Dr. Schipper is a professor of neurology and medicine at McGill University, a staff neurologist at Jewish General Hospital (Montreal) and director of a Neuroscience laboratory at the hospital's Lady Davis Institute. His long-standing interests are in the fields of Oxidative Stress, Brain Aging and Neurodegenerative Diseases. His major research focus is on the role(s) of heme oxygenase-1 (HO-1) and pathological brain iron deposition in the aging and diseased CNS.
Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer’s disea... more Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer’s disease, Parkinson’s disease, and other central nervous system disorders. By engaging in Fenton and other redox reactions, transition metals generate reactive chemical species implicated in the development of numerous neurological conditions. Oxidative stress, mitochondrial insufficiency, and abnormal transition metal mobilization may represent a core, mutually reinforcing neuropathological ‘lesion’ that provides a critical link between normal brain aging and neurodegeneration. Moreover, sustained upregulation of the heme-degrading enzyme, heme oxygenase-1, within the astrocytic compartment may be necessary and sufficient for the development of this pivotal tripartite lesion.
Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endo... more Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic ovarian condition which have been shown to result from the EV-induced hypothalamic pathology.
Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor ... more Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase–extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017–24]
Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer's d... more Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer's disease, Parkinson's disease, and other central nervous system disorders. By engaging in Fenton and other redox reactions, transition metals generate reactive chemical species implicated in the development of numerous neurological conditions. Oxidative stress, mitochondrial insufficiency, and abnormal transition metal mobilization may represent a core, mutually reinforcing neuropathological “lesion” that provides a critical link between normal brain aging and neurodegeneration. Moreover, sustained upregulation of the heme-degrading enzyme, heme oxygenase-1 within the astrocytic compartment may be necessary and sufficient for the development of this pivotal tripartite lesion.
Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer’s disea... more Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer’s disease, Parkinson’s disease, and other central nervous system disorders. By engaging in Fenton and other redox reactions, transition metals generate reactive chemical species implicated in the development of numerous neurological conditions. Oxidative stress, mitochondrial insufficiency, and abnormal transition metal mobilization may represent a core, mutually reinforcing neuropathological ‘lesion’ that provides a critical link between normal brain aging and neurodegeneration. Moreover, sustained upregulation of the heme-degrading enzyme, heme oxygenase-1, within the astrocytic compartment may be necessary and sufficient for the development of this pivotal tripartite lesion.
Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endo... more Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic ovarian condition which have been shown to result from the EV-induced hypothalamic pathology.
Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor ... more Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase–extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017–24]
Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer's d... more Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer's disease, Parkinson's disease, and other central nervous system disorders. By engaging in Fenton and other redox reactions, transition metals generate reactive chemical species implicated in the development of numerous neurological conditions. Oxidative stress, mitochondrial insufficiency, and abnormal transition metal mobilization may represent a core, mutually reinforcing neuropathological “lesion” that provides a critical link between normal brain aging and neurodegeneration. Moreover, sustained upregulation of the heme-degrading enzyme, heme oxygenase-1 within the astrocytic compartment may be necessary and sufficient for the development of this pivotal tripartite lesion.
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Papers by Hyman M Schipper