Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain |
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| Authors: | Ivo Bendix Meray Serdar Josephine Herz Clarissa von Haefen Fatme Nasser Benjamin Rohrer Stefanie Endesfelder Ursula Felderhoff-Mueser Claudia D. Spies Marco Sifringer |
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| Affiliation: | 1.Department of Pediatrics I, Neonatology, University Hospital Essen, Essen 45122, Germany; E-Mails: (M.S.); (J.H.); (U.F.-M.);2.Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany; E-Mails: (C.H.); (F.N.); (B.R.); (C.D.S.); (M.S.);3.Department of Neonatology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany; E-Mail: |
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| 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. |
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| Keywords: | developing brain NMDA receptor MK801 acetylcholinesterase extracellular matrix BDNF neuroprotection |
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