NEUROCHEMICAL RESEARCH
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2016
·Vol. 41
·期 7
·1662-1672
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IF 2.472
Song Xiaoyu,Zhou Biao,Zhang Pingping,Lei Di,Wang Yubin,Yao Guodong,Hayashi Toshihiko,Xia Mingyu,Tashiro Shin-ichi,Onodera Satoshi,Ikejima Takashi
Silibinin, a flavonoid derived from the herb milk thistle ( Silybum marianum ), has been used as a hepato-protectant in the clinical treatment of liver disease. In the present study, the effect of silibinin on lipopolysaccharide (LPS)-induced neuroinflammatory impairment in rats is investigated. Injection of LPS into lateral ventricle caused learning and memory impairment. Rats were treated with silibinin to see the effect in comparison with resveratrol as a positive control. Y-maze and Morris water maze tests showed that silibinin significantly attenuated memory damage caused by LPS treatment. At the molecular analysis, the levels of IL-1β and of IL-4 in the hippocampus were decreased and enhanced, respectively, by the treatment with silibinin. NF-κB expression was attenuated by silibinin treatment. Furthermore, generation of total reactive oxygen species (ROS) in the hippocampus was elevated in silibinin-treated groups, and so were the expressions of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). At the same time, LPS-induced reduction of neurons in hippocampus was reversed by silibinin. In conclusion, silibinin ameliorated the impairment of learning and memory of LPS-injection rats, possibly due to the activation of ROS–BDNF–TrkB pathway in the hippocampus as well as the suppression of inflammatory response. This study gives an insight on the beneficial consequences of ROS in central nervous system. Silibinin might be a potential candidate drug for neurodegenerative diseases.
研究领域:
神经科学
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药理学
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免疫学
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PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 19
·期 3
·1781-1790
·
IF 1.851
Yan Luo,Daogong Zhang,Yueling Chen,Zhongsheng Cao,Zhaomin Fan
The brain‑derived neurotrophic factor (BDNF) and c‑Jun NH 2‑terminal kinase (JNK) signaling pathways are therapeutic targets to prevent degeneration in the central nervous system. Dexamethasone (DXMS), a glucocorticoid, protects against vestibular brain injury, however, the molecular mechanisms have yet to be fully elucidated. To investigate whether the BDNF and JNK signaling pathways are involved in the protective effects of DXMS in rats with vestibular dysfunction, a rat model of severe vestibular deficits was established by middle ear injection of arsanilic acid (AA; 100 mg/ml; 0.05 ml). After 3 days, rat symptoms and behavior scores with vestibular disorders were detected. In brain tissues, histopathological alterations, cell apoptosis, expression levels and patterns of BDNF signaling pathway‑associated BDNF, tyrosine receptor kinase B (TrKB) and K+/Cl‑ cotransporter isoform 2 (KCC2), and the expression of apoptosis‑related cleaved‑caspase 3 and the JNK signaling pathway were detected. It was identified that DXMS relieved AA‑induced vestibular dysfunction, leading to improvement in rat behavior scores to normal levels, minimizing brain damage at the histopatholojnnkngical level, reducing cell apoptosis, enhancing the expression of BDNF, TrKB and KCC2, and downregulating cleaved‑caspase 3 and phosphorylated‑JNK1/2 in brain tissues. Together, these findings indicated the protective effect of DXMS on AA‑induced rat vestibular dysfunction, and that activating BDNF and inhibiting JNK singling pathways were the underlying mechanisms. In addition, with additional treatment of mifepristone (RU486), a specific glucocorticoid agonist, all the events elicited by DXMS mentioned above in the AA‑treated rat rats were reversed. In conclusion, DXMS was identified as a therapeutic agent targeting the BDNF and JNK singling pathways for AA‑induced rat vestibular dysfunction.
