Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Sun, Nan; Qin, Yajuan; Chu, Xu; Xia, Tian; Du, Ziwei; Zheng, Liping; Li, An-an; Meng, Fanyong; Zhang, Yu; Zhang, Jing; Liu, Xiao; Li, Tingyou; Zhu, Dong‐Ya; Zhou, Qi‐Gang

doi:10.1126/science.abo3566

Cited by 51 publications

(25 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For the interaction between 5-HT and OS (Figure 1E-OS), studies found 5-HT presented antioxidant properties in vitro, as indicted by the inhibited generations of ROS and iNOS (Vašíček et al, 2020), while N-acetyl 5-HT showed antioxidant and anti-apoptosis actions, by activating TrkB/CREB/BDNF pathway and antioxidant enzyme expression, in vitro and in vivo (Yoo et al, 2017). Recent studies demonstrated the possibility of designing fast-onset antidepressant, by dissociating 5-HTT from neuronal NOS in the DRN of mice, which indicates the critical involvement of 5-HT and OS interaction in depression pathogenesis (Guan & Pang, 2023;Kingwell, 2022;Sun et al, 2022;Ye et al, 2023). In turn, OS could cause central 5-HT deficiency through inducing neuroinflammation (Catena-Dell'Osso et al, 2013) and MGB disturbance (Stasi et al, 2019), by activating IDO/TDO enzymes and promoting KP of tryptophan metabolism, as expounded in the above sections correspondingly.…”

Section: Central 5-ht Deficiencymentioning

confidence: 99%

How Oxidative Stress Induces Depression?

Lei

Chen

et al. 2023

ASN Neuro

View full text Add to dashboard Cite

Depression increasingly affects a wide range and a large number of people worldwide, both physically and psychologically, which makes it a social problem requiring prompt attention and management. Accumulating clinical and animal studies have provided us with substantial insights of disease pathogenesis, especially central monoamine deficiency, which considerably promotes antidepressant research and clinical treatment. The first-line antidepressants mainly target the monoamine system, whose drawbacks mainly include slow action and treatment resistant. The novel antidepressant esketamine, targeting on central glutamatergic system, rapidly and robustly alleviates depression (including treatment-resistant depression), whose efficiency is shadowed by potential addictive and psychotomimetic side effects. Thus, exploring novel depression pathogenesis is necessary, for seeking more safe and effective therapeutic methods. Emerging evidence has revealed vital involvement of oxidative stress (OS) in depression, which inspires us to pursue antioxidant pathway for depression prevention and treatment. Fully uncovering the underlying mechanisms of OS-induced depression is the first step towards the avenue, thus we summarize and expound possible downstream pathways of OS, including mitochondrial impairment and related ATP deficiency, neuroinflammation, central glutamate excitotoxicity, brain-derived neurotrophic factor/tyrosine receptor kinase B dysfunction and serotonin deficiency, the microbiota-gut-brain axis disturbance and hypothalamic-pituitary-adrenocortical axis dysregulation. We also elaborate on the intricate interactions between the multiple aspects, and molecular mechanisms mediating the interplay. Through reviewing the related research progress in the field, we hope to depict an integral overview of how OS induces depression, in order to provide fresh ideas and novel targets for the final goal of efficient treatment of the disease.

show abstract

Section: Central 5-ht Deficiencymentioning

confidence: 99%

How Oxidative Stress Induces Depression?

Lei

Chen

et al. 2023

ASN Neuro

View full text Add to dashboard Cite

show abstract

“…Ketamine and its derivatives have rapid action but produce unwanted side-effects, including abuse potential, cognitive impairment, psychotomimetic/dissociative symptoms, and neurotoxicity [ 129 , 130 ]. Sun et al in our lab investigated the role of SERT-nNOS coupling in the dorsal raphe nucleus (DRN) and found that the DRN SERT-nNOS interaction is implicated in the modulation of depressive behaviors and dissociating SERT from nNOS in the DRN produces a fast-onset antidepressant effect, revealing a fast-onset antidepressant target [ 12 ]. By inhibiting 5-HT reuptake, SSRIs elevate 5-HT levels in the synaptic cleft and thereby increase the activation of postsynaptic 5-HT 1A Rs in the cortex, hippocampus, and other brain regions [ 131 ].…”

