitro paradigms and U-101033E did not protect grafted dopaminergic neurons in contrast to the neuroprotective effects previously reported for U-83836E and Tirilazad. Pretreatment with the iron chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic neurons, nor did it improve neuronal survival in the serum deprivation model. U-83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro-oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found that systemic treatment of the graft recipient rat with Tirilazad mesylate (before and during the first 3 days after grafting) improved survival of transplanted dopaminergic neurons to 180% of control values. Our results show that systemic treatment with a lipid peroxidation inhibitor for 3 days can promote graft survival, but also highlights the poor correlation between neuroprotective effect of pharmacological compounds in vitro and in grafts.  2002 Elsevier Science B.V. All rights reserved.

  • Additive effects of caspase inhibitor and Lazaroid on the survival of transplanted rat and human embryonic dopamine neurons
    Experimental neurology, 2000
    Co-Authors: Oskar Hansson, Jenny Karlsson, Roger F. Castilho, Gabriele S. Kaminski Schierle, Pierluigi Nicotera, Marcel Leist, Patrik Brundin
    Abstract:

    Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by Lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a Lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.

  • Effects of anaesthetics and Lazaroid U-83836E on survival of transplanted rat dopaminergic neurones.
    Brain research, 1999
    Co-Authors: Jenny Karlsson, R.m Love, D.j. Clarke, P. Brundin
    Abstract:

    We investigated whether different methods of anaesthesia, used on the pregnant rat when collecting embryonic donor tissue, and a lipid peroxidation inhibitor (Lazaroid U-83836E) affect the survival of grafted embryonic dopaminergic neurones in hemiparkinsonian rats. There was no difference in either functional recovery or survival of dopaminergic neurones between the different euthanasia groups: (a) isoflurane sedation followed by cervical dislocation, (b) equithesin- or (c) euthatal-anaesthesia. However, Lazaroid-treatment enhanced both behavioural recovery and transplant survival.

S Morita - One of the best experts on this subject based on the ideXlab platform.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0 degree C. The working model preparation (n = 7 in each group) showed a better cardiac output (74.6 +/- 25.7 versus 192.7 +/- 19.6 mL/min, P < .0001) and a lower lipid peroxide level (2.1 +/- 1.3 versus 0.6 +/- 0.3 nmol/mL. P < .05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n = 7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69 +/- 24% versus 140 +/- 67%, P < .05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid u74500a prevents vascular and myocardial dysfunction after 24 hour heart preservation a study based on cross circulated blood perfused rabbit hearts
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P<.0001) and a lower lipid peroxide level (2.1±1.3 versus 0.6±0.3 nmol/mL, P<.05) of the coronary effluent in the heart treated with Lazaroid. With a Langendorff preparation (n=7 in each group), we evaluated the vascular dilatory function. The endothelial function assessed by the percentage increase of coronary flow in response to acetylcholine in the solvent group was significantly lower than that of the Lazaroid group (69±24% versus 140±67%, P<.05), whereas no significant difference was observed between the groups regarding endothelium-independent vasodilatation as assessed by the responses to nitroglycerin and nitroprusside. Conclusions These results demonstrated an improved ventricular and endothelial function in the rabbit pretreated with Lazaroid before preservation accompanied by a reduction of lipid peroxidation, indicating the potential benefits for long-term heart preservation.

  • Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts.
    Circulation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Background The prevention of ventricular and vascular dysfunction has been recognized as an important factor in heart preservation. Because lipid peroxidation may cause cell membrane injury after ischemia and reperfusion, we hypothesized that the administration of a lipid peroxidation inhibitor Lazaroid (U74500A) would result in an improvement of functional recovery after the 24-hour preservation period. Methods and Results An isolated rabbit heart preparation perfused with support rabbit blood was used. Before preservation, 4 mg/kg of either Lazaroid or solvent was given to donor rabbits. The hearts were preserved with University of Wisconsin solution for 24 hours at 0°C. The working model preparation (n=7 in each group) showed a better cardiac output (74.6±25.7 versus 192.7±19.6 mL/min, P

  • the effect of Lazaroid u74500a a novel inhibitor of lipid peroxidation on 24 hour heart preservation a study based on a working model using cross circulated blood perfused rabbit hearts
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P<0.05) lower than those in group S. The Frank-Starling curve (indicating the left atrial pressure-aortic flow relationship) showed a significant left and upward shift in group L compared with that in group S (P<0.0001). The heart pretreated with U74500A showed less ischemia-reperfusion injury, better ventricular function, and a lower lipid peroxide level. We thus conclude that the inhibition of lipid peroxidation with Lazaroid appears to offer some potential benefits for long-term heart preservation.

  • The effect of Lazaroid (U74500A), a novel inhibitor of lipid peroxidation, on 24-hour heart preservation. A study based on a working model using cross-circulated blood-perfused rabbit hearts.
    Transplantation, 1996
    Co-Authors: T Nishida, S Morita, K Miyamoto, M Masuda, R Tominaga, Y Kawachi, H Yasui
    Abstract:

    Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with Lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L ; n=6) or solvent (group S ; n=7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0°C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase ; its isozyme, troponin-T ; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P