研究领域:
神经科学
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药理学
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前庭障碍
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
·
IF 5.7
Junjie Huang,Jiahao Zhu,Huijun Zheng,Enhui Zhu,Chenqi Yang,Liqin Ying,Yucong Zhou,Hao Liu
The neuroprotective effect of DAAOi is associated with increased levels of its substrate, D-Serine. • D-Serine can ameliorate cognitive and behavioral deficits in MCAO rats. • D-Serine may exert its neuroprotective effect by promoting the D-Serine/GluN2A/BDNF signaling pathway. To investigate the mechanisms of D-Amino acid oxidase inhibitor (DAAOi) in ameliorating cerebral ischemia-reperfusion (I/R) injury and the underlying neuroprotective effect of substrate D-Serine. A middle cerebral artery occlusion (MCAO) rat model and an oxygen-glucose deprivation (OGD)-induced HT22 cell model were used to mimic ischemic stroke. The modified Neurological Severity Scores (mNSS) and 2, 3, 5-triphenyltetrazolium chloride staining were applied to assess neurological behavioral scores and cerebral infarct area, respectively. The effects of DAAOi 4H-Furo[3,2-b]pyrrole-5- carboxylic acid (SUN) and D-Serine intervention on cognitive and behavioral functions in MCAO rats were evaluated by using the Y-maze and Novel Object Recognition Test (NORT). Intracerebral stereotaxic injection of Compound SUN and D-Serine (0.21 mg, 1.05 mg, 2.1 mg) significantly reduced cerebral infarct area, indicating that DAAOi might improve cerebral I/R injury by elevating D-Serine levels. Similarly, D-Serine significantly enhanced cognitive and behavioral performance in MCAO rats (mNSS: improved by 2.3 scores; Y-maze: spontaneous alternation rate increased by 14.76%; NORT: recognition index improved by 12.28%). D-Serine pretreatment (10 μM-10 mM) dose-dependently increased the viability of HT22 cells subjected to OGD. In both in vitro and in vivo models, D-Serine significantly increased the protein level of N-methyl-D-aspartate receptor subunit 2A (GluN2A). Additionally, D-Serine promoted the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 but inhibited the apoptosis-related p38 MAPK phosphorylation. This study demonstrated that the neuroprotective effect of DAAOi was at least partly mediated by elevating cerebral D-Serine levels, which regulated the GluN2A/BDNF axis to enhance synaptic plasticity and cognitive function. Download: Download high-res image (323KB) Download: Download full-size image
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
·
IF 5.2
Zhongting Lv,Xiang Li,Hanning Wu,Xiaowen Zhang,Wangyang Hu,Yong Xu,Jie Zhang,Li Ren
Chronic stress is a major contributor to hippocampal neurotoxicity and cognitive dysfunction. However, mechanism-oriented interventions remain limited. Bilobalide is a chemically defined sesquiterpene lactone from Ginkgo biloba with reported neuroprotective activity. Nevertheless, its effect on chronic stress-induced cognitive injury and its relationship to glucocorticoid receptor (GR) signaling remain unclear. Here, we evaluated bilobalide in chronic restraint stress (CRS) mice and in corticosterone (CORT)-challenged HT22 hippocampal neurons. Bilobalide improved short-term recognition, long-term recognition, and spatial memory in CRS mice, and alleviated neuronal injury in the hippocampal CA1, CA3, and dentate gyrus regions. These effects were accompanied by reduced lipid peroxidation, recovery of antioxidant capacity, attenuation of systemic inflammatory cytokine release and hippocampal inflammatory gene expression, suppression of apoptosis-related signaling, and preservation of dendritic architecture, synaptic ultrastructure, and synaptic proteins. Bilobalide also restored hippocampal BDNF/TrkB/PI3K/Akt signaling. In vivo and in vitro fractionation/immunofluorescence experiments showed that bilobalide restrained stress-enhanced GR nuclear translocation, and GRE-reporter assays showed reduced GR transactivation. Molecular docking and cellular thermal shift assay supported cellular target engagement of GR by bilobalide. Importantly, GR knockdown blunted bilobalide-mediated rescue of oxidative injury and of BDNF/TrkB/PI3K/Akt-associated synaptic signaling in CORT-injured HT22 cells. These data indicate that bilobalide protects against chronic stress-induced hippocampal neurotoxicity and memory impairment, at least in part, by limiting maladaptive GR signaling and preserving neurotrophic-synaptic homeostasis. Bilobalide therefore merits further evaluation as a mechanistically defined lead compound for stress-associated cognitive dysfunction.
