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Journal of anesthesia · Feb 2017
Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats.
- Daiki Yamanaka, Takashi Kawano, Atsushi Nishigaki, Bun Aoyama, Hiroki Tateiwa, Marie Shigematsu-Locatelli, Fabricio M Locatelli, and Masataka Yokoyama.
- Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
- J Anesth. 2017 Feb 1; 31 (1): 25-35.
PurposeIn the present study, we examined whether and by what mechanisms dexmedetomidine (DMED) prevents the development of systemic inflammation (SI)-induced cognitive dysfunction in aged rats.MethodsAnimals received a single intraperitoneal (i.p.) injection of either 5.0 mg/kg lipopolysaccharide (LPS) or vehicle. LPS-treated rats were further divided into three groups: early DMED, late DMED, or midazolam (MDZ) treatment (n = 12 each). Seven days after LPS injection, cognitive function was evaluated using a novel object recognition task, followed by measurement of hippocampal levels of proinflammatory cytokines and Toll-like receptor 4 (TLR-4) expression. For ex vivo experiments, microglia were isolated from the hippocampus for assessment of cytokine response to LPS.ResultsLPS-treated rats showed memory deficits, hippocampal neuroinflammation, and TLR-4 upregulation as compared to saline-treated animals. However, early DMED treatment was able to attenuate these SI-induced neurocognitive changes, whereas no benefits were observed in the MDZ and late DMED treatment groups. In ex vivo experiments, early DMED treatment prevented the development of SI-induced excessive microglial hyperactivation, which was blocked by the nonspecific α2-adrenergic receptor (AR) antagonist atipamezole or the specific α2A-AR antagonist BRL-44408, but not by the specific α2B/C-AR antagonist ARC-239. On the other hand, neither DMED nor MDZ had a direct effect on LPS-induced release of pro-inflammatory cytokines from hippocampal microglia at clinically relevant concentrations.ConclusionOur findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α2A-AR signaling pathway.
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