nNOS‐CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety
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| المؤلفون: | Dong-Ya Zhu, Na Li, Lei Chang, Li-Juan Zhu, Meng Si, Hu-Jiang Shi, Cheng Cheng Zhang |
| المصدر: | Br J Pharmacol |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Elevated plus maze, medicine.medical_specialty, medicine.drug_class, Nitric Oxide Synthase Type I, Anxiety, CREB, Anxiolytic, Open field, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurotrophic factors, Internal medicine, medicine, Animals, Chronic stress, Adaptor Proteins, Signal Transducing, Neurons, Pharmacology, biology, business.industry, medicine.disease, Anxiety Disorders, Research Papers, 030104 developmental biology, Endocrinology, Anti-Anxiety Agents, biology.protein, medicine.symptom, business, 030217 neurology & neurosurgery, Anxiety disorder |
| الوصف: | Background and purpose Anxiety disorder is a common mental health disorder. However, there are few safe and fast-acting anxiolytic drugs available that can treat anxiety disorder. We previously demonstrated that the interaction of neuronal NOS (nNOS) with its carboxy-terminal PDZ ligand (CAPON) is involved in regulating anxiety-related behaviours. Here, we further investigated the anxiolytic effects of nNOS-CAPON disruptors in chronic stress-induced anxiety in animals. Experimental approach Mice were intravenously treated with nNOS-CAPON disruptors, ZLc-002 or Tat-CAPON12C, at the last week of chronic mild stress (CMS) exposure. We also infused corticosterone (CORT) into the hippocampus of mice to model anxiety behaviours and also delivered ZLc-002 or Tat-CAPON12C on the last week of chronic CORT treatment via pre-implanted cannula. Anxiety-related behaviours were examined using elevated plus maze, open field, novelty-suppressed feeding and light-dark (LD) tests. The level of nNOS-CAPON interaction was determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). The neural mechanisms underlying the behavioural effects of nNOS-CAPON uncoupling in anxiety animal models were assessed by western blot, immunofluorescence and Golgi-Cox staining. Key results ZLc-002 and Tat-CAPON12C reversed CMS- or CORT-induced anxiety-related behaviours. ZLc-002 and Tat-CAPON12C increased synaptogenesis along with improved dendritic remodelling in CMS mice or CORT-treated cultured neurons. Meanwhile, blocking nNOS-CAPON interaction significantly activated the cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) pathway, which is associated with synaptic plasticity. Conclusion and implications Collectively, these results provide evidence for the anxiolytic effects of nNOS-CAPON uncouplers and their underlying mechanisms in anxiety disorders. |
| تدمد: | 1476-5381 0007-1188 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd99b21da0b54fd0d18a0a0f8539910a https://doi.org/10.1111/bph.15084 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....dd99b21da0b54fd0d18a0a0f8539910a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765381 00071188 |
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