Department of Biochemistry and Institute of Biomedical Research, Alberto Sols UAM-CSIC, Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Curr Drug Targets. 2010 Dec;11(12):1517-31. doi: 10.2174/1389450111009011517.
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.
血红素加氧酶-1（HO-1）是一种分解血红素为一氧化碳、游离铁和胆绿素的酶，参与细胞对抗氧化应激的防御，有人推测它可能是神经保护的新治疗靶点。在这篇综述中，我们讨论了大脑中 HO-1 基因（Hmox1）的最新调节发现，特别关注转录因子 Nrf2 和 HIF-1。Hmox1 的功能多态性与阿尔茨海默病和帕金森病的高风险相关。因此，我们回顾了 HO-1 及其酶产物在这两种病理以及缺血性脑损伤中的作用的现有知识。HO-1 在几种情况下调节炎症反应，因此我们讨论了其在调节大脑固有免疫细胞（小胶质细胞）中的作用。从治疗的角度来看，血脑屏障是直接调节血红素加氧酶活性的障碍，但激活转录因子 Nrf2 的药物，具有非常多样化的分子结构，可能是与其他抗氧化和解毒酶一起诱导 HO-1 的良好候选药物。更全面地了解调节脑细胞中 HO-1 表达的机制，以及这些机制如何参与神经病理学变化，对于开发这些新的治疗方法至关重要。
