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Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease ( PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide ( LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1β, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 reduction. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta ( SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Abstract: Glia cells are regarded as a mediator of neuroinflammation releasing pro-inflammatory cytokines and nitric oxide in the central nervous system. Microglia and astrocytes have been reported to play an important role in the progression of neurodegenerative diseases such as Alzheimer''s disease and Parkinson''s disease. m-Chlorophenylpiperazine (m-CPP) is used clinically to manipulate serotonergic function, though its precise mechanisms of actions are not well understood. m-CPP alters synaptic transmission and neuronal function in vertebrates by non-selective agonistic actions on 5-HT1 and 5-HT2 receptors. In the present study, the anti-inflammatory effect of m-CPP was investigated in lipopolysaccharide (LPS)-stimulated microglia and astrocyte cultures. Our results showed that m-CPP significantly decreased the production of nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) in microglia and astrocyte cultures. m-CPP also attenuated the expression of inducible nitric oxide synthase and pro-inflammatory cytokines such as IL-1β and TNF-α at mRNA levels. In addition, m-CPP inhibited nuclear factor-kappa B activation and phosphorylation of p38 mitogen-activated protein kinase in the LPS-stimulated microglia cells, providing molecular mechanisms of the anti-inflammatory effects. Moreover, m-CPP was neuroprotective as the drug reduced microglia-mediated neuroblastoma cell death in a microglia-neuron co-culture. These findings suggest that m-CPP may have important implications in the treatment of neuroinflammatory diseases. [Copyright &y& Elsevier]

• PHLDA1 expression is upregulated in LPS-activated microglia cells. • PHLDA1 knockdown inhibits microglial activation via suppressing NF-κB pathway. • PHLDA1 knockdown inhibits LPS-induced K63-linked ubiquitination of TRAF6. • PHLDA1 directly interacts with TRAF6 and enhances its K63-linked ubiquitination. • PHLDA1 deficiency suppresses the DA neuron loss in Parkinson's disease mice model. Microglia-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases including Parkinson's disease (PD). Pleckstrin homology-like domain family A member 1 (PHLDA1) plays an important role in immunological regulation, particularly in the Toll-like receptor-mediated immune response. Here, we explored the potential roles of PHLDA1 in microglia-mediated inflammation and neuronal protection. We found that PHLDA1 expression was rapidly increased in response to inflammatory stimuli in microglia cells in vivo or in vitro. Knockdown of PHLDA1 using adeno-associated virus serotype (AAV) ameliorated MPTP-induced motor deficits and inhibited neuroinflammation in mice. In support of this observation in vivo , we found that LPS-induced proinflammatory gene expression, including TNF-α, IL-1β, iNOS, and COX-2, was decreased in PHLDA1-deficient microglial cells. Mechanistic studies demonstrated that increased expression of PHLDA1, upon LPS stimulation in microglia, led to direct interaction with TRAF6 and enhanced its K63-linked ubiquitination-mediated NF-κB signaling activation. PHLDA1 deficiency interfered with TRAF6 K63-linked ubiquitination and inhibited microglial inflammatory responses. These findings reveal the first evidence that PHLDA1 is an important modulator of microglial function that is associated with microglia-mediated dopaminergic neurotoxicity. The data therefore provided the first evidence that PHLDA1 may be a potent modulator for neuroinflammation, and PHLDA1 may be a novel drug target for treatment of neuroinflammation-related diseases such as PD. [ABSTRACT FROM AUTHOR]

Neuroinflammation is involved in the process of several central nervous system (CNS) diseases such as Parkinson's disease, Alzheimer's disease, ischemia and multiple sclerosis. As the macrophages in the central nervous system, microglial cell function in the innate immunity of the brain and are largely responsible for the inflammation-mediated neurotoxicity. Prevention of microglia activation might alleviate neuronal damage and degeneration under the inflammatory conditions, and therefore, represents a possible therapeutic approach to the aforementioned CNS diseases. Here we report the synthesis of a number of non-steroidal anti-inflammatory drug (NSAID) conjugates, and the evaluation of their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and primary mouse microglial cells. Among the tested analogues, compounds 8 and 11 demonstrated potent inhibition of nitric oxide production with no or weak cell toxicity. Compound 8 also significantly suppressed the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, cyclooxygenase (COX)-2 as well as inducible nitric oxide synthase (iNOS) in LPS-stimulated BV-2 microglial cells. Further mechanistic studies indicated that compound 8 significantly suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and subsequent activation of activator of transcription 1 (AP-1). Furthermore, in a co-culture system, compound 8 inhibited the cytotoxicity generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Collectively, these experimental results demonstrated that compound 8 possessed potent anti-neuroinflammatory activity via inhibition of microglia activation, and might serve as a potential lead for the therapeutic treatment of neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]