Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice.
Rho kinase (ROCK) may play an important role in regulating biological events of cells, including proliferation, differentiation and survival/death. Blockade of ROCK promotes axonal regeneration and neuron survival in vivo and in vitro, thereby exhibiting potential clinical applications in spinal cord damage and stroke. Our previous studies have demonstrated that Fasudil, a selective ROCK inhibitor, induced neuroprotection in vitro. Here we used an in vivo model of hypoxia/reoxygenation (H/R) injury to examine the neuroprotective effect of Fasudil, and explore its possible mechanism(s) in vivo. H/R resulted in the loss of hippocampal neurons, accompanied by increased apoptosis of neurons in hippocampus. The expression of ROCK II and activity of ROCK in the brain were increased after H/R, and located only in microglia, but not in astrocytes and neurons. The administration of Fasudil inhibited the activity of ROCK in brain tissue and cultured microglia, and protected hippocampal neurons against H/R injury. Further immunohistochemical analysis and cytokine determination revealed that Fasudil inhibited inducible nitric oxide synthase immunoreactivity in microglia and pro-inflammatory factors in brain tissue after H/R, which is consistent with the observation wherein Fasudil reduced the pro-inflammatory factors nitric oxide, IL-1β, IL-6 and TNF-, and increased anti-inflammatory factor IL-10 in cultured microglia under normoxic or hypoxic conditions. Our results indicate that inhibition of ROCK by Fasudil may represent a useful therapeutic perspective by inhibiting microglial inflammatory responses in the CNS.
Ding
Jing
J
Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
Li
Qin-Ying
QY
Wang
Xin
X
Sun
Chang-Hai
CH
Lu
Chuan-Zhen
CZ
Xiao
Bao-Guo
BG
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018696:Neuroprotective Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052247:Nitric Oxide Synthase Type II; D054460:rho-Associated Kinases; C049347:fasudil; D010100:Oxygen