Biomaterials Science
·
2021
·Vol. 9
·期 13
·4765-4777
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IF 6.843
Shu Li,Chen Guo,Xingjiao Zhang,Xiaojing Liu,Jing Mu,Chunxia Liu,Yali Peng,Min Chang
Anxiety disorders are the most common mental diseases and can greatly disrupt everyday life. Although there has been substantial research on anxiety disorders, novel therapeutics are needed. Neuropeptide S (NPS) is a potential therapeutic candidate owing to its strong anxiolytic activity; however, some disadvantages, such as its poor metabolic stability and inability to cross the blood–brain barrier (BBB), limit its use in the clinic. Herein, inspired by nose-to-brain drug delivery strategies, an endogenous 20-amino-acid-long mNPS peptide was modified by incorporating palmitic acid into its functional Lys12 side chain (M-3), which was expected to facilitate nose-to-brain penetration and exert a prolonged anxiolytic-like effect compared to mNPS. We found that M-3 assembled into nanofibers that retained the bioactivity of NPS and exhibited obvious improvements in metabolic stability. Notably, as expected, self-assembled M-3 was able to penetrate into the brain and exert anxiolytic effects. The elevated plus-maze (EPM) results further revealed that M-3 could produce prolonged anxiolytic-like effects in mice. In vivo imaging studies revealed that self-assembled M-3 could be efficiently transported from the nasal cavity to the brain. Furthermore, when intranasally administered, this molecule exhibited a significantly prolonged anxiolytic-like effect, which further illustrated that this molecule has a potent nose-to-brain penetration in vivo. Overall, this self-assembled nanofiber showed potent nose-to-brain penetration ability and prolonged bioactivity.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2025
·
IF 7.7
Xiang Zuo,Huijuan Bai,Jinyu Qiu,Ruimin Li,Xiaochen Kuang,Yudi Zhao,Jingyi Tuo,Qili Zhao,Xin Zhao,Xizeng Feng
Anxiety Disorder is a common neurological disorder for which ubiquitous environmental endocrine disruptors may be risk factors. 17β-trenbolone (17-TB) has been recognized as a potential environmental endocrine disruptor and its neurotoxic effects have attracted attention. Tachykinin receptor 3 (TACR3), a G protein-coupled receptor involved in pubertal anxiety, and its underlying neural mechanisms remain enigmatic. Therefore, this study investigated the possible relationship between 17-TB and TACR3, testosterone (T), and synaptic plasticity. Our results showed that adolescent male Balb/c mice developed significant anxiety-like behavior after four weeks of exposure to environmentally relevant concentrations of 17-TB (100 μg/kg/day). Transcriptomic RNA-Seq results showed that 17-TB affected abnormal synaptic transmission signals in the hippocampus. Electrophysiological results showed that 17-TB reduced the activity of hippocampal dentate gyrus (DG) neurons and led to the downregulation of hippocampal TACR3 and T levels. In addition, Western blot, immunohistochemistry, ELISA, and qRT-PCR showed that 17-TB exposure led to the downregulation of key hippocampal synaptic proteins PSD95, Gephyrin, and Syn, and induced a metabolic imbalance in glutamate (Glu)/GABA signaling, affecting dopamine signaling. Interestingly, testosterone supplementation (10 mg/kg/day) was effective in ameliorating the above phenomena and alleviating anxiety-like behaviors. These results suggest that 17-TB modulates anxiety-related synaptic plasticity by regulating hippocampal TACR3 and T interactions in vivo. In conclusion, our study contributes to understanding the neurobehavioral and potential mechanistic effects of environmental 17-TB exposure in mammals. It alerts the public to the health risks of chemicals to mammals and suggests new research directions and potential therapeutic targets.
