期刊
PROGRESS IN NEUROBIOLOGY
卷 172, 期 -, 页码 40-70出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2018.06.008
关键词
alpha 1-Antitrypsin; Aging; Alzheimer disease; alpha-Synuclein; Astrocytes; Basal ganglia; Bilirubin; Carbon monoxide; Cerebral hemorrhage; Cerebral infarct; Corpora amylacea; Deferiprone; Dopamine; GABA; GFAP center dot HMOX1 mice; Glutathione; Gomori; Heme oxygenase-1; Hippocampus
资金
- Canadian Institutes of Health Research [MOP-68887]
- Mary Katz Claman Foundation
- ApoPharma Inc.
- Immunotec Inc.
Under stressful conditions, cellular heme catabolism to carbon monoxide, iron and biliverdin is mediated by the 32 kDa enzyme, heme oxygenase-1 (HO-1). A wide range of pro-oxidant and inflammatory stimuli act on diverse consensus sequences within the Hmox1 promoter to rapidly induce the gene. There is ample evidence attesting to the beneficial effects of HO-1 upregulation in brain. By converting pro-oxidant heme to the antioxidants, biliverdin and bilirubin, HO-1/biliverdin reductase may help restore a more favorable tissue redox microenvironment. Contrariwise, in some cell types and under certain circumstances, heme-derived carbon monoxide and iron may amplify intracellular oxidative stress and exacerbate the disease process. This inimical side of neural HO-1 has often been ignored in biomedical literature promulgating interventions aimed at boosting central HO-1 expression for the management of diverse CNS conditions and is the focus of the current review. A comprehensive model of astroglial stress is presented wherein sustained Hmox1 induction promotes oxidative mitochondrial membrane damage, iron sequestration and mitophagy (macroautophagy). The HO-1 mediated gliopathy renders nearby neuronal constituents vulnerable to oxidative injury and recapitulates 'core' neuro-pathological features of many aging-related neurodegenerative and some neurodevelopmental brain disorders. A balanced literature should acknowledge that, in a host of chronic human CNS afflictions, the glial HO-1 response may serve as a robust transducer of noxious stimuli, an important driver of relevant neuropathology and a potentially disease-modifying therapeutic target.
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