PMID- 17331496
OWN - NLM
STAT- MEDLINE
DCOM- 20070522
LR  - 20220321
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 561
IP  - 1-3
DP  - 2007 Apr 30
TI  - S18986: a positive modulator of AMPA-receptors enhances (S)-AMPA-mediated BDNF 
      mRNA and protein expression in rat primary cortical neuronal cultures.
PG  - 23-31
AB  - The present study describes the effect of 
      (S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S18986), a 
      positive allosteric modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole 
      propionic acid (AMPA) receptors, on (S)-AMPA-mediated increases in brain-derived 
      neurotrophic factor (BDNF) mRNA and protein expression in rat primary cortical 
      neuronal cultures. (S)-AMPA (0.01-300 microM) induced a concentration-dependent 
      increase in BDNF mRNA and protein expression (EC(50)=7 microM) with maximal 
      increases (50-fold) compared to untreated cultures observed between 5 and 12 h, 
      whereas for cellular protein levels, maximal expression was detected at 24 h. 
      S18986 alone (< or =300 microM) failed to increase basal BDNF expression. 
      However, S18986 (300 microM) in the presence of increasing concentrations of 
      (S)-AMPA maximally enhanced AMPA-induced expression of BDNF mRNA and protein 
      levels (3-5-fold). S18986 (100-300 microM) potentiated BDNF mRNA induced by 3 
      microM (S)-AMPA (2-3-fold). Under similar conditions, the AMPA allosteric 
      modulator cyclothiazide induced a potent stimulation of (S)-AMPA-mediated BDNF 
      expression (40-fold; EC(50)=18 microM), whereas IDRA-21 was inactive. Kinetic 
      studies indicated that S18986 (300 microM) in the presence of 3 microM (S)-AMPA 
      was capable of enhancing BDNF mRNA levels for up to 25 h, compared to 3 microM 
      (S)-AMPA alone. On the other hand, S18986 only partially enhanced 
      kainate-mediated expression of BDNF mRNA, but failed to significantly enhance 
      N-methyl-D-aspartate-stimulated BDNF expression levels. In support of these 
      observations, the competitive AMPA receptor antagonist NBQX 
      (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) but not 
      the selective NMDA-receptor antagonist, (+)-MK-801 
      [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], 
      abrogated S18986-induced effects on BDNF expression. S18986-mediated enhancement 
      of (S)-AMPA-evoked BDNF protein expression was markedly attenuated in Ca(2+)-free 
      culture conditions. Furthermore, from a series of kinase inhibitors only the 
      Calmodulin-Kinase II/IV inhibitor (KN-62, 25 microM) significantly inhibited 
      (-85%, P<0.001) AMPA+S18986 stimulated expression of BDNF mRNA. The present study 
      supports the observations that AMPA receptor allosteric modulators can enhance 
      the expression of BDNF mRNA and protein expression via the AMPA receptor in 
      cultured primary neurones. Consequently, the long-term elevation of endogenous 
      BDNF expression by pharmacological intervention with this class of compounds 
      represents a potentially promising therapeutic approach for behavioural disorders 
      implicating cognitive deficits.
FAU - Lockhart, Brian Paul
AU  - Lockhart BP
AD  - Servier Research Institute, Division of Molecular Pharmacology and 
      Pathophysiology, 125, Chemin de ronde, 78290 Croissy-sur-Seine, France. 
      brian.lockhart@fr.netgrs.com
FAU - Rodriguez, Marianne
AU  - Rodriguez M
FAU - Mourlevat, Sophie
AU  - Mourlevat S
FAU - Peron, Philippe
AU  - Peron P
FAU - Catesson, Sandra
AU  - Catesson S
FAU - Villain, Nadege
AU  - Villain N
FAU - Galizzi, Jean-Pierre
AU  - Galizzi JP
FAU - Boutin, Jean-Albert
AU  - Boutin JA
FAU - Lestage, Pierre
AU  - Lestage P
LA  - eng
PT  - Journal Article
DEP - 20070201
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Benzothiadiazines)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, AMPA)
RN  - 0 (S18986-1)
SB  - IM
MH  - Allosteric Regulation/drug effects
MH  - Animals
MH  - Benzothiadiazines/*pharmacology
MH  - Brain-Derived Neurotrophic Factor/*drug effects/genetics/*metabolism
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems
MH  - Gene Expression Regulation/*drug effects
MH  - Mental Disorders/drug therapy
MH  - Neuronal Plasticity/drug effects
MH  - Neurons/cytology/drug effects
MH  - Polymerase Chain Reaction
MH  - Protein Kinase Inhibitors
MH  - RNA, Messenger/*drug effects/metabolism
MH  - Rats
MH  - Receptors, AMPA/*drug effects/metabolism
EDAT- 2007/03/03 09:00
MHDA- 2007/05/23 09:00
CRDT- 2007/03/03 09:00
PHST- 2006/10/13 00:00 [received]
PHST- 2006/12/22 00:00 [revised]
PHST- 2007/01/16 00:00 [accepted]
PHST- 2007/03/03 09:00 [pubmed]
PHST- 2007/05/23 09:00 [medline]
PHST- 2007/03/03 09:00 [entrez]
AID - S0014-2999(07)00076-3 [pii]
AID - 10.1016/j.ejphar.2007.01.030 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2007 Apr 30;561(1-3):23-31. doi: 10.1016/j.ejphar.2007.01.030. 
      Epub 2007 Feb 1.