TNF a is synthesized cause by microglia, astrocytes and some populations of neurons and has several important functions in the CNS, includ ing injury mediated microglial and astrocyte activation, regulation of blood brain barrier permeability, febrile responses, glutamatergic transmission, and synaptic plas ticity. TNF a leads to activation of inhibitory kappa B by the I B kinase complex, which in turn leads to I B polyubiquitination and subsequent degrada tion by proteasome. Consequently, nuclear factor kappa B is phosphorylated, Inhibitors,Modulators,Libraries liberated from I B and translocates to the nucleus, where it binds to the promoter regions of NF B responsive genes and initiates transcription of genes such as those for the proinflam matory cytokines interleukin 6, IL 1, and TNF a.

Each member of NF B family, such as p65, c REL, Inhibitors,Modulators,Libraries RELB, p105 p50 and p100 p52, can form homodimers, as well as heterodimers Inhibitors,Modulators,Libraries with one another. The main activated form of NF B is a heterodimer of the Inhibitors,Modulators,Libraries p65 sub unit. Different phosphorylation patterns may recruit different transcriptional cofactors to the subunit and induce distinct profiles of gene expression. TNF a induces IL 6 release through the phosphorylation of NF B, p38 mitogen activated protein kinase and stress activated protein kinase c Jun N terminal kinase in rat C6 glioma cells. TNF a induces IL 6 expression through the p65 phosphorylation at Ser 276, but not at Ser 529 or Ser 536 in murine fibroblasts. However, the details of NF B phosphorylation in glial cells have not been clarified.

In addition to the I B NF B pathway, the main intra cellular signaling pathway activated by cytokines is the Janus family of tyrosine kinase signal transducer and activator of transcription pathway. The acti vation of the JAK STAT pathway leads to a rapid signal ing from the cell surface to the nucleus. Inhibitors,Modulators,Libraries JAK proteins are phosphorylated when cytokines bind to spe cific receptors, and subsequently activate STATs. The activated STATs translocate to the nucleus and transmit the signals, where they then bind to specific consensus sequences, thereby triggering gene transcription. Seven STAT proteins have been identified in mamma lian cells. Among them, STAT1 and STAT3 play important roles in post ischemic brain damage. IL 1b, an important cytokine, phosphorylates STAT3 in C6 cells. However, the precise role of the JAK STAT pathway in glial cells remains to be elucidated.

Oxidative stress refers to a selleckbio state with elevated levels of intracellular reactive oxygen species production and impaired function of antioxidant defense mechan isms. NADPH oxidase is a multi subunit enzyme that catalyzes the reduction of molecular oxygen and the oxi dation of NADPH to generate superoxide radicals. NADPH oxidase is widely distributed and has a variety of functions, such as regulation of immune system, cell growth, cell death and endothelial functions.