PMID- 38529699
OWN - NLM
STAT- MEDLINE
DCOM- 20240509
LR  - 20240509
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
VI  - 181
IP  - 12
DP  - 2024 Jun
TI  - Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic 
      seizures in mice carrying the GluN2A(N615S) mutation.
PG  - 1886-1894
LID - 10.1111/bph.16361 [doi]
AB  - BACKGROUND AND PURPOSE: GRIN-related disorders are neurodevelopmental disorders 
      caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A 
      large fraction of these mutations lead to a 'gain of function' (GoF) of the 
      NMDAR. Patients present with a range of symptoms including epilepsy, intellectual 
      disability, behavioural and motor. Controlling seizures is a significant unmet 
      medical need in most patients with GRIN-related disorders. Although several 
      hundred GRIN mutations have been identified in humans, until recently none of the 
      mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The 
      two recent exceptions both carry mutations of GluN2A. The aim of this study was 
      to assess the efficacy of radiprodil, a selective negative allosteric modulator 
      of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a 
      murine model carrying the GluN2A(N615S) homozygous mutation (Grin2a(S/S) mice). 
      EXPERIMENTAL APPROACH: Grin2a(S/S) mice were acutely treated with radiprodil at 
      different doses before the presentation of a high-frequency acoustic stimulus 
      commonly used for AGS induction. KEY RESULTS: Radiprodil significantly and 
      dose-dependently reduced the onset and severity of AGS in Grin2a(S/S) mice. 
      Surprisingly, the results revealed a sex-dependent difference in AGS 
      susceptibility and in the dose-dependent protection of radiprodil in the two 
      genders. Specifically, radiprodil was more effective in female versus male mice. 
      CONCLUSION AND IMPLICATIONS: Overall, our data clearly show that radiprodil, a 
      GluN2B selective negative allosteric modulator, may have the potential to control 
      seizures in patients with GRIN2A GoF mutations. Further studies are warranted to 
      better understand the sex-dependent effects observed in this study.
CI  - (c) 2024 GRIN Therapeutics. British Journal of Pharmacology published by John Wiley 
      & Sons Ltd on behalf of British Pharmacological Society.
FAU - Bertocchi, Ilaria
AU  - Bertocchi I
AD  - Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 
      Orbassano (Turin), Italy.
AD  - Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, 
      Italy.
AD  - Neuroscience Institute of Turin, Orbassano (Turin), Italy.
FAU - Cifarelli, Lorenzo
AU  - Cifarelli L
AD  - Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 
      Orbassano (Turin), Italy.
FAU - Oberto, Alessandra
AU  - Oberto A
AD  - Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 
      Orbassano (Turin), Italy.
AD  - Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, 
      Italy.
AD  - Neuroscience Institute of Turin, Orbassano (Turin), Italy.
FAU - Eva, Carola Eugenia
AU  - Eva CE
AD  - Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 
      Orbassano (Turin), Italy.
AD  - Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, 
      Italy.
AD  - Neuroscience Institute of Turin, Orbassano (Turin), Italy.
FAU - Sprengel, Rolf
AU  - Sprengel R
AD  - Max Planck Institute for Medical Research, Heidelberg, Germany.
FAU - Mirza, Naheed Rohman
AU  - Mirza NR
AD  - GRIN Therapeutics Inc, New York, NY, USA.
AD  - Sygnature Discovery, BioCity, Nottingham, UK.
FAU - Muglia, Pierandrea
AU  - Muglia P
AD  - GRIN Therapeutics Inc, New York, NY, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20240326
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (NR2B NMDA receptor)
RN  - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A)
RN  - 0 (Piperidines)
RN  - 0 (Anticonvulsants)
SB  - IM
MH  - Animals
MH  - *Receptors, N-Methyl-D-Aspartate/genetics
MH  - Male
MH  - Female
MH  - Mice
MH  - *Mutation
MH  - Piperidines/pharmacology/administration & dosage/therapeutic use
MH  - Epilepsy, Reflex/genetics/drug therapy
MH  - Allosteric Regulation/drug effects
MH  - Seizures/drug therapy/genetics
MH  - Mice, Inbred C57BL
MH  - Anticonvulsants/pharmacology/therapeutic use/administration & dosage
MH  - Dose-Response Relationship, Drug
OTO - NOTNLM
OT  - audiogenic seizures
OT  - dose-response curve
OT  - gain of function mutation
OT  - knock-in mice
EDAT- 2024/03/26 06:45
MHDA- 2024/05/09 06:42
CRDT- 2024/03/26 05:34
PHST- 2024/02/09 00:00 [revised]
PHST- 2023/08/04 00:00 [received]
PHST- 2024/02/15 00:00 [accepted]
PHST- 2024/05/09 06:42 [medline]
PHST- 2024/03/26 06:45 [pubmed]
PHST- 2024/03/26 05:34 [entrez]
AID - 10.1111/bph.16361 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2024 Jun;181(12):1886-1894. doi: 10.1111/bph.16361. Epub 2024 Mar 
      26.