The roles of S1P and its G cou pled receptor in the normal CNS are not known. It has recently been shown that activation of S1P results in changes in glial cells in vitro. If FTY720 selleck products gains access to the CNS there is the potential to modulate the activity of S1P with uncertain consequences for the patient. Steroid and vitamin D related Several genes coding for enzymes involved in steroid metabolism were downregulated by each of the three cytokine mixtures, including the gene for testosterone 6 beta hydroxylase, markedly downregulated by MM cytokines. Of note, Th1 cytokines upregulated the gene for vitamin D3 25 hydroxylase, the enzyme catalyzing the first step in activation of dehydrocholesterol to the active hormone, 1, 25 hydroxy vitamin D3.
However, both MM and Th2 cytokines down regulated 25 OH vitamin D3 24 hydroxylase, a key step in the inactivation of the active form of vitamin D3. Both are mitochondrial enzymes and members of cytochrome p450 family. In several studies vitamin D3 dietary supplementation pre vented the onset and progression of Inhibitors,Modulators,Libraries EAE. In MBP induced EAE in mice, the treated animals showed marked decreases Inhibitors,Modulators,Libraries in chemokines, iNOS and CD11b recruitment into the CNS, perhaps due to activated T cell apoptosis. One large study found that vitamin D3 supplemen tation reduced the risk of developing MS, while four smaller studies suggested a reduction in exacerbations. Our findings suggest that both MM and Th2 cytokines might act to attenuate the effects Inhibitors,Modulators,Libraries of the active forms of vitamin D3.
Miscellaneous proteins The classically proinflammatory Th1 and MM cytokines markedly upregulated Inhibitors,Modulators,Libraries the gene for iNOS, a critical protein in generation of NO, which gives rise to related reactive oxygen species such as peroxynitrite. Increases in iNOS have been reported in the CNS in EAE and in MS. There is evidence that NO could directly or indirectly, by forming peroxynitrite, damage oligodendro cytes, myelin and neuronsaxons. Reactive nitrogen species can also influence neuronal Na channels and thus cause damage, especially with rapid firing bare axons. It has also been suggested that NO could have an immumodulatory effect on inflammatory cells. NO production in inflammatory cells and in glial cells is induced by iNOS. As described in Results, employing QRT PCR we confirmed the upregulation of expression of the gene for iNOS by Th1 and MM cytokine mixtures and also found modest downregulation of the gene in response to Th2 cytokines.
Galanin is a peptide in the CNS and PNS which is upreg ulated in response Inhibitors,Modulators,Libraries to injury. While originally described selleckchem in various neurons it has been demonstrated in glia as well. and has a positive effect on neurite growth, cell survival and regeneration as well as involved in interactions with hormones, pain signaling pathways and other CNS functions.