研究领域:
神经科学
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毒理学
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内分泌学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xiaoyun Yun,Jianhui Wu,Jie Zhou,Linlin Song,Yongpei Tang,Hanghong Lo,Jerome P.L. Ng,Menghan Liu,Zhikang Wang,Liqun Qu,Huimiao Wang,Ruilong Zhang,Cairen Wang,Linna Wang,Jiujie Yang,Sookja Kim Chung,Vincent Kam Wai Wong,Betty Yuen Kwan Law
Background Anxiety disorders rank among the most ubiquitous neuropsychiatric disease classifications. Despite their substantial disease burden, the persistent lack of innovative, mechanistically grounded therapeutic interventions over the past two decades highlights an urgent need for novel pharmacological strategies. Purpose The aim of this study is to investigate the neuroprotective and anxiolytic effects of corilagin derived from plant sources, offering novel perspectives for the development of therapeutic strategies targeting anxiety disorders. Methods In this study, high-performance liquid chromatography-mass spectrometry analysis was performed on the crude extract of Phyllanthus emblica Linn. A glutamine-induced cell model and a scopolamine-induced anxiety model were established for in vitro and in vivo investigations, respectively. Anxiety-like behaviors were evaluated using Y-maze, open field tests, and fear conditioning experiments. Laser speckle contrast imaging was employed for relative and qualitative assessment of cerebral blood flow and perfusion in mice. Western blotting, quantitative real-time PCR, and flow cytometry were utilized to elucidate the underlying pathway mechanisms. Finally, RNA sequencing and recombinant adeno-associated virus (AAV)-mediated gene silencing experiments were conducted for target prediction and validation. Results Phyllanthus emblica Linn. derived corilagin showed a strong antioxidant activity in a glutamate-induced cell model. It also inhibited neuronal cell apoptosis caused by oxidative damage, rescued apoptosis from the late stage to the early stage and restored cellular viability. Corilagin alleviated anxiety as reflected by the improvement in scopolamine-induced mice’s behavior such as hyperlocomotion, working memory and emotion memory damage. By applying recombinant AAV-mediated Htr2c silencing shRNA, our findings indicate that corilagin targets the serotonergic system, producing anxiolytic effects by modulating Htr2c to influence 5-HT levels and activate the TrkB/CREB/BDNF pathway in the prefrontal cortex. Compared with the existing fluoxetine anxiolytic drug, this compound demonstrates unique liver-protective properties by downregulating the ALT and AST level. Conclusion This study revealed that corilagin, a bioactive hydrolysable tannin isolated from natural plants, has multiple efficacy in mitigating oxidative and apoptotic damage, alleviating anxiety. The superiority of corilagin as an Htr2c agonist lies in its lower risk of side effects, representing its potential as a novel therapeutic candidate through Htr2c-BDNF signaling modulation, offering a mechanistically innovative approach for both the prevention and clinical management of anxiety disorders.
研究领域:
神经药理学
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植物药理学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Science
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2024
·
IF 14.3
Ping-Fen Yang,Tai-Lei Nie,Xia-Nan Sun,Lan-Xin Xu,Cong Ma,Fang Wang,Li-Hong Long,Jian-Guo Chen
Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABA A R γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.
研究领域:
神经科学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2025
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IF 4.6
Wen-Hui Ni,Ke Wang,Yun Wang,Jia Lu,Chun-Ting Lu,Wen Rong,Yi-Feng Gu,Wen-Juan Qian,Hai-Long Zhang
Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.
研究领域:
药理学
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神经科学
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炎症研究
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DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2020
·Vol. 76
·期 12
·4210-4221
·
IF 3.75
Qiuyan Zhu,Yang Yang,Zhiting Lao,Yingying Zhong,Kun Zhang,Suqing Zhao
