Oxidative Stress and the CNS

Re^2: Symposium 139

Thanx for the detailed reply.
On Sun Dec 6, Hyman Schipper wrote
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>On Sun Dec 6, grover wrote
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>>Dr. Schipper: Hope you are enjoying the meeting. Great poster. If I am to understand the model correctly - it is based on a free radical mediated damage inducing hemoxygenase, followed by mitochondrial damage which leads to deposition of iron in mitochondria of astroglia. Three questions. First in what is the evidence that in Parkinson disesase, a mitochondrial damage preceeds hemoxygenase induction and iron deposition in astroglia? Second, how do you propose this model to produce a neuronal damage - simply as an ability of astroglia to protect and/or communicate with the neurons? Third, what would make this damage specific only to certain regions of the brain?
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>Dr. Grover: 1. Our model states that pro-oxidants induce glial HO-1, but not that oxidative DAMAGE is necessary for the up-regulation of this enzyme. 2. Although there is now ample evidence for increased HO-1 expression, aberrant iron deposition and mitochondrial injury in the Parkinson brain, it is very difficult, if not impossible, to determine the temporal sequence of these events upon pathological examination post-mortem human neural tissues. This is precisely why we feel that it is so important to develop in vitro and animal models that recapitulate many of the structural and biochemical abnormalities observed in the human condition. Our findings (reviewed in this symposium) suggest that the temporal sequence of events is indeed that given above (oxidative stress yields HO-1 induction yields mitochondrial iron sequestration yields mitochondrial injury yields further free radical generation--a vicious spiral of oxidative neural injury which may give neurodegenerative diseases a "life of their own" even after initiating neurotoxic insults have dissipated. 3. We have shown that PC12 cells grown atop astroglia enriched for mitochondrial iron by cysteamine pretreatment are far more vulnerable to dopamine-H2O2 challenge than PC12 cells grown atop normal, "iron-poor" astroglia (Frankel and Schipper, Soc Neurosci Abstr,23:1371,1997). Since the only difference in these co-cultures involved the astrocyte compartment, it is conceivable that free radicals generated within the glia may "leak" to the extracellular space and subsequently compromise nearby neuronal elements. (H2O2 is lipid soluble and can easily traverse cell membranes, and superoxide has been shown to be extruded from glia via anion channels). 4. The HO-1/mitochondrial iron uptake mechanism is, we believe, common to several human neurodegenerative disorders, including Parkinson's disease(PD), Alzheimer's disease(AD) and possibly amyotrophic lateral sclerosis. Thus, we do not think that this mechanism per se confers any anatomical specificity in these conditions (since the topography of the lesions differ markedly among these disorders). It may well be the anatomical distribution of the upstream oxidative stressor, such as dopamine in PD and b-amyloid peptide in AD, that is largely responsible for the (downstream) patterns of pathological iron deposition and mitochondrial insufficiency seen in these conditions. Your questions touch on important issues germane to the entire field of neurodegenerative disease research, and I hope I have adequately conveyed to you our perspective on some of these salient points.
>Hyman Schipper

Mon Dec 7