title: Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats.
abstract: In 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.
  
  
  
  Animals 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.
  
  
  
  LPS-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.
  
  
  
  Our 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.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Yamanaka
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan. takashika@kochi-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishigaki
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Bun
authors.initials: B
authors.lastname: Aoyama
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tateiwa
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Marie
authors.initials: M
authors.lastname: Shigematsu-Locatelli
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Fabricio M
authors.initials: FM
authors.lastname: Locatelli
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000375:Aging; D000818:Animals; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D020927:Dexmedetomidine / Q000627:therapeutic use*; D006624:Hippocampus / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000150:complications; D054833:Isoindoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D008569:Memory Disorders; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction
chemical_list: D006993:Hypnotics and Sedatives; D007093:Imidazoles; D054833:Isoindoles; D007546:Isoquinolines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010879:Piperazines; D020927:Dexmedetomidine; C032994:AR-C239; C072125:BRL 44408
keywords: Cognitive function; Dexmedetomidine; Microglia; Neuroinflammation