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高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2025
·
IF 2.5
Ziran Yu,Chenlu Feng,Ying Chen,Weidi Wang,Xiujuan Zhao
Perimenopausal depression is a psychiatric disorder that occurs around the time of menopause and seriously affects women's health. The pathogenesis of perimenopausal depression is unclear which affects its prevention and treatment. Quercetin is a flavonoid compound with antidepressant and estrogen-like effects. The aim of this research was to investigate the role of quercetin on adrenal gland metabolic disorders in perimenopausal depressed rats based on untargeted metabolomics. Female Wistar rats with no difference in sucrose preference were randomly separated into four groups (n = 12): sham-operated group; perimenopausal depression model group; model + 50 mg/kg.bw quercetin group; model + 0.27 mg/kg.bw 17β-estradiol group. After successful modeling, adrenal gland and hypothalamic samples were collected for metabolomics experiments and detection of related indicators. A total of 22 differential metabolites were identified in the model group, and pathway analysis revealed adrenal gland metabolism abnormalities including steroid hormone biosynthesis, arachidonic acid metabolism, and linoleic acid metabolism. Notably, Spearman’s rank correlation analysis between differential metabolites and rat behavioral results showed strong positive or negative correlations ( P < 0.01). Meanwhile, the hypothalamus of the model group showed TrkB-BDNF signaling pathway abnormality, and the HPA axis was found to play an important role in perimenopausal depression. Treatment with quercetin or 17β-estradiol restored these abnormal changes. It suggested that quercetin can regulate adrenal metabolic disorders through multiple pathways, thereby ameliorating perimenopausal depression.Further more, quercetin can modulate HPA axis through the TrkB-BDNF signaling pathway. This research provides new ideas for the application of quercetin in the precaution and treatment of perimenopausal depression.
研究领域:
药理学
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神经科学
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内分泌学
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PubMed
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
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2025
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IF 2.5
Zhao Wenxin,Gong Zelin,Wang Benjie,Wu Zhiyu,Guo Yiyuan,Wang Shurong,Zhai Hao,Zheng Xiaomei,Yang Lu
Autophagy dysfunction plays an influential role in fluoride-induced neurotoxicity, but the mechanism has not yet been clarified. The aim of this study was to investigate the effects of grape seed proanthocyanidin extract (GSPE) on sodium fluoride (NaF)-treated offspring SD rats and SH-SY5Y cells, and to elucidate the mechanism of mTOR/p70s6k-mediated autophagy signaling pathway action. The results of in vivo experiments showed that different doses of GSPE treatment could alleviate NaF-induced neurological damage, centering on the improvement of learning and memory ability, recovery of autonomous exploration ability, reduction of anxiety-like behaviors, restoration of neuronal structure in hippocampal tissues, and reduction of the expression of apoptotic protein cleaved-PARP. Meanwhile, GSPE significantly promoted autophagy in hippocampal tissues, as evidenced by the blockage of mTOR/p70s6k phosphorylation and the upregulation of LC3-II and downregulation of p62 expression. To further explore the mechanistic issues, we conducted cellular experiments, which suggested that GSPE pretreatment significantly increased cell viability and strengthened autophagy compared with the NaF group. These results were evidenced by the inhibition of mTOR/p70s6k phosphorylation and the upregulation of LC3-II protein. To further investigate the effect of GSPE on the mTOR/p70s6k pathway, the mTOR inhibitor rapamycin (RAPA) and activator MHY1485 were incorporated. The results indicated that GSPE inhibited the enhancement of mTOR phosphorylation in combination with MHY1485, and further inhibited the phosphorylation of mTOR in combination with RAPA, and the levels of LC3-II and p62 and immunofluorescence results also confirmed that the pretreatment of GSPE promoted cellular autophagy. Similarly, Hoechst33342 fluorescence intensity and apoptotic protein cleaved-PARP expression were further reduced after GSPE combined with RAPA or MHY1485. In addition, downstream of the mTOR/p70s6k pathway, brain-derived neurotrophic factor (BDNF), which has been widely used in studies of mood disorders, was significantly reduced by GSPE pretreatment, suggesting that GSPE may not only have a role in attenuating neurotoxicity, but also potentially in improving mood. In conclusion, the present study reveals that GSPE may alleviate fluoride-induced neurotoxicity by inhibiting the activation of the mTOR/p70s6k signaling pathway and thereby enhancing cellular autophagy and antagonizing apoptosis.
