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Airo Tsubura - One of the best experts on this subject based on the ideXlab platform.

  • Caspase-3 Inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene.
    Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2002
    Co-Authors: Katsuhiko Yoshizawa, Jihong Yang, Hideto Senzaki, Yasuhiko Kiyozuka, Nobuaki Shikata, Katsuji Kiuchi, Hiroyuki Nambu, Airo Tsubura
    Abstract:

    Background: The effect of a Caspase-3 Inhibitor on retinal degeneration in C3H mice carrying the rd gene, a mutation of a rod-specific phosphodiesterase, was investigated. Methods: A quantity of 2 mg/kg of Ac-DEVD-CHO, as Inhibitor, was injected intraperitoneally every other day from 8 days of age, and retinal damage was compared with that in saline-treated C3H mice at 13 days (1 day after the third treatment) and 17 days of age (1 day after the fifth treatment). Retina of ICR mice not carrying rd gene was also evaluated under the same protocol. The efficacy of Ac-DEVD-CHO was evaluated based on total retinal thickness and outer retinal thickness (thickness of outer nuclear layer and photoreceptor layer). An apoptotic index and a cell proliferation index for the photoreceptor cells, at 13 days of age, were calculated based on terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) labeling, respectively. Results: At 13 days of age, total and outer retinal thickness in saline-treated C3H mice were 140.3 µm and 37.5 µm, compared with 160.4 µm and 49.5 µm, respectively, in Ac-DEVD-CHO-treated C3H mice (P

  • Caspase 3 Inhibitor transiently delays inherited retinal degeneration in c3h mice carrying the rd gene
    Graefes Archive for Clinical and Experimental Ophthalmology, 2002
    Co-Authors: Katsuhiko Yoshizawa, Jihong Yang, Hideto Senzaki, Yasuhiko Kiyozuka, Nobuaki Shikata, Katsuji Kiuchi, Hiroyuki Nambu, Airo Tsubura
    Abstract:

    Background: The effect of a Caspase-3 Inhibitor on retinal degeneration in C3H mice carrying the rd gene, a mutation of a rod-specific phosphodiesterase, was investigated. Methods: A quantity of 2 mg/kg of Ac-DEVD-CHO, as Inhibitor, was injected intraperitoneally every other day from 8 days of age, and retinal damage was compared with that in saline-treated C3H mice at 13 days (1 day after the third treatment) and 17 days of age (1 day after the fifth treatment). Retina of ICR mice not carrying rd gene was also evaluated under the same protocol. The efficacy of Ac-DEVD-CHO was evaluated based on total retinal thickness and outer retinal thickness (thickness of outer nuclear layer and photoreceptor layer). An apoptotic index and a cell proliferation index for the photoreceptor cells, at 13 days of age, were calculated based on terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) labeling, respectively. Results: At 13 days of age, total and outer retinal thickness in saline-treated C3H mice were 140.3 µm and 37.5 µm, compared with 160.4 µm and 49.5 µm, respectively, in Ac-DEVD-CHO-treated C3H mice (P<0.01, respectively). In ICR mice, total and outer retinal thickness were 182.1 µm and 90.9 µm, respectively, in saline- treated mice and 183.8 µm and 89.6 µm in Ac-DEVD-CHO-treated mice (not significant). At this time, the TUNEL index was 23.52 cells/104 µm2 of outer nuclear layer in saline-treated C3H mice; Ac-DEVD-CHO treatment significantly reduced this value to 18.73 cells/104 µm2 (P<0.05). The TUNEL index in saline- and Ac-DEVD-CHO-treated ICR mice was 0.59 cells/104 µm2 and 0.80 cells/104 µm2, respectively (not significant); Ac-DEVD-CHO treatment had no influence on normally developing retina. The PCNA index was not affected by Ac-DEVD-CHO-treatment. However, at 17 days of age, Ac-DEVD-CHO treatment did not ameliorate retinal degeneration. Conclusions: The Caspase-3 Inhibitor was transiently effective in delaying retinal degeneration through inhibition of the apoptosis of photoreceptor cells in rd gene-carrying mice. The use of Caspase-3 Inhibitors may have therapeutic applications in the treatment of human retinal degeneration.

