title: Overexpression of NMDAR2B in an inflammatory model of Alzheimer's disease: modulation by NOS inhibitors.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a common form of age-related dementia, characterized by deposition of amyloid Aβ plaques, neuroinflammation and neurodegeneration. N-methyl-D-aspartate receptors (NMDAR) are postsynaptic glutamate receptors that play a role in memory formation and are targets for memantadine, an anti-AD drug. Nitric oxide (NO) signaling has been involved in both memory development through neuronal NO synthase (nNOS), and neuroinflammation through inducible NO synthase (iNOS) which mediates CNS inflammatory processes.
  
  
  OBJECTIVE
  To study the expression of the NMDAR2B subunit in an inflammatory model of AD before and after treatment with NO modulators.
  
  
  METHODS
  AD was induced in mice by a single dose of lipopolysaccharide (LPS). Behavioral tests for spatial and non-spatial memories and locomotor activity were performed to assess disease severity and progression. The effects of L-NAME (general NOS inhibitor), 1400W (iNOS inhibitor), diflunisal (systemic anti-inflammatory drug that does not cross the blood brain barrier), and L-arginine, the substrate for NOS was determined. Immunohistochemistry was done to confirm AD and brain lysates were tested for Aβ formation, levels of NMDAR2B subunits, and brain NO levels.
  
  
  RESULTS
  Systemic LPS induced AD, as shown by cognitive impairment; increased levels of Aβ and concomitant increase in the brain NO concentrations. This was associated with overexpression of NMDAR2B. All tested drugs improved behavioral dysfunction, prevented Aβ formation and NMDAR overexpression, and lead to decrease in NO concentration in the brain. L-Arginine alone, however, did not produce similar improvements.
  
  
  CONCLUSIONS
  NMDAR2B subunits are overexpressed in an inflammatory model of AD and NO inhibitors ameliorate this expression.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City 11835, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Maher
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City 11835 and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Nesrine Salah-Eldine
authors.initials: NS
authors.lastname: El-Sayed
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City 11835, Egypt.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Breitinger
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Main Entrance of Al Tagamoa Al Khames, New Cairo City 11835, Egypt. Electronic address: mohamed.gad@guc.edu.eg.
authors.forename: Mohamed Zakaria
authors.initials: MZ
authors.lastname: Gad
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D000578:Amidines / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004061:Diflunisal / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D000578:Amidines; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001596:Benzylamines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D004061:Diflunisal; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: Alzheimer; Diflunisal; LPS; NMDAR; NOS inhibitors; Nitric oxide