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  • br Multiple sclerosis MS is an


    Multiple sclerosis MS is an immune-mediated disease of the human CNS with a pathological signature featuring immunocyte infiltration, altered cytokine production, oligodendroglial degeneration, astrogliosis, microglial activation, multifocal demyelination and axonal degeneration (Schipper, 2004b). Excessive neural iron accumulation and oxidative stress have been documented in MS and a rodent model of the disease, experimental autoimmune encephalomyelitis (EAE) (Lassmann and van Horssen, 2016; LeVine and Chakrabarty, 2004). In 2001, we reported that proportions of GFAP-positive astrocytes immunoreactive for HO-1 were significantly increased in spinal cord plaques from postmortem MS patients relative to normal spinal white matter (Mehindate et al., 2001), a finding subsequently corroborated by others (van Horssen et al., 2008). The enhanced elaboration of proinflammatory cytokines, such as IL-1β and TNFα (Mehindate et al., 2001), or myelin basic protein (Businaro et al., 2002) may be responsible for HMOX1 induction in MS tissues. In addition, expression of Nrf2, a positive regulator of HMOX1, is markedly increased in MS tissues and localizes to glial EPZ5676 synthesis and oxidative substrate damage in areas of active demyelination (Licht-Mayer et al., 2015; van Horssen et al., 2010). IL-1β and TNFα upregulate HO-1 in cultured astrocytes and promote sequestration of non-transferrin-derived iron by the mitochondria; the latter effects can be pre-empted by co-treatment with HO inhibitors, antioxidants or blockers of mitochondrial permeability transition (Mehindate et al., 2001). Thus, the abnormal iron mobilization and electron transport chain abnormalities noted in foci of demyelination (Heidker et al., 2016; LeVine and Chakrabarty, 2004; Lu et al., 2000; Mehindate et al., 2001) may be downstream consequences of astroglial HO-1 overexpression in MS. In 2007, Stahnke et al. (Stahnke et al., 2007) reported upregulation of HO-1 protein in oligodendrocytes within early MS lesions and in microglia, macrophages and astrocytes in acute disseminated encephalomyelitis. In accord with a main thesis of the current review, these authors adduced evidence that acute Hmox1 induction in cultured OLN-93 oligodendroglia protects against H2O2 stress, whereas chronic overexpression of the enzyme enhances oxidative damage to the mitochondria and microtubular network (ibid.). Finally, as further evidence for a deleterious role of HO-1 in MS, suppression of HO activity was shown to ameliorate neural oxidative stress and locomotor impairment in SJL mice with EAE (Chakrabarty et al., 2003).
    Stroke and CNS trauma In 2000, Beschorner and co-workers published on cerebral HO-1 expression profiles in persons succumbing at different time intervals to closed traumatic brain injury or focal ischemic infarction (Beschorner et al., 2000). Within the first 24 h of the stroke, HO-1 immunoreactivity in the peri-infarct zones primarily implicated the astrocytic population, became steadily more prominent over the ensuing few weeks, and declined to levels approaching baseline after several months. Microglial/macrophage HO-1 expression was typically minimal in regions of bland infarction, but was more intense in the vicinity of associated hemorrhage. Weak-to-intermediate HO-1 staining of scattered neurons and endothelial cells was observed for a few months post-infarction. Both Beschorner’s group and Orihara and co-workers (Orihara et al., 2003) reported that in brain trauma specimens, HMOX1 induction occurs early, is robust and long-lived in microglia/macrophages, with milder expression of the gene in neurons, astroglia and endothelial cells. In a clinical study, Suzuki and co-investigators (Suzuki et al., 2003a) documented significantly diminished concentrations of CSF bilirubin and ferritin in cases of aneurysmal subarachnoid hemorrhage complicated by cerebral vasospasm, raising the possibility that augmentation of HO-1 activity may protect against this potentially serious development as suggested by prior animal studies (Section 3). As discussed in Sections 3 and 4, experiments exploring the roles of central Hmox1 induction in animal models of CNS vascular disease and trauma have yielded contradictory results, with some investigations supporting a neuroprotective action for HO-1 while others point to the enzyme as a source of further neuroendangerment. Although heme-derived bilirubin may confer acute cytoprotection, other products of the HO-1 reaction may contribute to longer-term mismanagement of brain iron homeostasis and neurometabolic failure in patients with stroke and CNS trauma, as conceptualized for the aging-related neurodegenerations.