Rho kinase inhibitor Fasudil induces neuroprotection and neurogenesis partially through astrocyte-derived G-CSF.
Rho-kinases (ROCK) are serine/threonine kinases that play an important role in fundamental processes of cell migration, proliferation and survival. Blockade of ROCK promotes axonal regeneration and neuroprotection, thereby exhibiting therapeutic potentials for clinical application to spinal cord damage and stroke. Here we explored the mechanisms of Fasudil, a ROCK inhibitor, in neuroprotection and neurogenesis by using oxygen-glucose deprivation (OGD) as an in vitro ischemia model. Fasudil stimulates astrocytes to produce granulocyte colony-stimulating factor (G-CSF). Astrocyte-conditioned medium treated with Fasudil (ACM-F) contributes to the generation of neurospheres, and decreases neuron death. Neutralization of G-CSF in ACM-F and blocking of G-CSF receptor in neuronal cell cultures revealed that Fasudil-induced neuroprotection and/or neurogenesis are mediated partially through astrocyte-derived G-CSF. Our results indicate that ROCK inhibition by Fasudil, protecting neurons and mobilizating neural stem cells, might represent a useful therapeutic perspective for various neurological disorders characterized by neuron death.
Ding
Jing
J
Institute of Neurology, Huashan Hospital, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Yu
Jie-Zhong
JZ
Li
Qin-Ying
QY
Wang
Xin
X
Lu
Chuan-Zhen
CZ
Xiao
Bao-Guo
BG
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005947:Glucose / Q000172:deficiency; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D005947:Glucose; C049347:fasudil