title: Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB.
abstract: Surgery induces learning and memory impairment. Neuroinflammation may contribute to this impairment. Nuclear factor κB (NF-κB) is an important transcription factor to regulate the expression of inflammatory cytokines. We hypothesize that inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC) reduces neuroinflammation and the impairment of learning and memory. To test this hypothesis, four-month-old male Fischer 344 rats were subjected to right carotid exploration under propofol and buprenorphine anesthesia. Some rats received two doses of 50mg/kg PDTC given intraperitoneally 30min before and 6h after the surgery. Rats were tested in the Barnes maze and fear conditioning paradigm begun 6days after the surgery. Expression of various proteins related to inflammation was examined in the hippocampus at 24h or 21days after the surgery. Here, surgery, but not anesthesia alone, had a significant effect on prolonging the time needed to identify the target hole during the training sessions of the Barnes maze. Surgery also increased the time for identifying the target hole in the long-term memory test and decreased context-related learning and memory in fear conditioning test. Also, surgery increased nuclear expression of p65, a NF-κB component, decreased cytoplasmic amount of inhibitor of NF-κB, and increased the expression of interleukin-1β, interleukin-6, ionized calcium binding adaptor molecule 1 and active matrix metalloproteinase 9 (MMP-9). Finally, surgery enhanced IgG extravasation in the hippocampus. These surgical effects were attenuated by PDTC. These results suggest that surgery, but not propofol-based anesthesia, induces neuroinflammation and impairment of learning and memory. PDTC attenuates these effects possibly by inhibiting NF-κB activation and the downstream MMP-9 activity.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA; Department of Anesthesiology, Shanghai 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Shanghai 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China. Electronic address: jiangw@sjtu.edu.en.
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA. Electronic address: zz3c@virginia.edu.
authors.forename: Z
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology; D002339:Carotid Arteries / Q000601:surgery*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D003213:Conditioning, Psychological / Q000187:drug effects; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D005239:Fear; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011183:Postoperative Complications / Q000188:drug therapy*; D015742:Propofol / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013859:Thiocarbamates / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000777:Anesthetics; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D002047:Buprenorphine; D020780:Matrix Metalloproteinase 9; D015742:Propofol
keywords: neuroinflammation; nuclear factor κB; pyrrolidine dithiocarbamate; rat; surgery