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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.
Highlights
Tobacco smoking is a worldwide health epidemic that is responsible for about 5 million deaths [1].Tobacco smoke exposure has been implicated in causing deleterious effects on the development of multiple organ systems [2], including the respiratory, nervous, and cardiovascular systems
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
Numerous animal studies have investigated the long-term implications of cigarette smoke exposure on cognitive functions, which shown that chronic mid-gestational nicotine exposure resulted in remarkably www.impactjournals.com/oncotarget decreased performance in adult mice in the radial-arm maze and Morris water maze tests [5], and nicotine administration resulted in an obvious effect on the mean performance of nicotine-treated rats compared to control-treated rats during the acquisition phase in the radialarm maze [6]
Summary
Tobacco smoking is a worldwide health epidemic that is responsible for about 5 million deaths [1].Tobacco smoke exposure has been implicated in causing deleterious effects on the development of multiple organ systems [2], including the respiratory, nervous, and cardiovascular systems. Numerous animal studies have investigated the long-term implications of cigarette smoke exposure on cognitive functions, which shown that chronic mid-gestational nicotine exposure resulted in remarkably www.impactjournals.com/oncotarget decreased performance in adult mice in the radial-arm maze and Morris water maze tests [5], and nicotine administration resulted in an obvious effect on the mean performance of nicotine-treated rats compared to control-treated rats during the acquisition phase in the radialarm maze [6]. Chronic cigarette smoke exposure is a serious inflammatory stimulus that induces the excess production of inflammatory cytokines, and causes deleterious effects on the nervous and respiratory systems. Inhibiting cigarette smoke-induced production of inflammatory cytokines is an attractive strategy in the development of drugs for cognitive function improvements. In the present study, we carried out a set of in vivo tests to investigate the cognitive improvement effects of fasudil in a cigarette smoke exposed animal model and explored the possible mechanisms
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