title: Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model.
abstract: Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalb
authors.forename: Clarissa
authors.initials: C
authors.lastname: von Haefen
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Annalena
authors.initials: A
authors.lastname: Tegethoff
authors.forename: Nadine
authors.initials: N
authors.lastname: Paeschke
authors.forename: Mariya
authors.initials: M
authors.lastname: Kostova
authors.forename: Aarne
authors.initials: A
authors.lastname: Feldheiser
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Spies
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009388:Neostigmine / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D010830:Physostigmine / Q000494:pharmacology*; D011183:Postoperative Complications / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009388:Neostigmine; D010830:Physostigmine