Abstract
Rho-associated coil kinase (ROCK) inhibitors reportedly prevent neurodegeneration, and abnormal ROCK activation in the central nervous system induces neurite collapse and retraction. However, it is unclear whether the ROCK inhibitor Y-27632 directly protects hippocampal neurons from excitotoxicity. Here, we determined the effects of Y-27632 on neuroprotection following kainic acid (KA)-induced seizures in mice and during glutamate-induced excitotoxicity in HT22 cells. One day after Y-27632 injection, mice were treated with KA and killed 1-2 days later. Fluoro-Jade B and rapid Golgi staining showed that Y-27632 protected against KA-induced neurodegeneration and neurite dystrophy. Y-27632 inhibited increases in hippocampal RhoA and ROCK2 in KA-treated mice as determined by western blot analysis. Immunohistochemical analysis revealed ROCK2-positive neurons and astrocytes in the KA-treated hippocampus. In HT22 cells, Y-27632 also protected neurons and neurite formation during glutamate-induced excitotoxicity in vitro. These results indicate that ROCK inhibition modulates neurite growth and protects neurons from excitotoxicity-induced cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Amides / therapeutic use*
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Animals
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Anticonvulsants / pharmacology
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Anticonvulsants / therapeutic use*
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Astrocytes / drug effects
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Astrocytes / enzymology
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Cell Death
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Cells, Cultured / drug effects
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Convulsants / antagonists & inhibitors
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Convulsants / toxicity
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Glial Fibrillary Acidic Protein
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Glutamic Acid / toxicity
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Hippocampus / cytology
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Hippocampus / drug effects*
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Hippocampus / enzymology
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Hippocampus / pathology
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Kainic Acid / toxicity
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Male
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Mice
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Mice, Inbred ICR
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Myosin Light Chains / biosynthesis
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Myosin Light Chains / genetics
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Nerve Tissue Proteins / antagonists & inhibitors*
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Neurites / drug effects
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Neurons / drug effects*
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Neurons / enzymology
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Neurons / ultrastructure
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Neurotoxins / toxicity*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Seizures / chemically induced
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Seizures / prevention & control*
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Single-Blind Method
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rho GTP-Binding Proteins / biosynthesis
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rho GTP-Binding Proteins / genetics
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rho-Associated Kinases / antagonists & inhibitors*
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rhoA GTP-Binding Protein
Substances
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Amides
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Anticonvulsants
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Convulsants
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Glial Fibrillary Acidic Protein
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Myosin Light Chains
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Nerve Tissue Proteins
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Neurotoxins
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Protein Kinase Inhibitors
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Pyridines
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glial fibrillary astrocytic protein, mouse
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Y 27632
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Glutamic Acid
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Rock1 protein, mouse
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Rock2 protein, mouse
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rho-Associated Kinases
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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Kainic Acid