title: Cytokine regulation by modulation of the NMDA receptor on astrocytes.
abstract: The N-methyl-d-aspartate receptor (NMDA-R) is crucial for synaptic transmission and plasticity. Over-activation, as well as complete blockade, of receptor function can lead to severe impairment. However, modest modulation of the receptor has been reported to be neuroprotective via endogenous regulation of the receptor and its subunit composition in response to pathophysiological conditions. As an important model for de- and remyelination in the central nervous system (CNS) we examined NMDA-R regulation in the mouse cuprizone model. We were able to show an upregulation of the NR2 subunit on hippocampal neurons during remyelination despite unchanged levels of NR1. In this model, remyelination is substantially influenced by astrocytes. We therefore addressed the question whether the NMDA-R on astrocytes could also be regulated and if this would influence the cytokine/chemokine expression profile of these cells. We used different stimuli such as NMDA and glutamate, LPS and TNFα in combination with NMDA-R antagonism using memantine and MK801 in astrocytic cell culture. Here we demonstrate that following NMDA stimulation NMDA-R block downregulated NR1 mRNA expression in astrocytes. Furthermore, NMDA-R blockade significantly decreased BMP-4 expression. Independent of NMDA-R blockade, memantine counteracted the production of inflammatory cytokines following LPS stimulation. These findings indicate that the NMDA-R is linked to astrocytic growth factor production and may be a promising target for therapeutic modulation.
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: Suehs.Kurt-Wolfram@mh-hannover.de.
authors.forename: Kurt-Wolfram
authors.initials: KW
authors.lastname: Sühs
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gudi
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Eckermann
authors.affiliation: Department of Neurology, University Clinic Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Fairless
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Refik
authors.initials: R
authors.lastname: Pul
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripuletz
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003471:Cuprizone; D016207:Cytokines / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D016207:Cytokines; D008070:Lipopolysaccharides; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D003471:Cuprizone
keywords: Astrocytes; BMP4; Cytokines; Memantine; NMDA receptor