Similar to BM, the number of monocytes was increased in spleen after long term pegfilgrastim treatment. Particularly the number of Ly6int population of monocytes which represented low or no pro inflammatory sellekchem cytokine activation in response to an inflammatory stimulus was elevated. These findings thus indicate that pegfilgrastim increased the production storage of Ly6C monocytes in BM and spleen. When mononuclear cell population was analyzed from the thigh muscle including the sciatic nerve at the symptomatic stage of ALS when there are pronounced deficits of motoric function, the Ly6C monocyte number was increased while lymphocyte number was decreased in response to pegfilgrastim treatment. Lymphocytes were distinguished Inhibitors,Modulators,Libraries from monocytes based on their side scatter and forward scatter properties and their expression of lymphocyte or monocyte markers as defined above.

GCSF probably increases the storage of certain Ly6C monocytes with migratory properties in spleen and BM. GCSF was also detected to increase the number of CCR2 expressing cells, which is a marker for migratory Inhibitors,Modulators,Libraries cells, in BM and spleen as analyzed with flow cytometry. In summary, this suggests the GCSF treatment increased the availability of mono cytes in the symptomatic stage of ALS in SOD1 mice. Since these cells have a favorable inflammatory profile, they may be recruited to the degenerative muscle as an attempt for recovery processes. Discussion GCSF has proven to be a safe treatment in ALS in phase I studies, administered as a single or repeated cycles with three months interval.

Inhibitors,Modulators,Libraries GCSF mobilizes hematopoietic stem cells from ALS patients in a consistent manner and GCSF mobi lized stem cells could be transplanted back to ALS patients causing no adverse effects. The clinical trials so far have shown limited Inhibitors,Modulators,Libraries improvement in ALS pathology. The reason for this may be the fact that GCSF was administered for a short period of time, only single or repeated cycles of few days of duration were given. Since long term usage of GCSF may have severe side effects such as splenomegaly and even a spleen rupture, the targeted GCSF delivery may be an option if the mechanisms of action of GCSF were known in detail. The intraspinal delivery of GCSF with an adeno associated virus GCSF vector was beneficial in mutant SOD1 mice, the neuromuscular junctions were preserved and motoneuron survival was increased.

Although the local intraspinal or intramuscular delivery of AAV GCSF, it still had a systemic effect with increased levels of GCSF in serum and the induction of hematopoiesis. Even though GCSF has a moderate effect on mutant SOD1 Inhibitors,Modulators,Libraries mouse survival, as we describe in this study, the GCSF mediated effects on the modu product information lation of inflammation are interesting and highly rele vant in the light of ALS pathology.