研究领域:
神经毒理学
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分子生物学
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药理学
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发育神经科学
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细胞自噬
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环境健康
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DOI
PubMed
高影响因子
PHYSIOLOGY & BEHAVIOR
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2022
·
IF 3.742
Yan Sun,Haiyan Zhu,Rongrong Cheng,Zhengquan Tang,Min Zhang
Akkermansia muciniphila is present in the mucus layer of its host gut, and its outer membrane protein Amuc_1100 has a significant ameliorative effect on metabolic disorders and emotional memory aspects of enteritis, obesity, depression, and anxiety in the host. Antibiotics affect gut microbial composition, leading to imbalance and behavioral changes in the gut-brain axis, while probiotics have a protective effect against behavioral changes caused by gut flora disorders. In the present study, a depressed mouse model using a broad-spectrum cocktail mixture resulted in increased anxiety and depression-like behavior, decreased serum and hippocampal levels of 5-hydroxytryptamine (5-HT), and increased serum corticosterone (cort) levels. After application of A. muciniphila and Amuc_1100, anxiety and depression-like behavior in antibiotic-treated mice were significantly alleviated. In addition, the brain derived neurotrophic factor / Tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway was altered, glial fibrillary acidic protein (GFAP) expression increased, and c-Fos protein expression decreased in the hippocampus of antibiotic-treated mice. After treatment with A. muciniphila and Amuc_1100, BDNF and TrkB levels were restored in the hippocampus and cortex. These results suggest that A. muciniphila and Amuc_1100 may alleviate antibiotic-induced anxiety and depression by affecting the BDNF/TrkB signaling pathway.
研究领域:
神经科学
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微生物学
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药理学
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行为科学
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PubMed
高影响因子
Molecular Medicine Reports
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2026
·Vol. 34
·期 3
·1-16
·
IF 5
Mengjie He,Zixuan Liu,Yuxin Chen,Xiaoru Wu,Xueling Dai,Qian Liu,Shuo Wang,Zeping Zuo,Yaxuan Sun
Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.
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PubMed
高影响因子
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
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2024
·Vol. 28
·期 6
·1011-1025
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IF 1.6
Xiaotian Yang,Yajie Qin,Huifang Zhou
BackgroundPrimary dysmenorrhea (PDM) is a prevalent menstrual disorder among women, often underreported and undertreated. Wen-Jing-Zhi-Tong Decoction (WJZTD), a patented Traditional Chinese Medicine (TCM) herbal decoction, has shown efficacy in treating PDM. However, the underlying therapeutic mechanism of WJZTD in PDM treatment remains to be elucidated.ObjectiveThis study aimed to employ integrative pharmacology and experimental validation to investigate the potential therapeutic mechanisms of WJZTD in treating PDM.MethodsThe bioactive compounds of WJZTD were identified by UPLC-Q-Exactive-Orbitrap MS/MS and GC-MS. Putative targets of WJZTD were obtained from Swiss Target Prediction, STITCH, and BATMAN-TCM databases. Known targets of PDM were retrieved from Gene Cards and Drug Bank databases. Protein-to-protein interactions were constructed to screen key targets using the STRING database. Subsequently, GO and KEGG pathway enrichment analyses were performed based on Metascape. Finally, a PDM rat model was established to validate the potential therapeutic mechanisms of WJZTD using Western Blot, PCR, and ELISA.Results390 bioactive compounds in WJZTD were identified through UPLC-Q-Exactive-Orbitrap MS/MS and GC-MS. Network pharmacology revealed 7 key compounds with 20 targets and pathways that are crucial for WJZTD in treating PDM. Behavioral tests confirmed that WJZTD can effectively ameliorate menstrual pain in PDM. WJZTD also inhibited prostaglandin production, thereby relieving uterine smooth muscle contraction. The downregulation of the BDNF/TrkB/ERK/CREB signaling pathway, identified as the key target and pathway through network pharmacology, may be crucial to the anti-nociceptive and anti-inflammatory effects of WJZTD in treating PDM.ConclusionThis study provides the first comprehensive analysis of the key compounds, targets, and pathways of WJZTD, laying a solid foundation for future pharmacological studies on PDM. The anti-nociceptive and anti-inflammatory effect may be attributed to the downregulation of the BDNF/TrkB/ERK/CREB signaling pathway.