  • Caspase-3 Inhibitor rescues N -methyl- N -nitrosourea-induced retinal degeneration in Sprague-Dawley rats.
    Experimental eye research, 2000
    Co-Authors: Katsuhiko Yoshizawa, Jihong Yang, Hideto Senzaki, Yoshiko Uemura, Yasuhiko Kiyozuka, Nobuaki Shikata, Yuji Oishi, Hirohiko Miki, Airo Tsubura
    Abstract:

    The effect of a Caspase-3 Inhibitor on N -methyl- N -nitrosourea (MNU)-induced retinal degeneration was investigated. Sixty mg kg(-1)MNU was given intraperitoneally to 50 day old female Sprague-Dawley rats, and 4000 ng Ac-DEVD-CHO, a Caspase-3 Inhibitor, was injected intravitreally twice at 0 and 10 hr after MNU. In both peripheral and central retina, an apoptotic index of the photoreceptor cells 24 hr after MNU treatment was calculated by TUNEL labeling, and retinal damage 7 days after MNU treatment was evaluated from retinal thickness and a retinal damage ratio (length of damaged retina : whole retinal length). In MNU-treated rats, the TUNEL index 24 hr post-MNU was 79.5% in the peripheral and 83.7% in the central retina, while the Ac-DEVD-CHO injection significantly reduced it to 59.7 and 71.8%, respectively. Total retinal thickness 7 days after MNU was 38 microm in the peripheral and 75 microm in the central retina. Ac-DEVD-CHO injection increased these values to 72 and 77 microm, respectively. The retinal damage ratio 7 days after MNU was 98.5%. Ac-DEVD-CHO injection significantly reduced this value to 54.4%. The use of a Caspase-3 Inhibitor was effective in the suppression of MNU-induced retinal apoptosis and may be a therapeutic intervention in human retinitis pigmentosa.

Liqiao Fan - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Caspase 3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice
    Chinese critical care medicine, 2010
    Co-Authors: Li-xia Liu, Yan Huo, Liqiao Fan
    Abstract:

    OBJECTIVE To observe the effects of Caspase-3 Inhibitor Ac-DEVD-CHO on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice. METHODS One hundred and two male C57BL/6 mice were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. The animals were assigned into three equal groups (n=34) according to random number table: sham group, model group, and Caspase-3 Inhibitor (CI) group. Thirty minutes before CLP, Ac-DEVD-CHO (4 μg/g) was injected subcutaneously in CI group. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined, and the concentrations of tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-10) were measured by enzyme linked immunosorbent assay (ELISA), the renal cell apoptosis rate was determined by flow cytometry and the expression of Caspase-3 mRNA was determined by real time reverse transcription-polymerase chain reaction (RT-PCR) at 6, 12 and 24 hours after operation. The 4-day and 7-day survival rates of three groups of mice were observed. RESULTS Compared with sham group, the concentrations of serum BUN, TNF-α, IL-6, IL-10 and the renal cell apoptosis rates, the Caspase-3 mRNA expression were increased significantly at all time points after CLP, the concentrations of serum Cr were increased significantly at 6 hours, with the 4-day and 7-day survival rates were decreased significantly. Compared with model group, in CI group, the concentrations of serum BUN were decreased significantly at all time points after operation and those of Cr were decreased significantly at 6 hours, then restored to those of the sham group at 12 hours and 24 hours; the concentrations of serum TNF-α, IL-6 were decreased and those of IL-10 elevated significantly at all time points [TNF-α (μg/L) 6 hours: 436.2±64.2 vs. 653.6±8.9, 12 hours: 233.4±85.4 vs. 579.7±137.1, 24 hours: 151.0±90.3 vs. 551.0±119.8; IL-6 (μg/L) 6 hours: 1 033.2±345.8 vs. 1 595.3±159.4, 12 hours : 366.3±68.3 vs. 1 330.7±249.8, 24 hours: 241.2±208.4 vs. 815.3±572.7; IL-10 (μg/L) 6 hours : 33.6±10.4 vs. 26.6±4.5, 12 hours: 37.2±5.0 vs. 24.5±4.3, 24 hours: 38.3±5.5 vs. 18.2±1.6, all P<0.05]; the renal cell apoptosis rate and the expression of Caspase-3 mRNA were decreased significantly at all time points [apoptosis rates 6 hours: (13.9±3.2)% vs. (18.3±1.4)%, 12 hours: (10.5±3.6)% vs. (15.9±3.5)%, 24 hours: (8.4±1.8)% vs. (12.5±2.1)%; Caspase-3 mRNA 6 hours: 1.95±0.16 vs. 3.84±0.35, 12 hours: 1.89±0.19 vs. 3.97±0.73, 24 hours : 2.01±0.20 vs. 4.97±0.24, all P<0.05]. The 4-day survival rate of CI group was improved (80% vs. 20%), but that of 7-day did not change (20% vs. 20%). CONCLUSION The modulation of Caspase-3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection may be associated with a decrease in renal cell apoptosis by Ac-DEVD-CHO.

  • The effect of Caspase-3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice
    Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue, 2010
    Co-Authors: Li-xia Liu, Yan Huo, Liqiao Fan
    Abstract:

    OBJECTIVE To observe the effects of Caspase-3 Inhibitor Ac-DEVD-CHO on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice. METHODS One hundred and two male C57BL/6 mice were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. The animals were assigned into three equal groups (n=34) according to random number table: sham group, model group, and Caspase-3 Inhibitor (CI) group. Thirty minutes before CLP, Ac-DEVD-CHO (4 μg/g) was injected subcutaneously in CI group. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined, and the concentrations of tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-10) were measured by enzyme linked immunosorbent assay (ELISA), the renal cell apoptosis rate was determined by flow cytometry and the expression of Caspase-3 mRNA was determined by real time reverse transcription-polymerase chain reaction (RT-PCR) at 6, 12 and 24 hours after operation. The 4-day and 7-day survival rates of three groups of mice were observed. RESULTS Compared with sham group, the concentrations of serum BUN, TNF-α, IL-6, IL-10 and the renal cell apoptosis rates, the Caspase-3 mRNA expression were increased significantly at all time points after CLP, the concentrations of serum Cr were increased significantly at 6 hours, with the 4-day and 7-day survival rates were decreased significantly. Compared with model group, in CI group, the concentrations of serum BUN were decreased significantly at all time points after operation and those of Cr were decreased significantly at 6 hours, then restored to those of the sham group at 12 hours and 24 hours; the concentrations of serum TNF-α, IL-6 were decreased and those of IL-10 elevated significantly at all time points [TNF-α (μg/L) 6 hours: 436.2±64.2 vs. 653.6±8.9, 12 hours: 233.4±85.4 vs. 579.7±137.1, 24 hours: 151.0±90.3 vs. 551.0±119.8; IL-6 (μg/L) 6 hours: 1 033.2±345.8 vs. 1 595.3±159.4, 12 hours : 366.3±68.3 vs. 1 330.7±249.8, 24 hours: 241.2±208.4 vs. 815.3±572.7; IL-10 (μg/L) 6 hours : 33.6±10.4 vs. 26.6±4.5, 12 hours: 37.2±5.0 vs. 24.5±4.3, 24 hours: 38.3±5.5 vs. 18.2±1.6, all P

Li-xia Liu - One of the best experts on this subject based on the ideXlab platform.

  • Role of the early intervention of Caspase-3 Inhibitor in acute kidney injury induced by sepsis
    Chinese journal of experimental surgery, 2012
    Co-Authors: Li-xia Liu, Yan Huo
    Abstract:

    Objective To explore the role of the early intervention of Caspase-3 Inhibitor (CI) in acute kidney injury (AKI) induced by sepsis.Methods Seventy-two healthy male C57BL/6 mice were assigned into three groups (n =24 each):sham group,cecal ligation and puncture (CLP) group and CI group.Thirty min afterCLP,Ac-DEVD-CHO (4 μg/g) was injected subcutaneously in CI group.The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined,and the renal cell apoptosis rate was measured by flow cytometry at 6,12 and 24 h after operation and the expression levels of renal Caspase-3,B lymphocytes/leukemia-2 (bcl-2) and bax proteins were detected by using immunohistochemistry at 24 h after operation.Pathological changes in renal tissues were observed under a light microscope.Results As compared with sham group,the concentrations of serum Cr at 6 h and BUN at 6 h and 12 h after operation were significantly increased (P ＜ 0.05),kidney tissue pathological damage score and renal cell apoptosis rate at all time points were significantly elevated ( P ＜ 0.05 ),and the renal expression levels of Caspase-3,bcl-2 and Bax proteins were significantly increased at 24 h after operation ( P ＜ 0.05 ) in CLP group.As compared with CLP group,the concentrations of serum Cr and BUN were decreased significantly at 6 h after operation [ serum Cr:(83.82 ± 10.15 ) μmol/L vs.( 123.05 ± 33.48) μmol/L; BUN:( 10.15 ±4.34) mmol/L vs.( 14.02 ± 3.51 ) mmol/L,all P ＜ 0.05 ] ; mouse kidney tissue pathological damage score and renal cell apoptosis rate at all time points were significantly decreased [ kidney tissue pathological damage score at 6 h:(0.88 ± 0.64) points vs.(2.17 ± 0.75 ) points,at 12 h:( 0.63 ±0.74) points vs.( 1.83 ±0.98) points,at 24 h:(1.83 ±0.98) points vs.(1.33 ±0.52) points; renal cell apoptosis rate at 6 h:(13.28 ±0.91)％ vs.(18.27 ±1.40)％,at 12 h:(9.71±0.91)％ vs.(15.86 ±3.51)％,at 24h:(8.45 ±0.55)％ vs.(12.48 ±2.14)％,allP＜0.05]; the expression levels of Caspase-3 and Bax in kidney tissue were down-regulated significantly ( P ＜ 0.05 ),but bcl-2 expression was up-regulated significantly (P ＜ 0.05 ) in CI group.Conclusion The selective Caspase-3 Inhibitor has renal protective effect on sepsis-related AKI by the inhibition of renal cell apoptosis. Key words: Sepsis; Acute kidney injury; Caspase-3; Apoptosis

