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 α7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 μM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 μM) nor raclopride, D2 receptor antagonist (10 μM) changed the memantine-induced effects. Propranolol (100 μM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 μM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 μM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 μM) 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.