Neurochemistry international最新文献_第10页

Probing impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and 1H-MRS at 7.0T MRI 利用CEST成像和7.0T MRI 1H-MRS探查睡眠剥夺对大鼠海马神经化学的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-10-01 Epub Date: 2025-07-15 DOI: 10.1016/j.neuint.2025.106020

Zhihong Zhao , Lvhao Wang , Xiaolei Zhang , Yue Chen , Xinhui Zheng , Renhua Wu

Purpose

Sleep is a physiological process that plays a crucial role in maintaining cognitive functions. The hippocampus, a key brain region implicated in cognition, is particularly sensitive to sleep deprivation. we aim to investigate impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and ¹H-MRS.

Methods

Twelve female Sprague-Dawley rats were randomly divided into sleep deprivation and control groups. All rats experienced Morris water maze training and testing from Day 1 to Day 6 and underwent MRI scans including CEST imaging and ¹H-MRS on Days 1 and Day 3. Lastly, rats were euthanized for Nissl staining.

Results

Sleep deprivation led to a significant decrease in CEST signals across various frequency offsets (0.5–3.5 ppm) in the hippocampus (P < 0.05). Meanwhile, sleep deprivation caused an increase in glutamate (P < 0.0001) with no alterations in other metabolites (P > 0.05). Behaviorally, sleep deprivation impaired learning-memory abilities, evidenced by reduced target quadrant distance (P < 0.001) and time (P < 0.01) in the Morris water maze. Histologically, sleep deprivation caused a decline of surviving neurons in the hippocampal CA1 and CA3 regions (P < 0.001). These indicators correlated negatively with the concentrations of glutamate (P < 0.05) and positively with most of the CEST signals (P < 0.05) in the hippocampus.

Conclusion

The integration of CEST imaging and ¹H-MRS offers a promising approach for identifying imaging biomarkers that aid in the assessment and management of sleep deprivation's impact on hippocampal neurochemistry.

目的：睡眠是一个生理过程，对维持认知功能起着至关重要的作用。海马体是大脑中与认知有关的关键区域，对睡眠不足特别敏感。我们的目的是利用CEST成像和1H-MRS研究睡眠剥夺对大鼠海马神经化学的影响。方法：将12只雌性Sprague-Dawley大鼠随机分为睡眠剥夺组和对照组。所有大鼠在第1天至第6天进行Morris水迷宫训练和测试，并在第1天和第3天进行MRI扫描，包括CEST成像和1H-MRS。最后对大鼠实施安乐死，进行尼氏染色。结果：睡眠剥夺导致海马不同频率偏移（0.5-3.5 ppm）的CEST信号显著减少（P0.05）。结论：CEST成像和1H-MRS的结合为识别成像生物标志物提供了一种很有前途的方法，有助于评估和管理睡眠剥夺对海马神经化学的影响。

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引用次数: 0

The potentiating activity of benzodiazepine site of the GABA(A) receptor is inhibited by competitive antagonists of orthosteric site GABA(A)受体苯二氮平的增强活性被正构位的竞争性拮抗剂所抑制

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-07-05 DOI: 10.1016/j.neuint.2025.106018

Elena I. Solntseva, Julia V. Bukanova, Rodion V. Kondratenko

Benzodiazepines (BDZs) are widely-prescribed drugs that act as positive allosteric modulators of GABA_A receptor, enhancing the GABA-elicited chloride current (I_GABA). In this work, we studied the influence of competitive antagonists of the GABA_A receptor gabazine (GBZ), bicuculline (Bic), and amiloride (Ami) on the potentiating effect of the agonist of BDZ site zolpidem (Zolp). These antagonists bind to their own sites, which partially overlap with the orthosteric site. The experiments were carried out on native GABA_A receptors in isolated Purkinje cells of the rat cerebellum. The I_GABA was measured using the patch-clamp technique and a system of fast application. The effects of the drugs on I_GABA were assessed by the change in the EC₅₀ value for GABA dose-effect curve constructed in the ranges of 0.5–100 μM GABA. Changes in EC₅₀ values as a percentage relative to the control were calculated. 0.5 μM Zolp shifted the GABA curve to the left and decreased the EC₅₀ by 54 % (from 4.8 μM to 2.2 μM). Competitive antagonists shifted the GABA curve to the right and increased the EC₅₀ to 72.6 μM (0.5 μM GBZ), 25.5 μM (500 μM Ami) and 28.8 μM (5 μM Bic). With the addition of Zolp, these EC₅₀ values decreased by 21–25 % and were 56.8 μM (GBZ), 19.2 μM (Ami), and 22.7 μM (Bic), respectively. The results show that the potentiating effect of Zolp is reduced by half in the presence of competitive GABA_A receptor antagonists (p < 0. 001).

