Abstract |
Non-competitive N-methyl-d-aspartate ( NMDA) blockers induce schizophrenic-like behavior in healthy volunteers and exacerbate symptomatology in schizophrenic patients. Hence, a compound able to enhance NMDA neurotransmission by increasing levels of d- serine, an endogenous full agonist at the glycine site of the NMDA receptors, could have anti-psychotic activity. One way to increase d- serine levels is the inhibition of d-amino acid oxidase (DAAO), the enzyme responsible for d- serine oxidation. Indeed AS057278, a potent in vitro (IC(50)=0.91 microM) and ex vivo (ED(50)=2.2-3.95 microM) DAAO inhibitor, was able to increase d- serine fraction in rat cortex and midbrain (10 mg/kg i.v.). AS057278 was able to normalize phencyclidine (PCP)-induced prepulse inhibition after acute (80 mg/kg) and chronic (20 mg/kg b.i.d.) oral administration in mice. Finally, AS057278 after oral chronic treatment (10 mg/kg b.i.d.) was able to normalize PCP-induced hyperlocomotion. These results suggest that AS057278 has the potential to anti-psychotic action toward both cognitive and positive symptoms of schizophrenia.
|
Authors | Tiziana Adage, Anne-Cécile Trillat, Anna Quattropani, Dominique Perrin, Laurent Cavarec, Jeffrey Shaw, Oxana Guerassimenko, Claudio Giachetti, Béatrice Gréco, Ilya Chumakov, Serge Halazy, Arthur Roach, Paola Zaratin |
Journal | European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
(Eur Neuropsychopharmacol)
Vol. 18
Issue 3
Pg. 200-14
(Mar 2008)
ISSN: 0924-977X [Print] Netherlands |
PMID | 17681761
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antipsychotic Agents
- Enzyme Inhibitors
- Hallucinogens
- Pyrazoles
- Receptors, N-Methyl-D-Aspartate
- Recombinant Proteins
- Serine
- Amino Acid Oxidoreductases
- D-Aspartate Oxidase
- Phencyclidine
- Glycine
- 5-methylpyrazole-3-carboxylic acid
|
Topics |
- Amino Acid Oxidoreductases
(antagonists & inhibitors)
- Animals
- Antipsychotic Agents
(pharmacology)
- Cell Line
- Cerebral Cortex
(metabolism)
- Colorimetry
- D-Aspartate Oxidase
(antagonists & inhibitors, genetics)
- Enzyme Inhibitors
(pharmacokinetics, pharmacology)
- Escherichia coli
(enzymology)
- Glycine
(metabolism)
- Hallucinogens
(pharmacology)
- Injections, Intravenous
- Male
- Mesencephalon
(metabolism)
- Motor Activity
(drug effects)
- Phencyclidine
(pharmacology)
- Plasmids
(genetics)
- Pyrazoles
(pharmacokinetics, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Receptors, N-Methyl-D-Aspartate
(drug effects)
- Recombinant Proteins
(chemistry)
- Reflex, Startle
(drug effects)
- Serine
(metabolism)
|