The Investigation of Anti-Neuroinflammatory Mechanisms of Differential Histone Deacetylase Regulators and Their Therapeutic Profiles in Experimental Intracerebral Haemorrahge and Encephalitis

A variety of pathological processes of the primary and secondary brain diseases are tightly related to neuroinflammation. The pathological mechanisms of neuroinflammation between neuron and glial interaction are highly complicated and not yet clearly understood. The treatment of neuroinflammatory disease is according to its aetiological condition, however, it is still elusive and largely empirical. Previous studies have been found that progressive neuroinflammation and blood-brain barrier disruption being directly involved in development of brain edema and neural injury in intracerebral haemorrage (ICH) stroke. Several pathological factors of neuroinflammatory mechanisms in ICH have been proposed including thrombin-induced neurotoxicity, overproduction of inflammatory mediators (cytokines and reactive oxygen species), dysregulation of phagocytes, hemoglobin-related iron constituents and matrix metalloproteinases (MMPs)-induced tissue degradation. Similarly, the pathological processes of encephalitis are tightly related with neuroinflammation as overproduction of proinflammatory cytokines from activated microglia and infiltrated monocytes. Among the regulation of production of these inflammatory mediators, histone acetyltransferase (HAT) and deacetylase (HDAC) play critical roles in the epigenetic regulation of inflammatory gene expression. Moreover, the acetylation of non-histone proteins is also modulated by these two enzymes, and is implicated in multiple regulatory processes of gene expression from signaling to transcription and protein degradation. The HDAC regulators could be classified as two categories such as HDAC inhibitors (HDACi) and activators The manipulation of protein acetylation by HDAC regulators causes chromatin remodeling, transcription activation and repression, cell-cycle arrest, cell differentiation (or iPS-like de-differentiation) and cell death. HDAC regulators may correct aberrant protein acetylation and regulate inflammatory gene expression at multiple steps, and are under consideration as promising anti-neuroinflammatory agents. However, HDACi have been recently shown to induce or repress the production of proinflammatory cytokines in different phagocytes and disease models. These controversial results revealed that the isoform-specific contribution of HDAC on regulation of neuroinflammatory function between the myeloid lineage (monocyte and microglia) and related mediators remain to be determined. In the preliminary studies, we had found an HDAC regulator with inhibition on MMP-9 activation and expression in activated human monocytic cells. It also exerted inhibitory effects on ICH-induced intracerebral MMP-9 activation. The purpose and aims of this project will investigate the four major issues. First, evaluation of the bioactivities of the potential HDAC regulators (activator and inhibitor) on the expression of inflammatory mediators and specific functions (phagocytosis, chemotaxis and differentiation) will be investigated in monocyte and microglial cells. In addition, the role of isoform-specific HDAC in their specific inhibition of cellular function will be determined. Secondly, clarification of the mechanisms or signaling pathways (including p65, ASK, MAPK, MKP and HSP) of HDAC regulator on inhibition of expression of proinflammatory mediators (TNF-and interleukin-6), effectors (MMPs and iNOS), and other specific functions. Especially, the functional relationships between specific gene expression/signaling and the effects of HDAC regulators will be analyzed by human microarrays. Thirdly, the animals models of ICH and LPS-/iron-induced encephalitis will be investigated to clarify the role of isoform-HDAC on the pathological mechanisms in neuroinflammation, especially the role of monocyte and microglia. The species-correlation of signal effectors and HDAC interactions will be also investigated by human tissue-array. Finally, the potential HDAC regulators will be evaluated their neuroprotective effects in in vivo models, providing new potential strategy for anti-neuroinflammatory therapy in ICH and encephalitis.