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Modulation of NMDA effects on agonist‐stimulated phosphoinositide turnover by memantine in neonatal rat cerebral cortex
Author(s) -
Mistry Rajendra,
Wilke Rolf,
Challiss R.A. John
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13275.x
Subject(s) - nmda receptor , memantine , inositol , agonist , inositol phosphate , chemistry , glutamate receptor , carbachol , endocrinology , medicine , metabotropic glutamate receptor , phosphatidylinositol , metabotropic receptor , pharmacology , receptor , biology , biochemistry , signal transduction
1 The ability of memantine (1‐amino‐3,5‐dimethyladamantane) to antagonize the modulatory effects of N‐methyl‐ d ‐aspartate (NMDA) on phosphoinositide turnover stimulated by muscarinic cholinoceptor‐and metabotropic glutamate receptor‐agonists has been examined in neonatal rat cerebral cortex slices. 2 Memantine antagonized the inhibitory effect of NMDA (100 μ m ) on both total [ 3 H]‐inositol phosphate ([ 3 H]‐InsP x ) and inositol 1,4,5‐trisphosphate (Ins(1,4,5)P 3 ) mass accumulations stimulated by carbachol (1 m m ) with EC 50 values of 21 and 16 μ m respectively. 3 Memantine concentration‐dependently antagonized (IC 50 24 μ m ) the ability of NMDA (10 μ m ) to potentiate [ 3 H]‐InsP x accumulation in response to a sub‐maximal concentration of the metabotropic glutamate receptor agonist, 1S,3R‐ACPD (10 μ m ). 4 The small (approx. 3 fold), concentration‐dependent increase in [ 3 H]‐InsP x accumulation stimulated by NMDA was completely antagonized by the prototypic NDMA receptor‐channel blocker, MK‐801 (1 μ m ) at all concentrations of NDMA studied (1 – 1000 μ m ). In contrast, antagonism by memantine (100 μ m ) was observed only at low concentrations of NMDA (1 – 10 μ m ), whilst [ 3 H]‐InsP x accumulation stimulated by high concentrations of NMDA (300 – 1000 μ m ) was markedly enhanced by memantine. 5 Assessment of the incorporation of [ 3 H]‐inositol into inositol phospholipids revealed that memantine (100 μ m ) caused an approximate 2 fold increase in the labelling of phosphatidylinositol, phos‐phatidylinositol 4‐phosphate and phosphatidylinositol 4,5‐bisphosphate. 6 H.p.l.c. separation of [ 3 H]‐inositol (poly)phosphates demonstrated that whilst memantine (100 μ m ) alone had no significant effect on the accumulation of any isomer, it substantially altered the profile of accumulation stimulated by NMDA (1 m m ), greatly facilitating accumulation of Ins(1,4,5)P 3 and inositol 1,3,4,5‐tetrakisphosphate (Ins(1,3,4,5)P 4 ). 7 These data provide evidence that memantine can antagonize the actions of NMDA in neonatal rat cerebral cortex slices in a manner consistent with this agent acting as a NMDA receptor‐channel blocker. In addition, at least two further actions of memantine can be proposed. Memantine increases the rate of [ 3 H]‐inositol incorporation into the cellular inositol phospholipid fraction, without significantly stimulating phosphoinositide turnover. Furthermore, memantine can substantially alter patterns of inositol (poly)phosphates stimulated by NMDA, promoting the accumulation of the established and putative second messengers Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 which are not increased by NMDA in the absence of memantine. It is unknown whether these latter loci of memantine action contribute to known therapeutic actions of this agent.