GM-CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis-related proteins.
Recently, we reported that GM-CSF showed therapeutic effects on the spinal cord injury (SCI) in rat model possibly via its anti-apoptotic activity in the nervous system. This study investigated the molecular mechanism of its anti-apoptotic and neuroprotective effects in N2a neuroblastoma cells and in rat SCI model. GM-CSF inhibited staurosporine-induced cytotoxicity and apoptosis of N2a cells. Single administration of GM-CSF either intraperitoneally or locally using a gelfoam, clearly reduced the apoptotic events in the surrounding region of the injury site in rat SCI model. Immunohistochemical analysis showed that apoptosis of cells occurred mainly in the neurons, but not significantly in the astrocytes in the surrounding regions. In both N2a cells and in rat SCI model, GM-CSF actually reduced the expression of pro-apoptotic proteins (p53, p21(WAF1/CIP1) and Bax), while further induced that of an anti-apoptotic protein (Bcl-2). In the Basso-Beattie-Bresnahan (BBB) locomotor test, the single GM-CSF administration showed better behavioral recovery than the untreated control only at early times within 1 week after injury. Overall, GM-CSF was shown to exert its neuroprotective effect on the neural injury by regulating the expression of apoptosis related genes, providing the molecular basis on its anti-apoptotic activity. Longer administration of GM-CSF appeared to be necessary for the sustained functional recovery from SCI.
Huang
Xian
X
Department of Neurosurgery, Inha University College of Medicine, Incheon, Republic of Korea.
Choi
Jung-Kyoung
JK
Park
So Ra
SR
Ha
Yoon
Y
Park
Hyeonseon
H
Yoon
Seung Hwan
SH
Park
Hyung Chun
HC
Park
Jong Oon
JO
Choi
Byung Hyune
BH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000633:toxicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000819:agonists / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494828:Bax protein, rat; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019311:Staurosporine