title: Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats.
abstract: BACKGROUND
  Postoperative cognitive dysfunction is a clinical entity that is associated with poor outcome. We determined the effectiveness of amantadine in reducing surgery-induced cognitive impairment and the role of glial cell line-derived neurotrophic factor (GDNF) in this effect.
  
  
  METHODS
  Four-month old male Fischer 344 rats were subjected to right carotid exposure under intravenous anesthesia. Some rats received intraperitoneal injection of 25 mg/kg/day amantadine for 3 days with the first dose at 15 min before the surgery or intracerebroventricular injection of GDNF or an anti-GDNF antibody at the end of surgery. One week later, rats were started to be tested by Barnes maze and fear conditioning. Hippocampus was harvested at 6 h, 24 h or 10 days after the surgery for biochemical analysis. C8-B4 cells, a microglial cell line, were pretreated with 1 ng/ml GDNF for 30 min before being exposed to 5 ng/ml lipopolysaccharide for 2 h.
  
  
  RESULTS
  Surgery increased the time to identify the target box in the Barnes maze when tested 1 day [22 (median) (11-66) (interquartile range) of control group vs. 158 (29-180) of surgery group, n = 15, P = 0.022) or 8 days after the training sessions and reduced context-related freezing behavior in the fear conditioning test. These effects were attenuated by amantadine (25 (14-90), n = 15, P = 0.029 compared with surgery group at 1 day after the training sessions in Barnes maze) and intracerebroventricular GDNF. Amantadine increased GDNF that was co-localized with glial fibrillary acidic protein, an astrocytic marker, in the hippocampus. Intracerebroventricular injection of an anti-GDNF antibody but not the denatured antibody blocked the effects of amantadine on cognition. Surgery induced neuroinflammation that was inhibited by amantadine. Lipopolysaccharide increased interleukin 1β production from C8-B4 cells. This effect was inhibited by GDNF.
  
  
  CONCLUSIONS
  Our results suggest that amantadine attenuated surgery-induced learning and memory impairment. This effect may be mediated by GDNF via inhibition of neuroinflammation.
authors.affiliation: From the Department of Anesthesiology, University of Virginia, Charlottesville, Virginia (J.Z., H.T., Z.Z.); Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China (J.Z., W.J.); Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (H.T.).
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongying
authors.initials: H
authors.lastname: Tan
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000547:Amantadine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000096:biosynthesis*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D057967:Infusions, Intraventricular; D008297:Male; D011183:Postoperative Complications / Q000188:drug therapy* / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000547:Amantadine