  • the effect of Caspase 3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice
    Chinese critical care medicine, 2010
    Co-Authors: Li-xia Liu, Yan Huo, Liqiao Fan
    Abstract:

    OBJECTIVE To observe the effects of Caspase-3 Inhibitor Ac-DEVD-CHO on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice. METHODS One hundred and two male C57BL/6 mice were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. The animals were assigned into three equal groups (n=34) according to random number table: sham group, model group, and Caspase-3 Inhibitor (CI) group. Thirty minutes before CLP, Ac-DEVD-CHO (4 μg/g) was injected subcutaneously in CI group. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined, and the concentrations of tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-10) were measured by enzyme linked immunosorbent assay (ELISA), the renal cell apoptosis rate was determined by flow cytometry and the expression of Caspase-3 mRNA was determined by real time reverse transcription-polymerase chain reaction (RT-PCR) at 6, 12 and 24 hours after operation. The 4-day and 7-day survival rates of three groups of mice were observed. RESULTS Compared with sham group, the concentrations of serum BUN, TNF-α, IL-6, IL-10 and the renal cell apoptosis rates, the Caspase-3 mRNA expression were increased significantly at all time points after CLP, the concentrations of serum Cr were increased significantly at 6 hours, with the 4-day and 7-day survival rates were decreased significantly. Compared with model group, in CI group, the concentrations of serum BUN were decreased significantly at all time points after operation and those of Cr were decreased significantly at 6 hours, then restored to those of the sham group at 12 hours and 24 hours; the concentrations of serum TNF-α, IL-6 were decreased and those of IL-10 elevated significantly at all time points [TNF-α (μg/L) 6 hours: 436.2±64.2 vs. 653.6±8.9, 12 hours: 233.4±85.4 vs. 579.7±137.1, 24 hours: 151.0±90.3 vs. 551.0±119.8; IL-6 (μg/L) 6 hours: 1 033.2±345.8 vs. 1 595.3±159.4, 12 hours : 366.3±68.3 vs. 1 330.7±249.8, 24 hours: 241.2±208.4 vs. 815.3±572.7; IL-10 (μg/L) 6 hours : 33.6±10.4 vs. 26.6±4.5, 12 hours: 37.2±5.0 vs. 24.5±4.3, 24 hours: 38.3±5.5 vs. 18.2±1.6, all P<0.05]; the renal cell apoptosis rate and the expression of Caspase-3 mRNA were decreased significantly at all time points [apoptosis rates 6 hours: (13.9±3.2)% vs. (18.3±1.4)%, 12 hours: (10.5±3.6)% vs. (15.9±3.5)%, 24 hours: (8.4±1.8)% vs. (12.5±2.1)%; Caspase-3 mRNA 6 hours: 1.95±0.16 vs. 3.84±0.35, 12 hours: 1.89±0.19 vs. 3.97±0.73, 24 hours : 2.01±0.20 vs. 4.97±0.24, all P<0.05]. The 4-day survival rate of CI group was improved (80% vs. 20%), but that of 7-day did not change (20% vs. 20%). CONCLUSION The modulation of Caspase-3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection may be associated with a decrease in renal cell apoptosis by Ac-DEVD-CHO.

