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The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO‐2 is constitutive, abundant and fairly ubiquitous, whereas HO‐1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO‐2, the ho‐1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro‐oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO‐1 protein is over‐expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age‐matched, cognitively intact controls and co‐localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO‐1 is markedly over‐expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up‐regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme‐derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO‐1 expression and the nature of the prevailing redox microenvironment. In ‘stressed’ astroglia, HO‐1 hyperactivity promotes mitochondrial sequestration of non‐transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging‐related neurodegenerative disorders. Glial HO‐1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.

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Glial heme oxygenase-1 is over-expressed in the CNS of subjects with Alzheimer disease (AD), Parkinson disease (PD) and multiple sclerosis (MS). Up-regulation of HO-1 in rat astroglia has been shown to facilitate iron sequestration by the mitochondrial compartment. To determine whether HO-1 induction promotes mitochondrial oxidative stress, assays for 8-epiPGF(2alpha) (ELISA), protein carbonyls (ELISA) and 8-OHdG (HPLC-EC) were used to quantify oxidative damage to lipids, proteins, and nucleic acids, respectively, in mitochondrial fractions and whole-cell compartments derived from cultured rat astroglia engineered to over-express human (h) HO-1 by transient transfection. Cell viability was assessed by trypan blue exclusion and the MTT assay, and cell proliferation was determined by [3H] thymidine incorporation and total cell counts. In rat astrocytes, hHO-1 over-expression (x 3 days) resulted in significant oxidative damage to mitochondrial lipids, proteins, and nucleic acids, partial growth arrest, and increased cell death. These effects were attenuated by incubation with 1 microM tin mesoporphyrin, a competitive HO inhibitor, or the iron chelator, deferoxamine. Up-regulation of HO-1 engenders oxidative mitochondrial injury in cultured rat astroglia. Heme-derived ferrous iron and carbon monoxide (CO) may mediate the oxidative modification of mitochondrial lipids, proteins and nucleic acids in these cells. Glial HO-1 hyperactivity may contribute to cellular oxidative stress, pathological iron deposition, and bioenergetic failure characteristic of degenerating and inflamed neural tissues and may constitute a rational target for therapeutic intervention in these conditions.

BackgroundThe nature and frequency of nonmotor symptoms in primary adult‐onset cervical dystonia (CD) and blepharospasm (BSP) patients in Chinese populations remain unknown.MethodsHamilton's Depression Scale (HAMD), Hamilton's Anxiety Scale (HAMA), Addenbrooke's Cognitive Examination Revised (ACE‐R), Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale were used to evaluate NMS in 120 patients with primary focal adult‐onset dystonia (60 with BSP and 60 with CD) and 60 age‐, sex‐, and education level‐ matched healthy controls (HCs). Motor symptoms of BSP and CD patients were evaluated by Jankovic rating scale and Toronto Western Spasmodic Torticollis Rating Scale‐severity scale separately.ResultsTwenty patients had depression, and 29 patients had anxiety. The mean HAMD and HAMA scores were significantly higher in patient groups. Thirty‐six patients had cognitive decline based on the cut‐off score of 75. The total score and scores of each domain of ACE‐R were significantly lower in patient groups than that in HCs. Quality of sleep was impaired in patient groups, and patients with CD had worse quality of sleep than patients with BSP. Thirty‐three BSP patients and 43 CD patients suffered from sleep disorder separately. The frequency of excessive daytime sleepiness did not differ between patients and HCs. No significant correlation was found between NMS and motor severity in the two forms of dystonia.ConclusionsCurrent study suggests that NMS are prevalent in Chinese CD and BSP patients, and the motor severity of dystonia did not contribute to the severity of nonmotor symptoms. Assessment of nonmotor symptoms should be considered in clinical management of focal dystonia

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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 hormonerefractory 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 signalregulated 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]