title: Fasudil, an inhibitor of Rho-associated coiled-coil kinase, improves cognitive impairments induced by smoke exposure.
abstract: The current study was designed to investigate the pathological changes in brain induced by smoke exposure, and explore whether fasudil could alleviate these impairments.Adult C57BL/6 mice were exposed to tobacco smoking for four months, and fasudil was treated from the third months. To investigate lung injuries, the immunohistochemistry of lung tissue, immune cell infiltrations, cytokine productions in bronchoalveolar lavage (BAL) fluid, and seurm inflammatory cytokines were evaluated. To investigate cognitive impairments, Morris water maze test, hippocampal inflammatory cytokines and Rho associated signaling pathways were evaluated.Our findings showed fasudil administration inhibited the inflitration of inflammatory cells (macrophages, neutrophils, and lymphocytes), suppressed the production of inflammatory cytokines both in the BAL fluid, serum, and hippocampus. Further, fasudil significantly improved the spatial learning and memory impairments and reduced the elevation of hippocampal inflammatory cytokines induced by tobacco smoking. Of note, expressions of RhoA, ROCK1, ROCK2, caspase-3, caspase-9, bax and the phosphorylation of NF-κBp65 were increased accompanying the smoke exposure-induced cognitive impairments, which were significantly inhibited by fasudil treatment as indicted in western blot and immunohistochemistry analysis.Our results showed that fasudil exhibited protective effects on smoke exposure induced cognitive deficits which might involve with the regulation of Rho/ROCK/NF-κB pathways. Further studies are warranted before clinical application of fasudil.
authors: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Deng
authors: D
authors: Xueyang
authors: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Ma
authors: M
authors: Zhanqiang
authors: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, PR China.|Central Laboratory, Nanjing Municipal Hospital of T.C.M, The Third Affiliated Hospital of Nanjing University of T.C.M, Nanjing 210001, China.
authors: Ma
authors: M
authors: Chunhua
authors: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Hao
authors: H
authors: Kun
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects; D013997:Time Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D047428:Protein Kinase Inhibitors; C498144:Rela protein, mouse; D014028:Tobacco Smoke Pollution; D051996:Transcription Factor RelA; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 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; C049347:fasudil
keywords: Rho/ROCK pathway; cognitive impairment; fasudil; smoke exposure