Neurodegenerative Evidence in Mice Brains with Cecal Ligation and Puncture-Induced Sepsis: Preventive Effect of the Free Radical Scavenger Edaravone

Hiroki Yokoo, Seiichi Chiba, Kengo Tomita, Michinori Takashina, Hiroshi Sagara, Saburo Yagisita, Yasuo Takano, Yuichi Hattori

Sepsis is a major clinical challenge and septic encephalopathy is its nasty complication. The pathogenesis and underlying mechanisms of septic encephalopathy are not well understood. This study sought to fully characterize sepsis-associated biochemical and histopathological changes in brains of mice after cecal ligation and puncture, regarded as a highly clinically relevant animal model of polymicrobial sepsis. Real-time PCR analysis showed that gene expression levels of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, were significantly up-regulated in brain tissues from septic mice, but to a much lesser extent when compared with those in peripheral tissues such as lungs. Blood-brain barrier (BBB) permeability was significantly increased in septic mice, as determined by the measurement of sodium fluorescein and Evans blue content. Sepsis resulted in increases in NADPH oxidase activity and expression of p47(phox) and p67(phox) and up-regulation of inducible nitric oxide (NO) synthase in brains, indicating that superoxide, produced by NADPH oxidase, reacts with NO to form peroxynitrite, that maybe lead to the loss of BBB integrity. Light and electron microscopic examination of septic mouse brain showed serious neuronal degeneration, as indicated by hyperchromatic, shrunken, pyknotic, and electron-dense neurons. These histopathological changes were prevented by treatment with the free radical scavenger edaravone. Together, these results suggest that sepsis can lead to rapid neurodegenerative changes in brains via free radical species production and possibly subsequent injury to the BBB. We may also provide a potentially useful therapeutic tool for treating septic encephalopathy.