Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases.
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.
Jazwa
Agnieszka
A
Department of Biochemistry and Institute of Biomedical Research, Alberto Sols UAM-CSIC, Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Cuadrado
Antonio
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006801:Humans; D058990:Molecular Targeted Therapy; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D051547:Heme Oxygenase-1