Increasing evidence indicates that microglia-driven chronic inflammatory responses playa pathological role in the central nervous system. Activation of microglia is pivotal in the initiation and progression of neuroinflammation. Inhibition of the microglial activation may provide an effective therapeutic intervention that alleviates the progression of the neurodegenerative diseases. Anti-inflammatory agents may be a useful candidate for such a therapeutic approach. Continual investigation of the mechanisms underlying microglial activation and regulation of neuroinflammation by endogenous or exogenous factors would not only lead to the discovery of novel neuroprotective agents, but also help to understand complex pathophysiology of neurodegenerative diseases.

The glucocorticoid receptor (GR) is an intracellular protein that is widely distributed throughout hippocampal and neocortical brain tissue. Mifepristone (RU486) is a potent GR antagonist that has also been shown to exhibit partial agonist-like effects. The precise location of the GR domain involved in the agonist-like activity of RU486 is unknown. Here, we examine this aspect of GR signaling by comparing human GR (hGR) construct with a Guyanese squirrel monkey GR (gsmGR) construct in which nuclear translocation and transactivation are known to be impaired. Using an objective translocation scoring method, we found that both hGR and gsmGR are translocated by RU486, and that nuclear translocation of hGR is significantly increased compared to gsmGR at 10 nM, 100 nM and 1000 nM RU486 in transiently transfected COS1 cells. While addition of RU486 to the cells transfected with hGR results in a 16-fold dose-dependent increase in transactivation compared to non-treated cells, no significant change in transactivation is observed with gsmGR at doses up to 100 nM RU486. Further experiments using six GR chimeras indicate that replacement of the hGR carboxyl-terminus of tau-1 transactivation domain (C-AF1, amino acids 132-428) with that from gsmGR diminishes hGR transactivation by RU486. These results demonstrate that RU486-induced transactivation of GR is determined in part by amino acids in the C-AF1 domain.

Opuntia ficus-indica var. saboten (Cactaceae) is widely cultivated in Jeju Island (South Korea) for use in the manufacture of health foods such as tea, jam and juice. Its fruit and stem have been traditionally used as oriental folk medicine to treat diabetes, hypertension, asthma, burns, edema and indigestion. During the search for naturally occurring antioxidative neuroprotective agents, it was found that the ethyl acetate fraction of the stems and fruits of Opuntia ficus-indica var. saboten exhibited potent antioxidant effect. Using a chromatographic fractionation method, several constituents were isolated from this fraction. Among isolates, KYS50182 showed the most potent in vitro and in vivo neuroprotective activities, suggesting that the flavonoid can serve as a lead structure for the development of neuroprotective agents by providing neuroprotection against oxidative and focal ischemic neuronal injuries.

Central to developing new treatment strategies for late onset sporadic Parkinson's disease (PD) and early onset familial PD is resolving the enigma of the specific vulnerability exhibited by substantia nigra dopamine (DA) neurons despite multiple risk factors. Neuropathological evidence from both human and experimental models of PD firmly supports a significant role for oxidative stress (OS) and mitochondrial dysfunction in the death of nigral DA neurons. Largely unknown are the genes underlying selective susceptibility of nigral DA neuron to OS and mitochondrial dysfunction and how they effect nigral DA cell death. To overcome the paucity of nigral DA neurons as well as the dilution effect of non-DA cells in brain tissues, we have developed wild type DA cell line model, SN4741 and mutant DJ-1 (-/-) DA cells, appropriate for microarray analysis and differential mitochondrial proteomics. Mutations in the DJ-1 gene (PARK7), localized in cytoplasm and mitochondria, cause autosomal recessive early onset PD. Through microarray analysis using SN4741 cells followed by validation tests, we have identified a novel phylogenically conserved neuroprotective gene, Oxi-a, which is specifically expressed in DA neurons. The knockdown of the gene dramatically increased vulnerability to as. Importantly as down-regulated the expression level of the gene and recovery of its expression via transient transfection exerted significant neuroprotection against as insult. We also have identified altered expression of mitochondrial proteins and other familial PD genes in DJ-1 (-/-) mutant cells by differential mitochondrial proteomics. In DJ-1 (-/-) cells the knockdown of the other familial PD genes (Parkin and PINK1) dramatically increased susceptibility to as. Thus, further functional characterization of the Oxi-$\alpha$ gene family and the mitochondrial alteration in the DJ-1 (-/-) cell model will provide the rationale for the neuroprotective therapy against both sporadic and familial PD.