br Neurodystrophic effects of HO It is

Neurodystrophic effects of HO-1 It is well known that neonatal hyperbilirubinemia (jaundice) may lead to irreversible neurological injury in children (kernicterus). This outcome can be prevented by photodegradation of circulating bilirubin or treatment with metalloporphyrin inhibitors of HO enzymatic activity (Qato and Maines, 1985). Pharmacological suppression of HO activity has been shown to lessen traumatic CA1 insults in rat hippocampal slices (Panizzon et al., 1996), decrease tissue necrosis and edema after focal cerebral hypoperfusion in rats (Kadoya et al., 1995) and provide neuroprotection in some (but not all – see Section 3) experimental models of intracerebral hemorrhage (Koeppen and Dickson, 1999; Wang and Dore, 2007). One study suggested that the effects of HO-1 activation in experimental intracerebral hemorrhage may be bimodal, mediating phenanthroline damage in the early aftermath of the hemorrhage while promoting neurological recovery in later stages of the illness (Zhang et al., 2017). A recent study suggested that astrocytic HO-1 may also mediate hyperglycemia-related neuronal apoptosis and neurological morbidity after cerebral infarction (Yang et al., 2017). The attenuation of aluminum neurotoxicity in mice following nimodipine treatment may be due to suppression of hippocampal HO-1 activity (Yuan et al., 2008). Germane to PD (see Section 9), and despite the potential for concomitant neurotrophic factor elaboration (Section 3), HO-1 may facilitate DA cell injury accruing from exposure to polychlorinated biphenyls (Lee et al., 2006). Variations in experimental design and species-specific considerations may account for the conflicting data regarding the participation of HO-1 in different disease states. As discussed at length below, sustained HO-1 overexpression in astroglia may provide a vital link between ambient stressors and downstream changes in mitochondrial iron homeostasis which may drive brain senescence and disease long after initiating insults may have dissipated.
‘Core’ cytopathology in stressed astroglia: transducer role of HO-1 Our overarching hypothesis is that repeated or sustained induction of astroglial HMOX1 in response to ambient stressors engenders the ‘core’ tetrad of cytopathological changes - non-transferrin iron deposition, oxidative stress, mitochondrial damage and macroautophagy - observed in a myriad of developmental, degenerative and inflammatory CNS disorders and, to a lesser extent, during normal brain aging (Schipper, 2004a; Schipper and Song, 2015). Detailed findings supporting a causative role of HO-1 in the development of each component of this tetrad are presented herein. Moreover, evidence is reviewed indicating that the elaboration of this signature cytopathology engages astrocytes and neuronal elements in mutually deleterious relationships which may perpetuate disease progression independently of the precipitating insults.
Pro-toxin bioactivation by stressed astroglia The HO-1-mediated gliopathy described in Section 5 is of considerable clinical interest in so far as it may jeopardize neuronal survival and function. Using electron paramagnetic resonance (EPR) spectroscopy, we determined that the glial mitochondrial iron (enhanced in cultured rat astrocytes by pre-treatment with the Hmox1 inducer, cysteamine) acts as a pseudo-peroxidase that fosters the conversion of catecholamines (DA) and catecholestrogens (2-hydroxyestradiol) to ortho-semiquinone radicals with potentially neurotoxic properties (Schipper, 2001; Schipper et al., 1991). Importantly, catecholaminergic PC12 cells cultured on astroglial monolayers enriched for mitochondrial iron by cysteamine pre-treatment were noted to be consistently more vulnerable to dopamine/H2O2-mediated cell death than PC12 cells grown atop control astrocytes (Frankel and Schipper, 1999). Similar outcomes were observed following exposure of PC12 cells cultured together with HMOX1-transfected astrocytes in response to oxidative challenge (Song et al., 2006). Following exposure to DA (1μM) and H2O2 (1μM), PC12 cell death was greater when these cells were co-cultured with HMOX1-transfected than with sham-transfected astroglia. PC12 cell death was significantly diminished in the presence of SnMP (1 μM), attesting to the canonical behavior and potency of the HMOX1 gene product in these experiments. Necrosis, as opposed to apoptosis, was considered the likely mechanism of PC12 cell death in these experiments on the basis of nuclear morphology. Patterns of PC12 cell killing akin to those observed in the co-culture studies, albeit on a smaller scale, resulted from exposure of PC12 cells to conditioned media derived from HMOX1-transfected vs. sham-transfected astroglia. Thus, HMOX1-transfected astrocytes treated with DA/H2O2 may predispose to neuronal injury by releasing neurotoxins or curtailing delivery of trophic substances (e.g. GSH, neurotrophic factors) to the extracellular milieu. For example, iron-related cycling of DA-derived semiquinones/quinones in glia overexpressing HO-1 generates superoxide which may be exported via anion channels (Kontos et al., 1985). The superoxide may also be reduced intracellularly to H2O2 which may traverse plasma membranes on account of its lipid solubility (Li et al., 2007). Finally, CO generated within astrocytes may diffuse to and influence other cellular compartments (Li et al., 2007). Vitamin C (200μM) significantly decreased (i) DA/H2O2–related death of PC12 cells cultured together with HMOX1-transfected astroglia and (ii) death of PC12 cells incubated with conditioned media from HMOX1-transfected astroglia. These observations implicate oxidative stress as a key contributor to PC12 cell killing in this paradigm. Death in PC12 cells co-cultured with HMOX1-transfected astrocytes was also reduced by treatment with deferoxamine (400 μM) or phenanthroline (100 μM) further supporting the notion that the mitochondrial iron deposited in astrocytes overexpressing HO-1 acts as a pseudo-peroxidase that bioactivates DA to neurotoxic intermediates in the presence of H2O2.