title: The therapeutic potential of atorvastatin in a mouse model of postoperative cognitive decline.
abstract: OBJECTIVE
  Postoperative cognitive decline is emerging as a significant complication of surgery among older adults. Animal models indicate a central role of hippocampal inflammatory responses in the pathophysiology of postoperative cognitive decline. We hypothesized that atorvastatin, shown to exert neuroprotective potential in central nervous system (CNS) disorders, would attenuate neuroinflammation and improve cognitive function in mice after surgery and anesthesia.
  
  
  METHODS
  C57BL6 adult mice were pretreated with atorvastatin (250 μg) or vehicle, orally, for 5 days before undergoing unilateral nephrectomy under isoflurane anesthesia. We evaluated behavioral parameters related to cognitive function (fear conditioning and Morris Water Maze) and determined systemic and hippocampal interleukin-1β levels, postoperatively. Endothelial COX-2 expression, gross NF-κB and microglial (IBA1, CD68) activation, synaptic function (synapsin-1, PSD95, COX-2), heme oxygenase-1, and GSK3β were also examined.
  
  
  RESULTS
  Surgery induced a significant reduction in hippocampal-dependent fear response that was attenuated by treatment with atorvastatin, which also preserved spatial memory on day 7 after surgery. Atorvastatin evoked significant protection from hippocampal interleukin-1β production, but not systemic interleukin-1β production, accompanied by a marked reduction in hippocampal endothelial COX-2, NF-κB activation and decreased microglial reactivity. Surgery triggered an acute decline in synapsin-1, paralleled by an increase in postsynaptic COX-2 that was partially attenuated by atorvastatin. Furthermore, phosphorylation and inactivation of neuronal GSK3β was significantly enhanced after atorvastatin treatment.
  
  
  CONCLUSIONS
  These findings indicate that cognitive decline is very likely associated with synaptic pathology after systemic and central inflammation induced by peripheral surgery/isoflurane anesthesia and suggest that the anti-inflammatory and neuroprotective properties of atorvastatin provide a rationale for its use as a therapeutic strategy for postoperative cognitive decline.
authors.affiliation: *Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom †Department of Pain Management, Gongli Hospital, Pudong, China ‡Department of Anaesthetics, Wycombe Hospital, Buckinghamshire Hospitals NHS Trust, High Wycombe, Buckinghamshire, United Kingdom §Department of Anesthesiology, Hubei University of Medicine, Hubei, China.
authors.forename: Marcela P
authors.initials: MP
authors.lastname: Vizcaychipi
authors.forename: Helena R
authors.initials: HR
authors.lastname: Watts
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Jack W
authors.initials: JW
authors.lastname: Penn
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Wan
authors.forename: Chen
authors.initials: C
authors.lastname: Pac-Soo
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000008:administration & dosage*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy / Q000009:adverse effects*; D011183:Postoperative Complications; D011758:Pyrroles / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin