Up-Regulation of Ho-1 Protected Proinflammatory Mediators-Induced Neurodegeneration in Brain( I )

Neuroinflammation is a hallmark of all major CNS neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD). Studies from mouse models that express disease-specific mutant proteins associated with the major neurodegenerative processes have underscored a critical role of mitochondria in the pathogenesis of these diseases. Recently, there is strong evidence that mitochondrial dysfunction is an early event in neurodegeneration. Mitochondria are one of the main cellular source of reactive oxygen species (ROS) and key regulators of cell death. Oxidative stresses are considered to play an important role in the induction of inflammatory proteins implicated in brain inflammatory processes. In our previous studies (國科會神經科學先 導計畫, 12/1/2008-11/30/2011), exposure of astrocytes and neurons to various insults has been shown to induce expression of inflammatory proteins such as COX-2, cPLA2, cytokines, and MMP-9 associated with neurodegenerative diseases and neuronal injury (共發表國外重要期刊, SCI, 12 篇論文). The induction of these proteins might be mediated through NADPH oxidase/ROS, various intracellular signaling pathways, and transcription factors associated with expression of inflammatory proteins in these cells. Given the important role of oxidative stress in neurodegeneration, therapeutic strategies which are directed at early interventions targeted at oxidative stress may be effective in delaying the development of neurodegeneration. Despite intense investigations, no effective therapy is available to prevent the progression of neurodegeneration. Although statins and peroxisome proliferation-activated receptors (PPARs) agonists are widely used in clinics, recent studies suggest that these drugs modulate neurodegeneration-related signaling processes and may be beneficial for neuroinflammation. Therefore, an approach which simultaneously induces various host defense mechanisms against oxidative injury may be more effective in combating neurodegeneration. Moreover, heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 has been shown to protect against the cytotoxicity of oxidative stress and apoptotic cell death. Therefore, there is an excellent rationale for the development of neuroprotective drugs based on the induction of HO-1 expression. The purpose of this proposal will dissect the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression induced by various chemicals, including statins, PPAR agonists, CoPPIX, and CO-RM2. In particular, we make an attempt to approach how redox-dependent transcriptional activators such as NF-E2 related factor 2 (Nrf2), NF-B and AP-1 control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including MAPKs, transactivation of growth factor receptors and PI3K/Akt in HO-1 regulation is engaged. Finally, up-regulation of HO-1 protected against pro-inflammatory mediator-induced expression of inflammatory proteins will be investigated in brain cells and animal model. These results will provide new insights into the mechanisms of HO-1 experession, supporting the hypothesis that HO-1/CO may contribute to protect against oxidative stress-mediated brain inflammation. Although the protective function by HO-1 have been investigated in some types of cells, the regulatory roles of major transcription factors (TFs) and signaling pathways that govern the inducible HO-1 gene expression induced by various chemicls and drugs are not completely understood in astrocytes and neurons. Thus this proposal will aim to gain a better understanding of the mechanisms through which HO-1 is up-regulated by various drugs within the brain, as well as how HO-1 exerts its protective effects against neuroinflammation induced by pro-inflammatory mediators. Moreover, increased understanding of signal transduction mechanisms implicated in HO-1 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies in neurodegeneration.

Project ID:PC10109-0140
External Project ID:NSC101-2321-B182-013