Dexmedetomidine Ameliorates Perioperative Neurocognitive Disorders by Suppressing Monocyte-Derived Macrophages in Mice With Preexisting Traumatic Brain Injury.

BACKGROUND Traumatic brain injury (TBI) initiates immune responses involving infiltration of monocyte-derived macrophages (MDMs) in the injured brain tissue. These MDMs play a key role in perioperative neurocognitive disorders (PNDs). We tested the hypothesis that preanesthetic treatment with dexmedetomidine (DEX) could suppress infiltration of MDMs into the hippocampus of TBI model mice, ameliorating PND. METHODS We first performed bone marrow transplantation from green fluorescent protein-transgenic mice to C57BL/6 mice to identify MDMs. We used only male mice for homogeneity. Four weeks after transplantation, a controlled cortical impact model of TBI was created using recipient mice. Four weeks after TBI, mice received pretreatment with DEX before general anesthesia (GA). Mice performed the Barnes maze test (8-12 mice/group) 2 weeks after GA and were euthanized for immunohistochemistry (4-5 mice/group) or immunoblotting (7 mice/group) 4 weeks after GA. RESULTS In Barnes maze tests, TBI model mice showed longer primary latency (mean difference, 76.5 [95% confidence interval, 41.4-111.6], P < .0001 versus Naive), primary path length (431.2 [98.5-763.9], P = .001 versus Naive), and more primary errors (5.7 [0.62-10.7], P = .017 versus Naive) than Naive mice on experimental day 3. Expression of MDMs in the hippocampus was significantly increased in TBI mice compared to Naive mice (2.1 [0.6-3.7], P = .003 versus Naive). Expression of monocyte chemotactic protein-1 (MCP1)-positive areas in the hippocampus was significantly increased in TBI mice compared to Naive mice (0.38 [0.09-0.68], P = .007 versus Naive). Immunoblotting indicated significantly increased expression of interleukin-1β in the hippocampus in TBI mice compared to Naive mice (1.59 [0.08-3.1], P = .035 versus Naive). In contrast, TBI mice pretreated with DEX were rescued from these changes and showed no significant difference from Naive mice. Yohimbine, an α2 receptor antagonist, mitigated the effects of DEX (primary latency: 68.3 [36.5-100.1], P < .0001 versus TBI-DEX; primary path length: 414.9 [120.0-709.9], P = .0002 versus DEX; primary errors: 6.6 [2.1-11.2], P = .0005 versus TBI-DEX; expression of MDMs: 2.9 [1.4-4.4], P = .0001 versus TBI-DEX; expression of MCP1: 0.4 [0.05-0.67], P = .017 versus TBI-DEX; expression of interleukin-1β: 1.8 [0.34-3.35], P = .01 versus TBI-DEX). CONCLUSIONS Preanesthetic treatment with DEX suppressed infiltration of MDMs in the hippocampus and ameliorated PND in TBI model mice. Preanesthetic treatment with DEX appears to suppress infiltration of MDMs in the hippocampus and may lead to new treatments for PND in patients with a history of TBI.