Section: Nnos-sert Interaction and Mddmentioning

confidence: 99%

“…We found that CMS exposure increases the nNOS-SERT interaction, blockade of which enhances SERT translocation to the cell surface selectively in DRN neurons, reduces extracellular 5-HT levels and 5-HT 1A R auto activity, and exhibits fast-onset antidepressant effects in mice. Using optogenetic stimulation and pharmacogenetic studies, we demonstrated that the rapid antidepressant effect depends on the increased firing of serotonergic DRN neurons and DRN-mPFC serotonergic circuit activity [ 12 ].…”

Section: Nnos-sert Interaction and Mddmentioning

confidence: 99%

“…By analyzing the chemical mechanism of binding the C-tail of SERT to the PDZ of nNOS in the DRN, the group of Prof. Li TY designed a common chemical structure and synthesized a series of compounds. The group of Prof. Zhou QG assessed the effects of a series of compounds on the SERT-nNOS interaction, using cultured 293T cells transfected with plasmids encoding nNOS and SERT, and showed that the small molecule ZZL-7 is a potent blocker of SERT-nNOS, and more importantly, intraperitoneal or intragastric administration of ZZL-7 produces a fast-onset antidepressant effect without abnormal behaviors, including locomotor activity, memory, aggressive behavior, addiction, or abnormal brain waves [ 12 ]. ZZL-7 may serve as a novel approach to selectively promote serotonergic signaling to create rapidly acting antidepressant activity.…”

Section: Nnos-sert Interaction and Mddmentioning

confidence: 99%

“…Moreover, nNOS also interacts with clathrin assembly lymphoid leukemia, Ca 2+ /calmodulin-dependent protein kinase II alpha, Disks large homolog 4, DLG2, 6-phosphofructokinase (muscle type), syntrophin, and dynein light chain [ 2 ]. In the past 20 years, our group has investigated the roles of nNOS and its coupling proteins in stroke, major depressive disorder (MDD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), Alzheimer's disease (AD), and chronic pathological pain, and revealed several new therapeutic targets and discovered several innovative candidate drugs [ 12 – 17 ], among which, ZL006-05 is going through a phase II clinical trial (sFDA, Registration No: CTR20221109, http://www.chinadrugtrials.org.cn/clinicaltrails.searchlistdetail.dhtml ).

Fig.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

Zhu

2023

Neurosci. Bull.

Self Cite

View full text Add to dashboard Cite

In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.

show abstract

Intranasal Delivery of Near‐Infrared and Magnetic Dual‐Response Nanospheres to Rapidly Produce Antidepressant‐Like and Cognitive Enhancement Effects

Hu,

Lian,

Weng

et al. 2024

Advanced Materials

View full text Add to dashboard Cite

Restricted by synaptic plasticity, dopamine receptor (DR) upregulation takes a long time to work. Moreover, the impact of the blood‐brain barrier (BBB) on delivery efficiency restricts the development of drugs. Taking inspiration from snuff bottles, a convenient, fast‐acting, and non‐addictive nasal drug delivery system has been developed to rapidly reshape the balance of synaptic transmitters. This optical and magnetic response system called CFs@DP, comprised of carbonized MIL‐100 (Fe) frameworks (CFs) and domperidone (DP), which can enter the brain via nasal administration. Under dual stimulation of near‐infrared (NIR) irradiation and catecholamine‐induced complexation, CFs@DP disintegrates to release iron ions and DP, causing upregulation of the dopamine type 1 (D1), type 2 (D2) receptors and brain‐derived neurotrophic factor (BDNF) to achieve a therapeutic effect. In vivo experiments demonstrated that the DR density of mice (postnatal day 50 – 60) increased in the prefrontal cortex (PFC) and the hippocampus (HPC) after 10 days of therapy, resulting in antidepressant‐like and cognitive enhancement effects. Interestingly, the cognitive enhancement effect of CFs@DP was even working in non‐iron deficiency (normal fed) mice, making it a promising candidate for application in enhancing learning ability.This article is protected by copyright. All rights reserved

show abstract

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Cited by 51 publications

References 72 publications

How Oxidative Stress Induces Depression?

How Oxidative Stress Induces Depression?

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

Intranasal Delivery of Near‐Infrared and Magnetic Dual‐Response Nanospheres to Rapidly Produce Antidepressant‐Like and Cognitive Enhancement Effects

Contact Info

Product

Resources

About