The Experts below are selected from a list of 837 Experts worldwide ranked by ideXlab platform

Irene Volitakis - One of the best experts on this subject based on the ideXlab platform.

  • effects of neonatal iron feeding and chronic Clioquinol administration on the parkinsonian human a53t transgenic mouse
    ACS Chemical Neuroscience, 2016
    Co-Authors: Jessica L Billings, Ashley I Bush, Robert A Cherny, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, David Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life.

  • Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse
    2016
    Co-Authors: Jessica L. Billings, Ashley I Bush, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, Robert A. Cherny, David I. Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson’s disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10–17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life

  • novel fluorinated 8 hydroxyquinoline based metal ionophores for exploring the metal hypothesis of alzheimer s disease
    ACS Medicinal Chemistry Letters, 2015
    Co-Authors: Steven H Liang, Irene Volitakis, Adam Southon, Benjamin H Fraser, Anwen M Krauseheuer, Bo Zhang, Timothy M Shoup, Rebecca M Lewis, Ivan Greguric, Ashley I Bush
    Abstract:

    Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer’s disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, Clioquinol, and PBT2. Compounds 15–17 and 28–30 showed exceptional metal ionophore ability (6–40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if ra...

  • novel fluorinated 8 hydroxyquinoline based metal ionophores for exploring the metal hypothesis of alzheimer s disease
    ACS Medicinal Chemistry Letters, 2015
    Co-Authors: Steven H Liang, Irene Volitakis, Adam Southon, Benjamin H Fraser, Anwen M Krauseheuer, Bo Zhang, Timothy M Shoup, Rebecca M Lewis, Yifeng Han, Ivan Greguric
    Abstract:

    Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer's disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, Clioquinol, and PBT2. Compounds 15-17 and 28-30 showed exceptional metal ionophore ability (6-40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with (18)F.

  • Novel Fluorinated 8‑Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer’s Disease
    2015
    Co-Authors: Steven H. Liang, Irene Volitakis, Am Krause-heuer, Benjamin H Fraser, Bo Zhang, Timothy M Shoup, Yifeng Han, Adam G. Southon, Rebecca Lewis, Ivan Greguric
    Abstract:

    Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer’s disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, Clioquinol, and PBT2. Compounds 15–17 and 28–30 showed exceptional metal ionophore ability (6–40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with 18F

David Finkelstein - One of the best experts on this subject based on the ideXlab platform.

  • Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis
    2016
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation an

  • effects of neonatal iron feeding and chronic Clioquinol administration on the parkinsonian human a53t transgenic mouse
    ACS Chemical Neuroscience, 2016
    Co-Authors: Jessica L Billings, Ashley I Bush, Robert A Cherny, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, David Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life.

  • Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica
    PLOS ONE, 2013
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

  • rapid restoration of cognition in alzheimer s transgenic mice with 8 hydroxy quinoline analogs is associated with decreased interstitial aβ
    Neuron, 2008
    Co-Authors: Robert A Cherny, Paul A Adlard, David Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Irene Volitakis
    Abstract:

    Summary As a disease-modifying approach for Alzheimer's disease (AD), Clioquinol (CQ) targets β-amyloid (As) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of As, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain As within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated As reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

  • rapid restoration of cognition in alzheimer s transgenic mice with 8 hydroxy quinoline analogs is associated with decreased interstitial aβ
    Neuron, 2008
    Co-Authors: Paul A Adlard, Robert A Cherny, Irene Volitakis, David Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Xiang Liu
    Abstract:

    As a disease-modifying approach for Alzheimer's disease (AD), Clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

Ashley I Bush - One of the best experts on this subject based on the ideXlab platform.

  • Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis
    2016
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation an

  • effects of neonatal iron feeding and chronic Clioquinol administration on the parkinsonian human a53t transgenic mouse
    ACS Chemical Neuroscience, 2016
    Co-Authors: Jessica L Billings, Ashley I Bush, Robert A Cherny, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, David Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life.

  • Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse
    2016
    Co-Authors: Jessica L. Billings, Ashley I Bush, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, Robert A. Cherny, David I. Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson’s disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10–17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life

  • novel fluorinated 8 hydroxyquinoline based metal ionophores for exploring the metal hypothesis of alzheimer s disease
    ACS Medicinal Chemistry Letters, 2015
    Co-Authors: Steven H Liang, Irene Volitakis, Adam Southon, Benjamin H Fraser, Anwen M Krauseheuer, Bo Zhang, Timothy M Shoup, Rebecca M Lewis, Ivan Greguric, Ashley I Bush
    Abstract:

    Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer’s disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, Clioquinol, and PBT2. Compounds 15–17 and 28–30 showed exceptional metal ionophore ability (6–40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if ra...

  • Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica
    PLOS ONE, 2013
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

Paul A Adlard - One of the best experts on this subject based on the ideXlab platform.

  • Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis
    2016
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation an

  • effects of neonatal iron feeding and chronic Clioquinol administration on the parkinsonian human a53t transgenic mouse
    ACS Chemical Neuroscience, 2016
    Co-Authors: Jessica L Billings, Ashley I Bush, Robert A Cherny, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, David Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life.

  • Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse
    2016
    Co-Authors: Jessica L. Billings, Ashley I Bush, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, Robert A. Cherny, David I. Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson’s disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10–17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life

  • Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica
    PLOS ONE, 2013
    Co-Authors: Jim Geiser, Ashley I Bush, Paul A Adlard, David Finkelstein, Robert C. De Lisle, Glen K. Andrews
    Abstract:

    Background Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary Clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

  • rapid restoration of cognition in alzheimer s transgenic mice with 8 hydroxy quinoline analogs is associated with decreased interstitial aβ
    Neuron, 2008
    Co-Authors: Robert A Cherny, Paul A Adlard, David Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Irene Volitakis
    Abstract:

    Summary As a disease-modifying approach for Alzheimer's disease (AD), Clioquinol (CQ) targets β-amyloid (As) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of As, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain As within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated As reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

Robert A Cherny - One of the best experts on this subject based on the ideXlab platform.

  • effects of neonatal iron feeding and chronic Clioquinol administration on the parkinsonian human a53t transgenic mouse
    ACS Chemical Neuroscience, 2016
    Co-Authors: Jessica L Billings, Ashley I Bush, Robert A Cherny, Dominic J Hare, Milawaty Nurjono, Irene Volitakis, Paul A Adlard, David Finkelstein
    Abstract:

    Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator Clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of Clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using Clioquinol later in life.

  • rapid restoration of cognition in alzheimer s transgenic mice with 8 hydroxy quinoline analogs is associated with decreased interstitial aβ
    Neuron, 2008
    Co-Authors: Robert A Cherny, Paul A Adlard, David Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Irene Volitakis
    Abstract:

    Summary As a disease-modifying approach for Alzheimer's disease (AD), Clioquinol (CQ) targets β-amyloid (As) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of As, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain As within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated As reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

  • rapid restoration of cognition in alzheimer s transgenic mice with 8 hydroxy quinoline analogs is associated with decreased interstitial aβ
    Neuron, 2008
    Co-Authors: Paul A Adlard, Robert A Cherny, Irene Volitakis, David Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Xiang Liu
    Abstract:

    As a disease-modifying approach for Alzheimer's disease (AD), Clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

  • metal protein attenuation with iodochlorhydroxyquin Clioquinol targeting aβ amyloid deposition and toxicity in alzheimer disease a pilot phase 2 clinical trial
    JAMA Neurology, 2003
    Co-Authors: Craig W Ritchie, Ashley I Bush, Andrew Mackinnon, Steve Macfarlane, Maree Mastwyk, Lachlan Macgregor, Lyn Kiers, Robert A Cherny, Qiaoxin Li, Amanda Tammer
    Abstract:

    Background Alzheimer disease (AD) may be caused by the toxic accumulation of β-amyloid (Aβ). Objective To test this theory, we developed a clinical intervention using Clioquinol, a metal-protein–attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Aβ, thereby promoting Aβ dissolution and diminishing its toxic properties. Methods A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. Results Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, ≥25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the Clioquinol group. Plasma Aβ 42 levels declined in the Clioquinol group and increased in the placebo group. Plasma zinc levels rose in the Clioquinol-treated group. The drug was well tolerated. Conclusion Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein–attenuating compound.

  • treatment with a copper zinc chelator markedly and rapidly inhibits β amyloid accumulation in alzheimer s disease transgenic mice
    Neuron, 2001
    Co-Authors: Robert A Cherny, Irene Volitakis, Craig S Atwood, Michel Xilinas, Danielle N Gray, Walton D Jones, Catriona Mclean, Kevin J Barnham, Fiona W Fraser, Youngseon Kim
    Abstract:

    Abstract Inhibition of neocortical β-amyloid (Aβ) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Aβ deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Aβ deposition (−375 μg/g wet weight, p=0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with Clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Aβ (1.45% of total cerebral Aβ); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Aβ as a novel therapy for the prevention and treatment of AD.