Targeting Heme Oxygenase-1 for Neuroprotection and Neuroinflammation in Neurodegenerative Diseases

Abstract

Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, free iron, and biliverdin, participates in the cell defence against oxidative stress and it has been speculated that it might be a new therapeutic target for neuroprotection. In this review, we discuss recent findings on the regulation of the HO-1 gene, Hmox1, in the brain with particular focus on the transcription factors Nrf2 and HIF-1. Functional polymorphisms in Hmox1 have been associated with high risk for Alzheimer's and Parkinson's disease. Hence, we review the current knowledge on the role of HO-1 and its enzymatic products on these two pathologies as well as ischemic brain injury. HO-1 modulates the inflammatory response in several scenarios, and therefore we discuss its role in modulation of the innate immune cell of the brain, microglia. From the therapeutic side, the blood brain barrier represents an obstacle to directly modulate heme oxygenase activity, but drugs activating the transcription actor Nrf2, which have a very diverse molecular structure, may be good candidates to induce HO-1 in concert with other antioxidant and detoxification enzymes. A more complete understanding on the mechanisms regulating HO-1 expression in brain cells and how these mechanisms are involved in neuropathological changes will be essential to develop these new therapeutic approaches.

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

“…3) Several phytochemicals, such as resveratrol, curcumin, flavonoids, and carnosol, can upregulate HO-1 expression via the Nrf2 pathway. 41) Studies on the regulation and amplification of HO-1 by pharmacological approaches may lead to the discovery of novel drugs for the treatment of a variety of diseases.…”

“…2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported. 3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.…”

Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

“…NRF2 regulates the expression of a battery of cytoprotective genes that share in common a cis-acting enhancer sequence termed antioxidant response element (ARE) (8,9). These genes include those coding the antioxidant enzymes heme oxygenase-1 (HO-1) and NADP(H) quinone oxidoreductase (NQO1), enzymes of glutathione metabolism and protein degradation, through the proteasome and autophagy routes (10,11).…”

Hydrogen Medicine Therapy: An Effective and Promising Novel Treatment for Multiple Organ Dysfunction Syndrome (MODS) Induced by Influenza and Other Viral Infections Diseases?

“…Given the theory that molecular hydrogen can both significantly down regulate expressions of inflammation-related genes and selectively reduce hydroxyl radical and Peroxynitrite, we have reasons to consider that cytokine storm and oxidative stress can be suppressed when getting infected with avian influenza and other severe viruses [1,11,12,[43][44][45]. Our theory is unique because it not only puts forward a new kind of non-toxic antiviral therapy but also makes hydrogen-based medicine able to heal disease in to the whole body.…”