Up-Regulation of Ho-1 by Statins, Ppars Agonists, Coppix, and Corm-2 Protecting against Oxidative Stress-Mediated Brain Neurodegeneration

Neuroinflammation is a hallmark of all major CNS neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD). There is strong evidence that oxidative stresses are considered to play an important role in the induction of inflammatory proteins implicated in brain inflammatory processes. In our previous studies, we have demonstrated the involvement of redox signals (ROS production) in the development of neuroinflammation and neuronal death. Many of the well-known inflammatory target proteins, such as MMP-9, COX-2, and cPLA2, can be up-regulated by various proinflammatory factors, including IL-1, BK, thrombin, LPS, LTA or viral infection, via a ROS signal-dependent manner in neuroglial cells. The induction of these proteins might be mediated through NADPH oxidase/ROS, various intracellular signaling pathways, and transcription factors 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 the intensive investigations, there is no effectively therapeutic strategy available to prevent the progression of neurodegeneration. Therefore, development of anti-oxidative and anti-inflammatory effects of drugs may be beneficial to block the pathological progression of these diseases. Although statins and peroxisome proliferation-activated receptors (PPARs) agonists are widely used in clinics, recent studies suggest that these drugs could modulate neurodegeneration-related signaling processes and may be beneficial for neuroinflammation. Therefore, this project will continue to 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. Statins and PPAR agonists have attracted considerable attention in treating various neurodegenerative diseases. They could attenuate the proinflammatory signalings such as cytokine and oxygen radical formation, mediated through the induction of antioxidant defense protein HO-1 in various cell types. Despite the intense level of interest, there is a deficiency in information on how statins and PPAR agonists exert neuroprotective effects in the brain diseases. Therefore, the purpose of this proposal will dissect the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression induced by statins, PPAR agonists, CoPPIX, and CORM-2. In particular, we make an attempt to approach how redox-dependently transcriptional activators such as NF-E2 related factor 2 (Nrf2), Sp1, and AP-1 control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including Rho/ROCK, NADPH oxidase/ROS, 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 expression, supporting the hypothesis that HO-1/CO may contribute to protect against oxidative stress-mediated brain inflammation. Although the protective function by HO-1 has been investigated in various cell types, the regulatory roles of major transcription factors (TFs) and signaling pathways that govern the inducible HO-1 gene expression induced by various chemicals and drugs are not completely understood in astrocytes and neurons. Our proposal is to connect what is known and the gaps in our knowledge on the mechanisms underlying statins, PPAR agonists, CoPPIX, and CORM-2 exert their potentials in the induction of anti-oxidant enzymes such as HO-1 and anti-inflammatory effects which may be beneficial for treatment of neurodegenerative diseases. Understanding the molecular mechanisms of these chemicals induced expression of HO-1 in the brain would provide insight into specific drug targets and also provide the rationale for development of novel drugs for the treatment of neurodegenerative diseases.

Project ID:PC10701-0072
External Project ID:MOST105-2320-B182-005-MY3