Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central α2A adrenoceptor

Sepsis-associated encephalopathy (SAE) is a significant clinical issue that is associated with increased mortality and cost of health care. Dexmedetomidine, an alpha 2 adrenoceptor agonist that is used to provide sedation, has been shown to induce neuroprotection under various conditions. This study was designed to determine whether dexmedetomidine protects against SAE and whether alpha 2 adrenoceptor plays a role in this protection. Sixto eight week old CD-1 male mice were subjected to cecal ligation and puncture (CLP). They were treated with intraperitoneal injection of dexmedetomidine in the presence or absence of alpha 2 adrenoceptor antagonists, atipamezole or yohimbine, or an alpha 2A adrenoceptor antagonist, BRL-44408. Hippocampus and blood were harvested for measuring cytokines. Mice were subjected to Barnes maze and fear conditioning 14 days after CLP to evaluate their learning and memory. CLP significantly increased the proinflammatory cytokines including tumor necrosis factor alpha, interleukin (IL)-6 and IL-1 beta in the blood and hippocampus. CLP also increased the permeability of blood-brain barrier (BBB) and impaired learning and memory. These CLP detrimental effects were attenuated by dexmedetomidine. Intracerebroventricular application of atipamezole, yohimbine or BRL-44408 blocked the protection of dexmedetomidine on the brain but not on the systemic inflammation. Astrocytes but not microglia expressed alpha 2A adrenoceptors. Microglial depletion did not abolish the protective effects of dexmedetomidine. These results suggest that dexmedetomidine reduces systemic inflammation, neuroinflammation, injury of BBB and cognitive dysfunction in septic mice. The protective effects of dexmedetomidine on the brain may be mediated by alpha 2A adrenoceptors in the astrocytes.

Automated summary

Sepsis-associated encephalopathy (SAE) is a significant clinical issue associated with increased mortality and healthcare costs. Dexmedetomidine, an alpha 2 adrenoceptor agonist, has been shown to induce neuroprotection in septic mice by reducing systemic inflammation, neuroinflammation, blood-brain barrier injury, and cognitive dysfunction, possibly through activation of alpha 2A adrenoceptors in astrocytes.