Since one of the down stream effectors of nitric oxide is Nrf2, we further determined the Nrf2 target genes in the spinal cord. There was upregulation of HO1 and NQO1 selleck chemicals llc in mutant SOD1 mice compared to wt mice but pegfilgrastim did not affect the expression of these Nrf2 target genes. The expression of iNOS was thus not combined with Nrf2 target gene expression of HO1 and NQO1, but these were regulated indepen dently. This also suggests that the protective effects of pegfilgrastim in mutant SOD1 mice were not mediated by Nrf2. GCSF attenuates inflammation in microglia and peripheral monocytes Since TNFa was highly upregulated in the spinal cord of mutant SOD1 mice, we further determined the effect of GCSF on inflammatory cells in the CNS and peripheral hematopoietic organs.

GCSF decreased inflammation induced TNFa release in primary microglia cells in vitro. GCSF also decreased the TNFa release in bone marrow monocytes in vitro obtained from wt and mutant SOD1 mice. Furthermore, TNFa release was decreased in BM monocytes obtained from long term pegfilgrastim treated mutant SOD1 mice compared to vehicle treated Inhibitors,Modulators,Libraries littermates, suggesting a notable relevance in vivo. In addi tion to the reduction of TNFa production, the NO release was increased with GCSF in Inhibitors,Modulators,Libraries mutant SOD1 BM monocytes in vitro and in BM and spleen monocytes obtained from Inhibitors,Modulators,Libraries long term pegfilgrastim trea ted SOD1 mice. GCSF modulates cell populations in peripheral hematopoietic organs and in degenerating muscle When measuring spleen size, we discovered decreases in weight and length of end stage mutant SOD1 mice compared to wt controls Inhibitors,Modulators,Libraries at the same age.

In comparison, the body weight of mutant SOD1 mice at the end stage had dropped to 75 14% of wt mouse weight. Pegfilgrastim treatment increased the spleen size of mutant SOD1 mice in a similar manner to wt mice indicating a long term biological efficacy of GCSF on SOD1 mice. We further analyzed Inhibitors,Modulators,Libraries hematopoietic cell populations after long term pegfilgrastim treatment from 20 week old mutant SOD1 mice. GCSF increased the number of total splenocytes but not the total num ber of BM leukocytes. In BM, the number of lym phocytes was either not affected and 0. 4 0. 1 million in GCSF treated or decreased in response to pegfilgrastim treatment. On contrary to this, the number of Ly6C monocytes was increased in BM after pegfilgrastim treatment.

Notably, the number of Ly6Cint cells was increased. Ly6C is a marker for myeloid lineage of cells and a component of myeloid differentiation antigen Ly6C Ly6G, the latter expressed mainly in polymorphonuclear lineage of mye loid cells. Ly6C cells also expressed CD11b, an integrin involved in adhesive selleck products interactions and migration of mye loid cells. The number of cells expressing CD115, the receptor for macrophage colony stimulating factor was however not increased by pegfilgrastim.