Exploring the beneficial role of ROCK inhibitors in sepsis-induced cerebral and cognitive injury in rats

Sepsis-induced cerebral injury is a systemic inflammatory response associated with high mortality rate and cognitive impairment. Rho/ROCK pathway activation is involved in initiating the inflammatory response and promoting cerebral dysfunction. The present study explored the beneficial effects of ROCK inhibitors in sepsis-induced cerebral injury and cognitive impairment in rats. The model of sepsis was established by employing cecal ligation and puncture (CLP). CLP significantly augmented cerebral injury assessed in terms of intensified activity of caspases-3 and decrease in BCL-2 in the brain along with the release of S100β and NSE, and assessed on day 7. Significant increase in inflammatory biomarkers IL-1β and TNF-α as well as increase in the protein levels of ROCK1 and ROCK2 was observed in the brain. A significant decrease in learning and memory ability was observed because of increased escape latency time on day 4 and significant decrease in time spent in the target quadrant on day 7 in CLP-subjected rats. Administration of nonselective ROCK inhibitor, fasudil (10 and 30 mg/kg), and selective ROCK1 inhibitor, Y27632 (10 and 30 mg/kg), attenuated the sepsis-induced increase in the S100β and NSE, IL-1β, TNF-α, BCL-2, caspase-3, ROCK1 and ROCK2 in septic rats and significantly memory and learning.The beneficial effects of Y27632 and fasudil were comparable suggesting the key role of ROCK1 in sepsis-induced deleterious effects. It may be concluded that sepsis may increase cerebral and cognitive injury through Rho-kinase/ROCK pathway in septic rats, and ROCK inhibitors may be potentially employed to overcome sepsis-induced deleterious effects in the brain.