JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 6
·e70372
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IF 4.2
Wang Huikang,Cao Shiya,Pan Di,Faisal Ayub Kiani,Li Hao,Nan Sha,Lin Xuan,Mahmoud M. Abouelfetouh,Zulfiqar Ahmed,Ding Mingxing,Ding Yi
Neuropathic pain (NP), resulting from nerve damage, is difficult to manage and often requires long-term treatment. However, prolonged use of pain medications can lead to addiction and reduced effectiveness over time. Understanding drug tolerance is essential for developing improved pain management strategies. Dexmedetomidine (DEX) is effective in targeting the α2 -adrenergic receptor, providing relief from pain, especially NP. However, its extended use leads to tolerance and hinders its clinical utility. Herein, we investigated tolerance mechanisms and potential applications of this drug in managing NP. Adult C57BL/6 mice (male) were distributed into DEX Dosage Groups ( n = 48), DEX Tolerance Model Groups ( n = 32), SGK1 Inhibitor GSK650394 Groups ( n = 48), and NF - κB Inhibitor PDTC Groups ( n = 32) to explore dexmedetomidine's effects on NP and tolerance mechanisms. NP was established via selective ligation of the sciatic nerve branch (SNI), followed by administration of DEX. The results revealed a dose-dependent analgesic effect of DEX, with significant increases in pain thresholds observed compared to the sham group ( p < 0.05). Optimal efficacy was found at a dose of 30 μg/kg, indicating its potential as an effective treatment for NP ( p < 0.05). However, continuous administration of DEX over 13 days induced analgesic tolerance, evidenced by an initial increase in pain thresholds followed by a gradual decrease ( p < 0.05). Despite an initial efficacy in elevating pain thresholds, the analgesic effect of DEX diminished over time, returning to pre-dose levels after 5 days ( p < 0.05). Transcriptome sequencing of spinal cord samples from mice receiving multiple DEX injections revealed differential gene expression patterns, notably upregulation of SGK1 , NR2A , and NR2B subunits ( p < 0.05). Inhibiting SGK1 mitigated DEX-induced tolerance, suggesting its involvement in tolerance development ( p < 0.05). Moreover, NF - κB inhibition reversed DEX-induced tolerance and implicated the SGK1 - NF - κB pathway in the mediation of analgesic tolerance. To sum up, these findings revealed the molecular mechanism underlying DEX-induced analgesic tolerance in the NP model and offer potential avenues for future therapeutic interventions.
研究领域:
药理学
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疼痛管理
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分子生物学
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高影响因子
JOURNAL OF NEUROSCIENCE
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2025
·
IF 4
Tianyi Yang,Yan Chen,Maolin Wang,Ren Ren,Fang Yan,Peng Xu,Bin Di
Nitrous oxide use Disorder（NUD）has recently received increasing social concern for its sharp rise among young people. However, the underlying mechanisms of NUD remain largely unexplored, which obstructs treatment strategy development and may exacerbate the epidemic of N2O abuse. Thus, specifying the essential mechanisms and targets in NUD are desperately needed. Here we unveiled a series of molecular adaptations regarding N2O reward memory in Nucleus accumbens (NAc) of mice through multi-omics approaches comprising transcriptomics, proteomics, metabolomics approaches. Our miRNA transcriptomics and pull-down proteomics analyzes uncovered that miR-7220-5p regulated N2O-induced conditioned-place preference (CPP) and associated increase of dendritic spine density in NAc of male mice. Our pull-down proteomics and metabolomics analyzes revealed that miR-7220-5p modulated ERK signaling pathway by directly binding with NR2B receptor. In summary, our work confirmed that restoring miR-7220-5p expression in NAc protected against synaptic abnormality via the NR2B/ERK/CREB signaling, thereby attenuating CPP behaviors in NUD. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed a potential therapeutic strategy for NUD and provided comprehensive resources of biological data to support future investigations of NUD treatment.Significance Statement Nitrous oxide Use Disorder (NUD) has recently received tremendously increasing social concern for its sharp rise among young people. Although the neurological consequences and their etiologies of consuming N2O have been well elucidated, the underlying mechanisms of NUD remain largely unexplored, which obstructs the development of clinical treatment strategies and may exacerbate the epidemic of N2O abuse. Our work uncovered the role of miR-7220-5p/NR2B/ERK/CREB signaling against synaptic abnormality/CPP behaviors. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed therapeutic targets for overcoming NUD behaviors and the omics data provided comprehensive biological resources to support future investigations of NUD.