研究领域:
中药学
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药理学
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分子生物学
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DOI
高影响因子
PHYSIOLOGY & BEHAVIOR
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2017
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IF 2.341
Xiaoyu Song,Bo Liu,Lingyu Cui,Biao Zhou,Weiwei Liu,Fanxing Xu,Toshihiko Hayashi,Shunji Hattori,Yuko Ushiki-Kaku,Shin-ichi Tashiro,Takashi Ikejima
Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin , a flavonoid derived from milk thistle ( Silybum marianum ), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Aβ-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Aβ1-42-treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Aβ1-42-injected rats. Silibinin-treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression.
研究领域:
神经科学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Chen Jinglin,Wei Yumeng,Li Nong,Pi Chao,Zhao Wenmei,Zhong Yueting,Li Wen,Shen Hongping,Yang Yan,Zheng Wenwu,Jiang Jun,Liu Zerong,Liu Kezhi,Zhao Ling
The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC 50 : 17.500 ± 0.267 μg/mL) compared to ascorbic acid (IC 50 : 38.858 ± 0.263 μg/mL) and curcumin (27.189 ± 0.192 μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28 days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test ( P < 0.001) and significantly reduced the immobility period in the tail suspension test ( P < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of 5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant. Graphical Abstract
研究领域:
药理学
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神经科学
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分子生物学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Jiangyan Rao,Hongpu Li,Haonan Zhang,Xiaoxia Xiang,Xinyu Ding,Li Li,Funeng Geng,Hongyi Qi
Ethnopharmacological relevance Periplaneta americana (L.) (PA) has been used in traditional Chinese medicine for thousands of years for the effect of invigorating blood circulation and removing blood stasis . Modern pharmacological research shown that PA extract exhibits promising effects in promoting wound healing and regeneration, as well as in brain diseases such as Parkinson's disease (PD). However, whether it is effective for neuroregeneration and neurological function recovery after stroke still unknown. Aim of the study This study aims to investigate the potential effect of PA extract to promote brain remodeling through the activation of endogenous neurogenesis and angiogenesis, in addition, preliminary exploration of its regulatory mechanism. Methods Firstly, BrdU proliferation assay and immunofluorescence (IF) staining were used to evaluate the effect of PA extract on the neurogenesis and angiogenesis in vitro and in vivo . Subsequently, the effects of PA extract on brain injury in stroke rats were assessed by TTC and HE. While mNSS score, adhesive removal test, rota-rod test, and morris water maze test were used to assess the impact of PA extract on neurological function in post-stroke rats. Finally, the molecular mechanisms of PA extract regulation were explored by RNA-Seq and western blotting . Results The number of BrdU + cells in C17.2 cells, NSCs and BMECs dramatically increased, as well as the expression of astrocyte marker protein GFAP and neuronal marker protein Tuj-1 in C17.2 and NSCs. Moreover, PA extract also increased the number of BrdU + DCX + , BrdU + GFAP + , BrdU + CD31 + cells in the SGZ area of transient middle cerebral artery occlusion model (tMCAO) rats. TTC and HE staining revealed that PA extract significantly reduced the infarction volume and ameliorated the pathological damage. Behavioral tests demonstrated that treatment with PA extract reduced the mNSS score and the time required to remove adhesive tape, while increasing the time spent on the rotarod. Additionally, in the morris water maze test, the frequency of crossing platform and the time spent in the platform quadrant increased. Finally, RNA-Seq and Western blot revealed that PA extract increased the expression of p-ERK, p-CREB and BDNF . Importantly, PA extract mediated proliferation and differentiation of C17.2 and NSCs reversed by the ERK inhibitor SCH772984 and the BDNF inhibitor ANA-12, respectively. Conclusion Our study demonstrated that PA extract promoted neurogenesis and angiogenesis by activating the CREB/ERK signaling pathway and upregulating BDNF expression, thereby recovering neurological dysfunction in post-stroke.
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高影响因子
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