It is also likely

It is also likely that BBIs effect on IL 10 may involve a negative reg ulation of TLR4 LPS signalling, such as reduction of the production of programmed cell death protein 4. Despite extensive research on neurodegenerative dis eases, the mechanisms of neurodegeneration remain to be determined. One accepted mechanism is that micro glia activation by environmental factors is responsible for neuronal injury. In addition to resident microglia in the CNS, peripheral macrophages infiltrat ing into the CNS also play a role in neuroinflammation and neuronal loss under several pathological conditions. Several studies have demonstrated that microglial activation Inhibitors,Modulators,Libraries by stimuli such as LPS, amyloid b or TNF a is toxic to neurons. Plasma LPS levels are dramatically increased in certain pathological condi tions including sepsis, inflammatory bowel disease, and HIV infection.

LPS triggers monocyte macrophage activation through CD14 and TLR4 mediated signalling, resulting in release of inflammatory cytokines. During neurodegeneration and neurodevelopment, inflammatory cytokines play an important role in the modulation of neuronal survival. The neurotoxic potential of inflammatory cytokines, such as IL 1b, IL 6 and TNF Inhibitors,Modulators,Libraries a, in the CNS has been extensively documented. Experimentally, LPS has been extensively used as a microglia macrophage activator for the induction of inflammatory dopaminergic neurodegeneration in ani mal models of Parkinsons disease.

Although the mechanisms involved in Inhibitors,Modulators,Libraries the anti inflammatory actions of BBI remain to be determined, the nature of BBI as a serine protease inhibitor explains its ability to inhibit pro inflammatory cyto kine production, as serine Inhibitors,Modulators,Libraries proteases induce release of pro inflammatory cytokines in epithelial cells and macrophages. Inhibitors,Modulators,Libraries Neurophil derived serine pro teases could cause non infectious inflammatory pro cesses. The serine protease inhibitor attenuates chemotactic cytokine pro duction in human lung fibroblasts in vitro and in human whole blood in vivo. The role of serine protease in the induction of proinflammatory cyto kines has been further confirmed by a recent study demonstrating that Ab induced neurotoxicity is greatly attenuated in serine racemase knockout mice compared to wild type mice. In summary, we provide compelling experimental evidence that BBI, through inhibition of proinflammatory cytokine production and induction of IL 10, attenuates LPS macrophage induced neurotoxicity.

BBI also inhibited ROS production, which reduced macrophage aggregation and activation. Since there is lack of effective treatments for neurological disorders, to explore natural products such as BBI as potential treatments for selleck screening library inflammation mediated neuronal injury is of great interest. Our data support the need of future studies for the development of BBI based supplementary therapy for the treatment of neuroinflammation and neurodegeneration.

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