Luvadaxistat: A Novel Potent and Selective d-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia

N-methyl- d -aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d -serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d -amino acid oxidase (DAAO) has t...

Full description

Saved in:
Bibliographic Details
Published in:Neurochemical research 2023-10, Vol.48 (10), p.3027-3041
Main Authors: Fradley, Rosa, Goetghebeur, Pascal, Miller, David, Burley, Russell, Almond, Sarah, Gruart i Massó, Agnès, Delgado García, José M., Zhu, Bin, Howley, Eimear, Neill, Jo C., Grayson, Ben, Gaskin, Philip, Carlton, Mark, Gray, Ian, Serrats, Jordi, Davies, Ceri H.
Format: Article
Language:English
Subjects:
Amino acid oxidase
Amino acids
Animal models
Antipsychotics
Associative learning
Biochemistry
Biomedical and Life Sciences
Biomedicine
Brain
Cell Biology
Cerebellum
Cerebrospinal fluid
Clinical trials
Cognition
Cognitive ability
Cognitive tasks
D-Amino-acid oxidase
D-Serine
Dosage
Emotional behavior
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Impairment
Inhibitors
Long-term potentiation
Mental disorders
N-Methyl-D-aspartic acid receptors
Neurochemistry
Neurology
Neurosciences
Original Paper
Patients
Psychotropic drugs
Receptors
Rodents
Schizophrenia
Social behavior
Social factors
Synaptic plasticity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:N-methyl- d -aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d -serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d -amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases d -serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.
ISSN:0364-3190
1573-6903
DOI:10.1007/s11064-023-03956-2