BACKGROUND Pyrethroids, a class of insecticides, that act on the nervous system of insects. Frequent consumption of foods with pyrethroid residues increase the risk of developmental and neurological diseases in humans. Assessing the toxicity of novel synthetic pyrethroids to mammals is also critical to the development of agrochemicals. RESULTS Using mice as models, the acute and chronic toxicity of deltamethrin, permethrin, dihaloacetylated pyrethroids to mammals was researched by gavage administration. Acute toxicity assessment displayed that the median lethal dose (LD 50 ) of deltamethrin, permethrin and dihaloacetylated heterocyclic pyrethroids DCA-O, DCA-01, and DCA-11 tested were greater than 500 mg/kg of weight. Furthermore, chronic toxicity assessment demonstrated that deltamethrin, permethrin caused epidermal damage near the genitals, while dihaloacetylated heterocyclic pyrethroids DCA-O, DCA-01, and DCA-11 showed no relevant symptoms. However, both the acute and chronic toxicity assessment suggested that pyrethroids exposure induced mice loss weight. Additionally, the elevated plus maze (EPM) test showed that pyrethroids caused anxiety-like behaviors and no motor defects in Kunming mice. Beside, during the sucrose preference test (SPT), 60-day pyrethroids exposure increased excitatory behaviors in mice. However, the neurochemical studies displayed that pyrethroids exposure increased the total amount of glutamate (Gln), glutamine (Glu) and γ -aminobutyric acid (GABA) in the mice's blood. CONCLUSION Pyrethroids exposure induced weight loss in mice, although the acute oral toxicity of deltamethrin, permethrin and dihaloacetylated heterocyclic pyrethroids DCA-O, DCA-01, and DCA-11 was low. However, regarding chronic toxicity, deltamethrin, permethrin and dihaloacetylated heterocyclic pyrethroids DCA-O, DCA-01, and DCA-11 induced anxiety-like behaviors, excitatory behaviors, Gln-Glu-GABA circulatory dysfunction in blood. Particularly, deltamethrin, though permethrin also had reproductive toxicity. © 2020 Society of Chemical Industry
研究领域:
毒理学
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神经科学
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农业化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Zhaoxiang Song,Huaduan Liang,Chu Xue,Shuxian Wang,Younan Ren,Zhuang Zhang,Tifei Xu,Bo Niu,Mengmeng Song,Mengru Liu,Xu Qin,Jie Li,Xianya Zhao,Fang Zhao,Jianhua Shen,Zhengyu Cao,Kai Wang
Transient receptor potential canonical channels 4 and 5 (TRPC4/5) are nonselective cation channels involved in emotional regulation, positioning them to be promising targets for treating mental disorders such as anxiety and depression. HC-070, a potent TRPC4/5 inhibitor, exhibits significant anxiolytic and antidepressant effects in animal models, though its drug-like properties require optimization. In this study, we applied a property-based drug design (PBDD) approach to optimize HC-070, leading to the discovery of compound 32, which shows improved LipE and Fsp3 values, reduced hERG blocking activity, enhanced metabolic stability, increased aqueous solubility, and superior oral bioavailability. Oral administration of compound 32 in mouse models demonstrates anxiolytic and antidepressant efficacy comparable to fluoxetine. This study supports the therapeutic potential of TRPC4/5 inhibitors for mental disorders and identifies compound 32 as a promising candidate for further investigation. Furthermore, our work underscores the value of PBDD in optimizing lead compounds during drug discovery process.
研究领域:
药理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2025
·
IF 8.4
Zhang Jia-qi,Li Shu-yi,Yin Cui,Ji Ying,Zhang Xiang,Liu Dan-yang,Yang Hang,Niu Yong,Cui Gui-yun,Zhou Chun-yi,Xiao Cheng
Anxiety and depression are common non-motor symptoms severely affecting the quality of life in patients with Parkinson’s disease, but the underlying pathophysiological mechanisms remain elusive. As dopaminergic (DA) system and the subthalamic nucleus (STN) are involved in motor control and emotional processing, we herein investigated the role of DA circuitry in the STN in regulating depression in parkinsonian mice. A hemi-parkinsonian mouse model was established by injection of 6-OHDA into the right medial forebrain bundle (MFB), desipramine (20 mg/kg, i.p.) was injected 30 min before the intracranial injection. Motor function was monitored in open field test and apomorphine-induced contra-lesional rotation and rotarod tests; anxiety- and depression-like behaviors were assessed with the open field test, elevated plus maze, tail suspension test and forced swim test. We found that the hemi-parkinsonian mice displayed motor dysfunction and depression-like behaviors at different time points. Fiber photometry recording revealed that STN neurons were hypersensitive to anxiety- and depression-like stimulation; chemogenetic inhibition of STN neurons mitigated anxiety- and depression-like behaviors. While dopamine release was significantly reduced in the STN of the parkinsonian mice in response to anxiety- and depression-like stimulation, the expression of D1- and D2-like dopamine receptors was time-dependently changed. Intracranial injection of either D1- or D2-like dopamine receptor agonist into the STN mitigated anxiety- and depression-like behaviors in the parkinsonian mice. We conclude that STN DA circuitry may be promising targets to treat anxiety and depression in PD.
