title: Inhibition of acetylcholinesterase modulates NMDA receptor antagonist mediated alterations in the developing brain.
abstract: Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.
authors.affiliation: Department of Pediatrics I, Neonatology, University Hospital Essen, Essen 45122, Germany. ivo.bendix@uk-essen.de.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Department of Pediatrics I, Neonatology, University Hospital Essen, Essen 45122, Germany. meray.serdar@uk-essen.de.
authors.forename: Meray
authors.initials: M
authors.lastname: Serdar
authors.affiliation: Department of Pediatrics I, Neonatology, University Hospital Essen, Essen 45122, Germany. josephine.herz@uk-essen.de.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. clarissa.von-haefen@charite.de.
authors.forename: Clarissa
authors.initials: C
authors.lastname: von Haefen
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. fatme21@hotmail.de.
authors.forename: Fatme
authors.initials: F
authors.lastname: Nasser
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. benjamin.rohrer@charite.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rohrer
authors.affiliation: Department of Neonatology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. stefanie.endesfelder@charite.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.affiliation: Department of Pediatrics I, Neonatology, University Hospital Essen, Essen 45122, Germany. ursula.felderhoff@uk-essen.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. claudia.spies@charite.de.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Spies
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany. marco.sifringer@charite.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019716:Tissue Inhibitor of Metalloproteinase-2; D016291:Dizocilpine Maleate; D010830:Physostigmine; D000110:Acetylcholinesterase; D020778:Matrix Metalloproteinase 2