Role of Rho Kinase and Fasudil on Synaptic Plasticity in Multiple Sclerosis.
In addition to myelin loss and oligodendrocyte injury, axonal damage is a major cause of irreversible neurological disability in multiple sclerosis (MS). A series of studies have demonstrated that Rho kinase (ROCK) is involved in synaptic plasticity of neurons. Here, we found that ROCK activity in MS serum was elevated compared with serum from healthy controls. In experimental autoimmune encephalomyelitis (EAE), ROCK activity was also increased in serum, spleen, brain and spinal cord. Neuron injury with scratch and TNF-α stimulation induced the up-regulation of ROCK activity. When serum of MS patients was co-cultured with mouse cortical neurons in vitro, MS serum caused neurite shortening and reduction of cell viability, while the addition of Fasudil partially restored synaptic morphology of neurons, revealing that MS sera inhibited neurite outgrowth and synapse formation. The expression of synaptophysin was decreased in MS serum-neurons, and elevated in the presence of Fasudil. In contrast, the expression of phosphorylated collapsin response mediator protein-2 (CRMP-2) was elevated in MS serum-neurons and decreased in the presence of Fasudil. However, the addition of anti-ROCK I/II mixed antibodies in MS serum partially declined ROCK activity, but did not improve neurite outgrowth of neurons, revealing that Fasudil should prevent synaptic damage possibly through inhibiting intracellular ROCK activation mediated with MS serum. Our results indicate that axonal loss in MS may be related to increased ROCK activity. Fasudil could promote synaptogenesis and thus may contribute to preventing irreversible neurological disability associated with MS.
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.|Department of Rehabilitation, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.
Chan
C
Chen
Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
Jie-Zhong
JZ
Yu
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.
Qiong
Q
Zhang
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.
Yong-Fei
YF
Zhao
Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
Chun-Yun
CY
Liu
Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
Yan-Hua
YH
Li
"2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
Wan-Fang
WF
Yang
Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.|"2011" Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
Cun-Gen
CG
Ma
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China. bgxiao@shmu.edu.cn.
Bao-Guo
BG
Xiao
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology; D003470:Culture Media / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology*; D004789:Enzyme Activation; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D044967:Serum; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology; D016708:Synaptophysin / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000097:blood / Q000502:physiology*
D003470:Culture Media; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; C569015:Syp protein, mouse; D014409:Tumor Necrosis Factor-alpha; C095114:collapsin response mediator protein-2; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
Cortical neuron; Fasudil; Multiple sclerosis; Rho kinase; Synapse