title: Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats.
abstract: Long duration of anesthesia may induce toxicity in the developing brain. However, little is known about the effects of the combination of surgery and anesthesia on the developing brain. The mechanisms for the effects are not clear. To determine these effects, postnatal day 7 male and female Sprague-Dawley rats were exposed to 3% sevoflurane for 2 h with or without right common carotid exposure. Pyrrolidine dithiocarbamate (PDTC), an anti-inflammatory agent, was given 30 min before and 6 h after the carotid exposure. Anti-glial cell-derived neurotrophic factor (GDNF) antibody or GDNF was given at the end of sevoflurane exposure. We found that anesthesia-surgery induced learning and memory impairment assessed by Barnes maze and fear conditioning. Anesthesia-surgery also induced neuroinflammation and reduced the level of glial cell-derived neurotrophic factor (GDNF, 10.6 ± 0.6 pg/mg protein of control rats vs. 7.7 ± 0.4 pg/mg protein of anesthesia-surgery rats, n = 17, p = 0.007) and neurogenesis in the hippocampus. PDTC inhibited these surgical effects (GDNF level 9.7 ± 0.6 pg/mg protein of anesthesia-surgery plus PDTC rats, n = 17, p = 0.763 vs. control rats). Intracerebroventricular injection of an anti-GDNF antibody but not its heat-inactivated form induced learning and memory impairment in control rats. Intracerebroventricular injection of GDNF attenuated learning and memory impairment after anesthesia-surgery. We conclude that anesthesia-surgery in neonatal rats induces neuroinflammation, which then leads to a decreased level of GDNF and neurogenesis in the hippocampus and cognitive impairment. GDNF decrease plays an important role in anesthesia-surgery-induced cognitive impairment.
  
  
  
  Anesthesia-surgery in neonatal rats induces neuroinflammation. Neuroinflammation leads to decreased levels of GDNF. Neuroinflammation reduces hippocampal neurogenesis and induces cognitive impairment. GDNF decrease is important for anesthesia-surgery-induced cognitive impairment.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, 22901, USA.|Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Gui
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, 22901, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, 22901, USA. zz3c@virginia.edu.|Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China. zz3c@virginia.edu.|Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, PO Box 800710, Charlottesville, VA, 22908-0710, USA. zz3c@virginia.edu.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000758:Anesthesia / Q000009:adverse effects*; D000818:Animals; D060825:Cognitive Dysfunction / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007858:Learning; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D055495:Neurogenesis; D017207:Rats, Sprague-Dawley; D014656:Vascular Surgical Procedures / Q000009:adverse effects*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: Cognition; Glial cell-derived neurotrophic factor; Neonatal rat; Neurogenesis