The Rho-kinase (ROCK) inhibitor Y-27632 protects against excitotoxicity-induced neuronal death in vivo and in vitro.
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.
Department of Anatomy and Neurobiology, Institute of Health Sciences, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, 816 Beongil 15 Jinju-daero, Jinju, Gyeongnam 660-290, Republic of Korea.
Byeong Tak
BT
Jeon
Eun Ae
EA
Jeong
Sun-Young
SY
Park
Hyeonwi
H
Son
Hyun Joo
HJ
Shin
Dong Hoon
DH
Lee
Hyun Joon
HJ
Kim
Sang Soo
SS
Kang
Gyeong Jae
GJ
Cho
Wan Sung
WS
Choi
Gu Seob
GS
Roh
D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D016923:Cell Death; D002478:Cells, Cultured / Q000187:drug effects; D003292:Convulsants / Q000037:antagonists & inhibitors / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D009498:Neurotoxins / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D016037:Single-Blind Method; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein
D000577:Amides; D000927:Anticonvulsants; D003292:Convulsants; D005904:Glial Fibrillary Acidic Protein; D018994:Myosin Light Chains; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C528900:glial fibrillary astrocytic protein, mouse; C108830:Y 27632; D018698:Glutamic Acid; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D007608:Kainic Acid