  • The effect of Caspase-3 Inhibitor on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice
    Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue, 2010
    Co-Authors: Li-xia Liu, Yan Huo, Liqiao Fan
    Abstract:

    OBJECTIVE To observe the effects of Caspase-3 Inhibitor Ac-DEVD-CHO on the concentrations of serum inflammatory cytokines in sepsis related acute kidney injury induced by peritoneal cavity infection in mice. METHODS One hundred and two male C57BL/6 mice were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. The animals were assigned into three equal groups (n=34) according to random number table: sham group, model group, and Caspase-3 Inhibitor (CI) group. Thirty minutes before CLP, Ac-DEVD-CHO (4 μg/g) was injected subcutaneously in CI group. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined, and the concentrations of tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-10) were measured by enzyme linked immunosorbent assay (ELISA), the renal cell apoptosis rate was determined by flow cytometry and the expression of Caspase-3 mRNA was determined by real time reverse transcription-polymerase chain reaction (RT-PCR) at 6, 12 and 24 hours after operation. The 4-day and 7-day survival rates of three groups of mice were observed. RESULTS Compared with sham group, the concentrations of serum BUN, TNF-α, IL-6, IL-10 and the renal cell apoptosis rates, the Caspase-3 mRNA expression were increased significantly at all time points after CLP, the concentrations of serum Cr were increased significantly at 6 hours, with the 4-day and 7-day survival rates were decreased significantly. Compared with model group, in CI group, the concentrations of serum BUN were decreased significantly at all time points after operation and those of Cr were decreased significantly at 6 hours, then restored to those of the sham group at 12 hours and 24 hours; the concentrations of serum TNF-α, IL-6 were decreased and those of IL-10 elevated significantly at all time points [TNF-α (μg/L) 6 hours: 436.2±64.2 vs. 653.6±8.9, 12 hours: 233.4±85.4 vs. 579.7±137.1, 24 hours: 151.0±90.3 vs. 551.0±119.8; IL-6 (μg/L) 6 hours: 1 033.2±345.8 vs. 1 595.3±159.4, 12 hours : 366.3±68.3 vs. 1 330.7±249.8, 24 hours: 241.2±208.4 vs. 815.3±572.7; IL-10 (μg/L) 6 hours : 33.6±10.4 vs. 26.6±4.5, 12 hours: 37.2±5.0 vs. 24.5±4.3, 24 hours: 38.3±5.5 vs. 18.2±1.6, all P

Thomas N. Chase - One of the best experts on this subject based on the ideXlab platform.

  • NMDA and non-NMDA receptor-stimulated IκB-α degradation: differential effects of the Caspase-3 Inhibitor DEVD·CHO, ethanol and free radical scavenger OPC-14117
    Brain research, 2000
    Co-Authors: Masami Nakai, Zheng-hong Qin, Yumei Wang, Thomas N. Chase
    Abstract:

    Abstract The excitotoxic response of striatal neurons to NMDA and non-NMDA receptor agonists involves the nuclear translocation of transcription factor nuclear factor-kappa B (NF-κB) due to IκB-α degradation. Resultant augmentation in c-Myc, p53 and cyclin D1 expression presages the apoptotic-like destruction of these cells in vivo. To differentiate molecular events triggered by intrastriatally injected quinolinic acid (QA, 60 nmol) and kainic acid (KA, 2.5 nmol), we compared the effects of a Caspase-3 Inhibitor (DEVD·CHO, 8 μg intrastriatally), a free radical scavenger (OPC-14117; 600 mg/kg, orally) and ethanol (2.14–8.6 μmol, intrastriatally or 25–100 mmol/kg, orally) on changes induced by these glutamatergic agonists on NF-κB cascade components and the apoptotic death of rat striatal neurons in vivo. The results indicated that the QA-induced degradation of IκB-α is almost totally mediated by a Caspase-3-dependent mechanism, while KA-induced IκB-α degradation is only partially dependent on Caspase-3. OPC-14117 attenuated the effects of QA but not KA on IκB-α degradation, suggesting that oxidative stress contributes to the QA- but not the KA-induced degradation of IκB-α. In contrast, ethanol inhibited the KA- but not the QA-induced degradation of IκB-α and the ensuing DNA fragmentation and loss of striatal GABAergic neurons. It would now appear that NF-κB activation in striatal neurons induced by NMDA or KA receptor stimulation involves different biochemical mechanisms. Since excitotoxicity associated with NF-κB activation may contribute to neuronal degenerative disorders such as Huntington's disease, a more detailed understanding of biochemical events underlying ionotrophic glutamate receptor-stimulated cell death may assist in the discovery of alternative approaches to interdicting the deleterious consequences of excitotoxic insult.