研究领域:
神经科学
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药理学
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行为学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 20
·4702
·
IF 3.267
Nan Zhang,Mu Luo,Lei He,Lei Yao
Gardenia jasminoidesEllis is a famous fragrant flower in China. Previous pharmacological research mainly focuses on its fruit. In this study, the essential oil of the flower of ‘Shanzhizi’, which was a major variety for traditional Chinese medicine use, was extracted by hydro distillation and analyzed by GC-MS. Mouse anxiety models included open field, elevated plus maze (EPM), and light and dark box (LDB), which were used to evaluate its anxiolytic effect via inhalation. The involvement of monoamine system was studied by pretreatment with neurotransmitter receptor antagonists WAY100635, flumazenil and sulpiride. The monoamine neurotransmitters contents in the prefrontal cortex (PFC) and hippocampus after aroma inhalation were also analyzed. The results showed that inhalation ofG. jasminoidesessential oil could significantly elevated the time and entries into open arms in EPM tests and the time explored in the light chamber in LDB tests with no sedative effect. WAY100635 and sulpiride, but not flumazenil, blocked its anxiolytic effect. Inhalation ofG. jasminoidesessential oil significantly down-regulated the 5-HIAA/5-HT in the PFC and reduced the 5-HIAA content in hippocampus compared to the control treatment. In conclusion, inhalation of gardenia essential oil showed an anxiolytic effect in mice. Monoamine, especially the serotonergic system, was involved in its anxiolytic effect.Keywords:Gardenia jasminoides;essential oil;inhalation;anxiolytic effect;serotonergic neurotransmission
研究领域:
药理学
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神经科学
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植物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2019
·
IF 2.439
Kai Zhang,Jing Lu,Lei Yao
Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light–dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT 1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D 1 receptor antagonist) or sulpiride (dopamine D 2 /D 3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D 1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.
研究领域:
药理学
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神经科学
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行为学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
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2018
·Vol. 23
·期 9
·2329
·
IF 3.098
Shao-Nan Wang,Yong-Sheng Ding,Xiao-Jie Ma,Cheng-Bowen Zhao,Ming-Xuan Lin,Jing Luo,Yi-Nan Jiang,Shuai He,Jian-You Guo,Jin-Li Shi
Zhi zhu xiang(ZZX for short) is the root and rhizome ofValeriana jatamansiJones, which is a Traditional Chinese Medicine (TCM) used to treat various mood disorders for more than 2000 years, especially anxiety. The aim of the present work was to identify the bioactive chemical markers inZhi zhu xiangimproving anxiety in rats by a fingerprint-efficacy study. More specifically, the chemical fingerprint of ZZX samples collected from 10 different regions was determined by High Performance Liquid Chromatography (HPLC) and the similarity analyses were calculated based on 10 common characteristic peaks. The anti-anxiety effect of ZZX on empty bottle stimulated rats was examined through the Open Field Test (OFT) and the Elevated Plus Maze Test (EPM). Then we measured the concentration of CRF, ACTH, and CORT in rat’s plasma by the enzyme-linked immune sorbent assay (ELISA) kit, while the concentration of monoamine and metabolites (NE, DA, DOPAC, HVA, 5-HT, 5-HIAA) in the rat’s cerebral cortex and hippocampus was analysed by HPLC coupled with an Electrochemical Detector. At last, the fingerprint-efficacy study between chemical fingerprint and anti-anxiety effect of ZZX was accomplished by partial least squares regression (PLSR). As a result, we screened out four compounds (hesperidin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C) as the bioactive chemical markers for the anti-anxiety effect of ZZX. The fingerprint-efficacy study we established might provide a feasible way and some elicitation for the identification of the bioactive chemical markers for TCM.Keywords:anti-anxiety;Valeriana jatamansiJones;fingerprint-efficacy relationship;PLSR
研究领域:
中药学
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神经生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2018
·
IF 6.014
Qian Zhang,Chuncao Xu,Shiqi Lin,Huanbin Zhou,Gangtao Yao,Hu Liu,Lili Wang,Xin Pan,Guilan Quan,Chuanbin Wu
Dissolving microneedles carried drug molecules can effectively penetrate the stratum corneum of skin to improve the transdermal drug delivery. The traditional Chinese medicine acupuncture is based on the needle stimulation at a specific location (acupoint) to generate and transmit biochemical and physiological signals which alter the pathophysiological state of patients. However, the pain associated with conventional acupuncture needles and the requirement of highly trained professionals limit the development of acupuncture in non-Asian countries. The purpose of this study is to investigate whether the dissolving microneedles can be utilized as a self-administered painless replacement for acupuncture and locally released drug molecules can achieve expected therapeutic outcomes. Immunosuppressive rats were treated with acupuncture at Zusanli (ST36) acupoint using microneedles containing thymopentin. The immune functions and psychological mood of the immunosuppressed animals were examined. The proliferation of splenocytes was examined by CCK-8 assay. CD4 and CD8 expression patterns in spleen cells were detected by flow cytometry. The current study showed that use of either microneedles containing thymopentin or conventional acupuncture both resulted in immune cell proliferation, which was confirmed by flow cytometry. Furthermore, either conventional acupuncture or microneedles were able to effectively mitigate the anxiety caused by immune-suppression when applied on the ST36.
研究领域:
中药学
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免疫学
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药剂学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）