研究领域:
神经科学
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分子生物学
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药理学
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生物信息学
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精神病学
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细胞信号传导
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成瘾研究
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高影响因子
Science Bulletin
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2024
·
IF 18.8
Xia Jie,Zhang Lixing,Zhu Wucheng,Tu Juchuanli,Peng Xilei,Deng Qiaodan,Li Siqin,He Xueyan,Dong Haonan,Liu Cuicui,Chen Xian,Xu Jiahui,Ma Wei,Xiao Yi,Liu Wen,Hu Guohong,Jiang Yi-Zhou,Chen Ceshi,Bian Xiu-Wu,Shao Zhi-Ming,Liu Suling
Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.
研究领域:
肿瘤学
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免疫学
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生物化学
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分子生物学
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DOI
高影响因子
Neural Regeneration Research
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2020
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IF 3.171
Jian-Zhu Bo,Ling Xue,Shuang Li,Jing-Wen Yin,Zheng-Yao Li,Xi Wang,Jun-Feng Wang,Yan-Shu Zhang
Although exogenous D-serine has been applied as a neural regulatory intervention in many studies, the role played by D-serine in hippocampal injuries caused by lead exposure remains poorly understood. Rat models of chronic lead exposure were established through the administration of 0.05% lead acetate for 8 weeks. Simultaneously, rats were administered 30 or 60 mg/kg D-serine, intraperitoneally, twice a day. Our results showed that D-serine treatment shortened the escape latency from the Morris water maze, increased the number of times that mice crossed the original platform location, and alleviated the pathological damage experienced by hippocampal neurons in response to lead exposure. Although D-serine administration did not increase the expression levels of the N-methyl-D-aspartate receptor subtype 2B (NR2B) in the hippocampi of lead-exposed rats, 60 mg/kg D-serine treatment restored the expression levels of NR2A, which are reduced by lead exposure. These findings suggested that D-serine can alleviate learning and memory impairments induced by lead exposure and that the underlying mechanism is associated with the increased expression of NR2A in the hippocampus. This study was approved by the Animal Ethics Committee of North China University of Science and Technology, China (approval No. LX2018155) on December 21, 2018.
研究领域:
神经科学
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毒理学
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药理学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Shuxian Zang,Ziyun Ban,Lingchen Hou,Yuxuan Zhang,Yuanyuan Wang,Yuanyuan Zhang,Chaonan Wang,Depei Li,Feiyu An,Yuqi Liu,Yunyun Geng,Yonggang Gao
Ethnopharmacological relevance The herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao), collectively referred to as Chaihu-Baishao (CB), has been historically utilized in traditional Chinese medicine for the treatment of depression. However, the mechanisms underlying its therapeutic benefits have not been clearly defined. Aim of the study This study investigated whether CB alleviates depressive symptoms by modulating the interaction between the voltage-gated calcium channel subunit α2δ-1 and the N-methyl-D-aspartate receptor (NMDAR) subunit NMDAR2B (NR2B), thereby restoring hippocampal synaptic plasticity. Materials and methods In vivo , the chronic social defeat stress (CSDS) mouse model was employed to assess the impact of CB on depression-like behaviors, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impairments in hippocampal neuronal and synaptic plasticity, as well as the expression and interaction of α2δ-1 and NR2B. In vitro , corticosterone (CORT) was utilized to induce cellular injury. In PC12 cells, the therapeutic effects of CB-containing serum and the α2δ-1 inhibitor gabapentin (GBP) were assessed, focusing on the interaction between α2δ-1 and NR2B, as well as the expression levels of synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN). The role of CB was further corroborated using Cacna2d1 gene knockout cells. Molecular docking techniques were employed to predict the key active components within CB that target α2δ-1 and NR2B, hereby exerting antidepressant effects. Results In vivo studies demonstrated that CB significantly alleviated depression-like behaviors in mice, decreased levels of adrenocorticotropic hormone (ACTH) and CORT. Furthermore, CB relieved structural damage to hippocampal neurons and synapses, downregulated the expression of α2δ-1 and NR2B, inhibited their interaction and restored synaptic protein expression. In vitro experiments revealed that CB mitigated CORT-induced cellular damage, suppressed the α2δ-1-NR2B interaction, and enhanced synaptic proteins expression. Additionally, studies involving GBP treatment and Cacna2d1 -knockout confirmed that α2δ-1 plays a regulatory role in NR2B expression and synaptic plasticity. Molecular docking analyses identified Saikosaponin C, Saikosaponin B4, and Bupleuroside I as potential key components. Conclusion The findings of this study elucidate a novel mechanism through which CB exerts its antidepressant effects, specifically by modulating the α2δ-1-NR2B interaction and restoring of synaptic plasticity within the hippocampus.
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