Peripherally administered GCSF is taken into the CNS most probably by a receptor mediated transport. In the CNS, GCSF receptors are expressed in neurons and microglia but not astrocytes. GCSF receptor is also expressed in peripheral monocytes and granulo cytes. In humans, GCSF administration selleck kinase inhibitor increases the production of hematopoietic stem cells, granulocytes and monocytes. GCSF therapy has been in phase I clinical trials for ALS where it has been proven to be a safe treatment for ALS. However, the mechan ism of action of GCSF is not fully known in ALS. This study provides data for the usage Inhibitors,Modulators,Libraries of GCSF with sustained action in a mouse model of ALS. The long term treatment with pegfilgrastim prolonged the survival Inhibitors,Modulators,Libraries of mutant SOD1 mice and attenuated both astro and microgliosis in the spinal cord.

Pegfilgrastim also modu lated the inflammatory cell populations in the bone marrow and spleen in mutant SOD1 mice and reduced the production Inhibitors,Modulators,Libraries of pro inflammatory cytokine TNFa. GCSF also reduced the inflammatory activation of microglia in vitro. After long term pegfilgrastim treat ment, the increased storage of Ly6C cells in the BM and spleen was accompanied by increased migration of monocytes, or their survival in the degenerative muscle at the symptomatic stage of ALS. This suggests that GCSF therapy delays the progression of ALS in a trans genic mouse model through the attenuation of inflam mation in both the CNS and the periphery. Methods Animals SOD1 G93A 1Gur J trans genic mice carrying a high copy number of human mutant G93A SOD1 Inhibitors,Modulators,Libraries were obtained from Jackson Laboratory and maintained on C57BL 6J congenic back ground.

SOD1 G93A mice manifest motor deficits between 17 19 weeks of age. Paralysis and end stage of the disease are reached by age of 24 26 weeks. Male SOD1 mice were used for Inhibitors,Modulators,Libraries survival and histological stu dies. Disease onset was determined by the wire hang test. Each mouse was suspended while hanging from a wire cage top and latency was recorded. Deficits in motor performance were defined by the inability to hang for more than 3 minutes. The test was repeated 1 2 times per week until the mouse was sacrificed. For survival studies, the clinical end stage was defined as the inability of a mouse to right itself in a period of 30 sec onds which was regarded as a criterion for mouse sacri fice.

Animal experiments were conducted according to the national regulations of the usage and welfare of laboratory animals and approved by the Animal Experi ment Committee in the State Provincial Office of reference 2 South ern Finland. Pegfilgrastim treatment A single injection of pegfilgrastim has been determined to equal to multiple injections of filgrastim in order to mobilize stem cells or treat neutropenia. We treated the mice with a submaximal dosage of pegfilgrastim as esti mated from previous studies performed with wt mice.