Systemic administration of ZLc-002 exerts anxiolytic-like effects by dissociation of nNOS from CAPON in adult mice.
Biochem Biophys Res Commun
; 523(2): 299-306, 2020 03 05.
Article
en En
| MEDLINE
| ID: mdl-31864709
ABSTRACT
Anxiety is recognized as primary clinical phenotype of psychiatric disorders. However, many patients with anxiety have not yet received effective treatment. Our previous study demonstrated that hippocampal nNOS-CAPON interaction is implicated in anxiety-related behaviors, and blocking nNOS-CAPON interaction in the hippocampus produces anxiolytic-like effects. Here, ZLc-002, a small molecule inhibitor of nNOS-CAPON coupling, was evaluated for anxiolytic-like properties after systemic administered using anxiety behavioral tests, including open-field (OF), elevated plus maze (EPM), novelty-suppressed feeding (NSF) and light-dark (LD) tests. We reported that ZLc-002 when administered intraperitoneally at the dose of 40 or 80 mg/kg/d for 14 days produces anxiolytic-like effects. Furthermore, the similar effects of ZLc-002 were observed when administered intravenously at the dose of 10, 20 or 40 mg/kg/d for 7 days. More importantly, the mice dosing with 80 mg/kg/d ZLc-002 intraperitoneally or 40 mg/kg/d ZLc-002 intravenously for 3 days exerted significant behavioral effects. However, intragastric administration with ZLc-002 was devoid of effect on anxiety behaviors, even at high doses. Furthermore, intraperitoneal or intravenous treatment of ZLc-002 significantly disrupted the interaction between nNOS and CAPON in the hippocampus of adult mice, and there was a significant anxiolytic-like effect of ZLc-002 at day 3 after intrahippocampal microinjection. Our results verified that systemic administration of putative small molecule inhibitor of nNOS-CAPON can be used for the treatment of anxiety disorders.
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MEDLINE
Asunto principal:
Ansiolíticos
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Proteínas Adaptadoras Transductoras de Señales
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Óxido Nítrico Sintasa de Tipo I
Límite:
Animals
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En
Revista:
Biochem Biophys Res Commun
Año:
2020
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Article