  • nmda and non nmda receptor stimulated iκb α degradation differential effects of the Caspase 3 Inhibitor devd cho ethanol and free radical scavenger opc 14117
    Brain Research, 2000
    Co-Authors: Masami Nakai, Zheng-hong Qin, Yumei Wang, Thomas N. Chase
    Abstract:

    Abstract The excitotoxic response of striatal neurons to NMDA and non-NMDA receptor agonists involves the nuclear translocation of transcription factor nuclear factor-kappa B (NF-κB) due to IκB-α degradation. Resultant augmentation in c-Myc, p53 and cyclin D1 expression presages the apoptotic-like destruction of these cells in vivo. To differentiate molecular events triggered by intrastriatally injected quinolinic acid (QA, 60 nmol) and kainic acid (KA, 2.5 nmol), we compared the effects of a Caspase-3 Inhibitor (DEVD·CHO, 8 μg intrastriatally), a free radical scavenger (OPC-14117; 600 mg/kg, orally) and ethanol (2.14–8.6 μmol, intrastriatally or 25–100 mmol/kg, orally) on changes induced by these glutamatergic agonists on NF-κB cascade components and the apoptotic death of rat striatal neurons in vivo. The results indicated that the QA-induced degradation of IκB-α is almost totally mediated by a Caspase-3-dependent mechanism, while KA-induced IκB-α degradation is only partially dependent on Caspase-3. OPC-14117 attenuated the effects of QA but not KA on IκB-α degradation, suggesting that oxidative stress contributes to the QA- but not the KA-induced degradation of IκB-α. In contrast, ethanol inhibited the KA- but not the QA-induced degradation of IκB-α and the ensuing DNA fragmentation and loss of striatal GABAergic neurons. It would now appear that NF-κB activation in striatal neurons induced by NMDA or KA receptor stimulation involves different biochemical mechanisms. Since excitotoxicity associated with NF-κB activation may contribute to neuronal degenerative disorders such as Huntington's disease, a more detailed understanding of biochemical events underlying ionotrophic glutamate receptor-stimulated cell death may assist in the discovery of alternative approaches to interdicting the deleterious consequences of excitotoxic insult.

Bernhard A. Sabel - One of the best experts on this subject based on the ideXlab platform.

  • Caspase-3 Inhibitor Z-DEVD-FMK enhances retinal ganglion cell survival and vision restoration after rabbit traumatic optic nerve injury.
    Restorative neurology and neuroscience, 2015
    Co-Authors: Yuanyuan Liu, Hua Yan, Song Chen, Bernhard A. Sabel
    Abstract:

    PURPOSE Vision loss after traumatic optic nerve injury is considered irreversible because of the retrograde loss of retinal ganglion cells (RGCs) which undergo apoptosis. Because the second messenger Caspase-3 plays a major role in apoptosis, we now evaluated the efficacy of the specific Caspase-3 Inhibitor, Z-DEVD-FMK, in a rabbit model of fluid percussion injury (FPI) which mimics traumatic optic nerve injury in humans to enhance cell survival and improve vision. METHODS Survival of RGCs and recovery of vision were studied using retinal morphological markers and visual evoked potentials (VEP), respectively. The FPI traumatized animals were treated in their right eye with a single intravitreal or peribulbar injection of Z-DEVD-FMK 30 min post-injury compared to 2% DMSO control injections in their left eye. RESULTS Intravitreal Z-DEVD-FMK, but not control injections, led to down-regulation of capase-3 and reduced, in a dose-dependent manner, RGCs apoptosis from 7 to 21 days post-injury. These morphological improvements were accompanied by vision restoration as documented by VEP. The neuroprotection after intravitreal injection of Z-DEVD-FMK was more effective than the peribulbar application. CONCLUSIONS The Caspase-3 Inhibitor Z-DEVD-FMK is neuroprotective by inhibiting RGCs apoptosis when injected 30 min after optic nerve damage and significantly promotes restoration of vision. A controlled clinical trial is now needed to evaluate the efficacy and safety of Z-DEVD-FMK in humans.