Role of granulocyte—macrophage colony—stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury

Abstract

<jats:p content-type="fine-print"><jats:italic>Object.</jats:italic> Granulocyte—macrophage colony—stimulating factor (GM-CSF) is a potent hemopoietic cytokine that stimulates stem cell proliferation in the bone marrow and inhibits apoptotic cell death in leukocytes. Its effects in the central nervous system, however, are still unclear. The present study was undertaken to determine if GM-CSF can rescue neuronal cells from apoptosis and improve neurological function in a spinal cord injury (SCI) model.</jats:p> <jats:p content-type="fine-print"><jats:italic>Methods.</jats:italic> To study the effect of GM-CSF on apoptotic neuronal death, the authors used a staurosporine-induced neuronal death model in an N2A cell line (in vitro) and in a rat SCI model (in vivo). The N2A cells were preincubated with GM-CSF for 60 minutes before being exposed to staurosporine for 24 hours. To inhibit GM-CSF, N2A cells were pretreated with antibodies against the GM-CSF receptor for 60 minutes. Clip compression was used to induce SCI. Animals were treated with daily doses of GM-CSF (20 µg/day) for 5 days. The number of apoptotic cells in the spinal cord and neurological improvements were assessed.</jats:p> <jats:p content-type="fine-print">Pretreatment with GM-CSF was found to protect N2A cells significantly from apoptosis, and neutralizing antibodies for the GM-CSF receptors inhibited the rescuing effect of GM-CSF on apoptosis. In the rat SCI model, neurological function improved significantly in the GM-CSF—treated group compared with controls treated with phosphate-buffered saline. Terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling staining showed that GM-CSF administration reduced apoptosis in the injured spinal cord.</jats:p> <jats:p content-type="fine-print"><jats:italic>Conclusions.</jats:italic> Treatment of SCI with GM-CSF showed beneficial effects. Neuronal protection against apoptosis is viewed as a likely mechanism underlying the therapeutic effect of GM-CSF in SCI.</jats:p>

A Neuroprotective Function for the Hematopoietic Protein Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)

“…Support for a neuroprotective action of GM-CSF in the CNS also comes from another disease model, spinal cord contusion (Ha et al, 2005). The authors could show effects of GM-CSF treatment (20 mg/day for 5 days) on the improvement of the BBB score, and show decreased apoptosis in the spinal cord.…”

“…Granulocyte-macrophage colony-stimulating factor receptor expression has been noted in neurons in the fetal human brain (Dame et al, 1999), supporting the notion that GM-CSF likely also has a neurodevelopmental role. Neuronal staining has been reported in the adult spinal cord (Ha et al, 2005). Recently, presence of the GM-CSF receptor on hypothalamic neurons in the adult brain has been described (Reed et al, 2005).…”

Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

“…We also observed significant locomotor recovery in the EpoSV-GM-CSF-transfected NSC-transplanted group, a new development in preceding reports that have stated that only GM-CSF could enhance locomoter function in the spinal cord contusion injury. 45 Because of the low survival rate of NSC in the SCI, 20,21 in this study, we attempted to demonstrate NSC survivalenhancement by hypoxia-induced GM-CSF as a result of locomoter function improvement. We concluded that the enhanced in vivo recovery effect had been caused by two indistinguishable factors: hypoxia-induced GM-CSF, and GM-CSF-induced transplanted cell survival and differentiation in the SCI.…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…Ha et al first demonstrated that GM‐CSF improves functional outcome after rat contusive SCI 46. The improvement is probably due to the prevention of apoptosis of the cells, including neurons,46 via reduction of the expression of the proapoptotic proteins p53, p21, and Bax, and induction of nucleophosmin‐144 and the antiapoptotic protein B‐cell lymphoma 2 (Bcl‐2) 45.…”

“…The improvement is probably due to the prevention of apoptosis of the cells, including neurons,46 via reduction of the expression of the proapoptotic proteins p53, p21, and Bax, and induction of nucleophosmin‐144 and the antiapoptotic protein B‐cell lymphoma 2 (Bcl‐2) 45. Additionally, GM‐CSF increased BDNF expression by macrophages, and subsequently stimulated axonal regeneration 49.…”