Intrathecal granulocyte colony-stimulating factor modulate glial cell line-derived neurotrophic factor and vascular endothelial growth factor A expression in glial cells after experimental spinal cord ischemia.

The hematopoietic growth factor, granulocyte colony-stimulating factor (G-CSF), has become one of the few growth factors approved for clinical use. It has therapeutic potential for numerous neurodegenerative diseases; however, at present the cellular effects of G-CSF on the central nervous system remain unclear and in need of investigation. In the present study, we used spinal cord ischemia, a neurodegenerative model, to examine the effects of intrathecal (i.t.) G-CSF on glial cell (microglia and astrocyte) activation and neuroprotective factor expression, including glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor A (VEGF-A) protein expression. Our results indicate that i.t. G-CSF could enhance ischemia-induced microglial activation and inhibit ischemia-induced astrocyte activation. Both GDNF and VEGF-A are upregulated after injury, and i.t. G-CSF could enhance GDNF and VEGF-A expressions after injury. Interestingly, our results indicate that performing i.t. G-CSF alone on normal animals could have the effect of microglial and astrocyte activation and enhanced GDNF and VEGF-A expressions. Furthermore, through laser scanning confocal microscopy, we found that astrocytes may contribute to the majority of GDNF and VEGF-A expressions of G-CSF after spinal cord ischemia. Overall, this G-CSF-induced upregulation suggests that activation of endogenous neuroprotective mechanisms could resist neurodegenerative insults. These observations demonstrate the cellular mechanism of i.t. G-CSF after spinal cord ischemia and confirm the neuroprotective effect of G-CSF after spinal cord ischemia injury.

Chen CH ，Huang SY ，Chen NF ，Feng CW ，Hung HC ，Sung CS ，Jean YH ，Wen ZH ，Chen WF ... -  《-》

Suppressive effects of intrathecal granulocyte colony-stimulating factor on excessive release of excitatory amino acids in the spinal cerebrospinal fluid of rats with cord ischemia: role of glutamate transporters.

Chen WF ，Sung CS ，Jean YH ，Su TM ，Wang HC ，Ho JT ，Huang SY ，Lin CS ，Wen ZH ... -  《-》

Intrathecally injected granulocyte colony-stimulating factor produced neuroprotective effects in spinal cord ischemia via the mitogen-activated protein kinase and Akt pathways.

Chen WF ，Jean YH ，Sung CS ，Wu GJ ，Huang SY ，Ho JT ，Su TM ，Wen ZH ... -  《NEUROSCIENCE》

Neuroprotective Effects of Direct Intrathecal Administration of Granulocyte Colony-Stimulating Factor in Rats with Spinal Cord Injury.

To date, no reliable methods have proven effective for treating spinal cord injury (SCI). Even systemic administration of methylprednisolone (MP) remains controversial. We previously reported that intrathecal (i.t.) administration of granulocyte colony-stimulating factor (G-CSF) improves outcome after experimental spinal cord ischemic insults in rats. The present study aimed to examine the neuroprotective efficacy of i.t. G-CSF or MP in rats with SCI. Female rats were subjected to spinal cord contusion injury at T10 using NYU impactor. We i.t. administered G-CSF (10 μg) or MP (one bolus of 100 μg, followed by 18 μg/h infusion for 23 h) immediately after SCI. Both G-CSF and MP significantly improved the rats' motor function after SCI. Immunofluorescence staining revealed suppressed expression of transforming growth factor-beta 1 (TGF-β1), chondroitin sulfate proteoglycans (neurocan and phosphacan), OX-42 and tumor necrosis factor alpha after i.t. G-CSF, but not MP, in rats with SCI. In addition, G-CSF significantly decreased the expression of astrocytic TGF-β1 and glial fibrillary acidic protein around the injury site. Furthermore, rats with G-CSF treatment showed increased neurofilament expression beyond the glial scars. Direct i.t. administration of G-CSF provides a promising therapeutic option for SCI or related spinal diseases.

Chen WF ，Chen CH ，Chen NF ，Sung CS ，Wen ZH ... -  《-》

Granulocyte colony-stimulating factor improves alternative activation of microglia under microenvironment of spinal cord injury.

Granulocyte colony-stimulating factor (G-CSF) was investigated in the present study to examine whether it could affect the activation status of microglia under microenvironment of spinal cord injury and provide a potential therapeutic treatment for spinal cord injury. We established mouse spinal cord hemisection model and injected recombinant human G-CSF (rhG-CSF) subcutaneously. The results demonstrated that G-CSF could recruit microglia to the injury site in the first 72h after spinal cord injury. Moreover, G-CSF inhibits the expression of pro-inflammatory factors and promotes the expression of neurotrophic factors. Additionally, G-CSF also increases the expression of markers of M2 macrophage and inhibits the expression of markers of M1 macrophage in BV2 microglia in vitro model, favoring the M2 polarization of microglia under the microenvironment of spinal cord hemisection. NFκB signal pathway was involved in G-CSF-induced polarization of BV2 microglia. As a conclusion, we suggested that administration of G-CSF within the first 72h after spinal cord injury might reduce early inflammation-induced detrimental effect and promote an anti-inflammatory response that favors repair via improving alternative activation of microglia. Administration of G-CSF in the acute phase of spinal cord injury may be a promising strategy in restorative therapy after spinal cord injury.

Guo Y ，Zhang H ，Yang J ，Liu S ，Bing L ，Gao J ，Hao A ... -  《-》