Intrathecal Upregulation of Granulocyte Colony Stimulating Factor and Its Neuroprotective Actions on Motor Neurons in Amyotrophic Lateral Sclerosis

Abstract

To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed fluorescent bead-based immunoassay. We also conducted immunohistochemical analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors. We found that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. In spinal cords, G-CSF was expressed in reactive astrocytes in ALS cases but not controls, whereas G-CSF receptor expression was significantly decreased in motor neurons of spinal cords from ALS cases. Biologically, G-CSF had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress. We suggested that G-CSF has potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motor neuron damage.

Increased Il-8 Levels in the Cerebrospinal Fluid of Patients with Amyotrophic Lateral Sclerosis

“…Our data are at variance with the report by Tanaka et al who did not find differences in the CSF levels of IL-8 between ALS patients and controls with other non inflammatory neurological disease, although the positive correlation between MCP-I and IL-8 led the authors to suggest a "proinflammatory cytokine cascade after microglial activation" (23). One possibility to explain this discrepancy is that the difference in our study was evident only in men, and the M/F ratio is 2.2 in our cohort and 1.05 in the study by Tanaka et al…”

Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy

“…G-CSF is an essential growth factor in hematopoiesis and may play a role in brain repair. It is neuroprotective and beneficial to functional restoration when administered after brain ischemia (45) and may also have significant neuroprotective effects on motoneuron cell lines in models of ALS (46). A pilot study of G-CSF mobilization of peripheral blood stem cells in ALS has been conducted, under the hypothesis that transiently increasing the number of circulating hematopoietic stem cells might be beneficial in treatment of this disease (47).…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…These CD34+ PBSCs were initially identified after cancer patients received hematotoxic chemotherapy [106], and it was later shown that these circulating hematopoietic progenitor cells could migrate into the central nervous system (CNS) and provide support for diseased MNs [107]. G-CSF itself is suggested to have a neuroprotective effect [108]. Thus, a number of strategies were implemented using G-CSF to mobilize or collect and redistribute PBSCs to the CNS in ALS.…”