Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism.
We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.
Kloc
Renata
R
Department of Experimental and Clinical Pharmacology, Skubiszewski Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.
Luchowska
Elzbieta
E
Wielosz
Marian
M
Owe-Larsson
Bjorn
B
Urbanska
Ewa M
EM
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D002227:Carbazoles; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D010880:Piperidines; D011758:Pyrroles; C069701:NPC 15437; C057416:KT 5720; C088643:LY 235959; D017868:Cyclic AMP-Dependent Protein Kinases; D007736:Kynurenic Acid; D008559:Memantine