苯二氮卓类药物（BDZs）作为GABAA受体的正变构调节剂，增强gaba诱导的氯离子电流（IGABA），被广泛使用。在这项工作中，我们研究了GABAA受体的竞争拮抗剂gabazine (GBZ), bicuculline （Bic）和amiloride （Ami）对BDZ部位激动剂唑吡坦（Zolp）增强作用的影响。这些拮抗剂与它们自己的位点结合，这些位点与正位位点部分重叠。实验采用大鼠小脑浦肯野细胞天然GABAA受体进行。采用膜片钳技术和快速应用系统测量IGABA。在0.5 ~ 100 μM GABA范围内，通过构建GABA剂量效应曲线EC50值的变化来评价药物对IGABA的影响。计算EC50值相对于对照组的百分比变化。0.5 μM Zolp使GABA曲线左移，EC50降低54%（从4.8 μM降至2.2 μM）。竞争拮抗剂使GABA曲线右移，EC50分别升高至72.6 μM （0.5 μM GBZ）、25.5 μM （500 μM Ami）和28.8 μM （5 μM Bic）。Zolp的加入使EC50值降低了21 ~ 25%，分别为56.8 μM （GBZ）、19.2 μM （Ami）和22.7 μM （Bic）。结果表明，在竞争性GABAA受体拮抗剂存在时，Zolp的增强作用降低了一半(p <；0. 001)。

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引用次数: 0

DNA methylation and hydroxymethylation dynamics in the aging brain and its impact on ischemic stroke 衰老脑中的DNA甲基化和羟甲基化动力学及其对缺血性脑卒中的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-06-11 DOI: 10.1016/j.neuint.2025.106007

Vijay Arruri , Pallavi Joshi , Raghu Vemuganti

DNA methylation and hydroxymethylation patterns at the 5th carbon of cytosine (5mC and 5hmC) in CpG dinucleotides tightly regulate gene transcription in normal physiology, aging, and associated diseases, including ischemic stroke. Resilience to ischemic brain injury depends on the interplay of diverse neural and non-neural cell types, whose gene expression and identity are predominantly regulated by brain-enriched epigenetic mechanisms, particularly the dynamics of 5mC and 5hmC in response to changing transcriptional demands under ischemic stress. In this review, we discussed the role of 5mC and 5hmC in aging and the pathophysiology of stroke. Given the high degree of inter-individual variability in stroke studies and its multifactorial etiology, we emphasize the need for personalized, temporally controlled, epigenome-based therapies to improve stroke outcomes.

CpG二核苷酸中胞嘧啶第5碳（5mC和5hmC）的DNA甲基化和羟甲基化模式密切调节正常生理、衰老和相关疾病（包括缺血性中风）的基因转录。对缺血性脑损伤的恢复取决于多种神经和非神经细胞类型的相互作用，其基因表达和身份主要由脑富集的表观遗传机制调节，特别是5mC和5hmC在缺血应激下响应转录需求变化的动态。本文就5mC和5hmC在衰老和脑卒中病理生理中的作用进行综述。鉴于卒中研究的高度个体间变异性及其多因素病因学，我们强调需要个性化、暂时控制、基于表观基因组的治疗来改善卒中预后。

引用次数: 0

Thiamet-G ameliorates Parkinson's disease-associated cognitive impairment via increasing O-GlcNAcylation of STING in the microglia Thiamet-G通过增加小胶质细胞中STING的o - glcn酰化来改善帕金森病相关的认知障碍

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-06-26 DOI: 10.1016/j.neuint.2025.106014

Shanshan Zhu , Nan Wang , Shuyang Chen , Ju Zou , Sijie Tan

Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.

小胶质细胞的激活有助于帕金森病（PD）相关认知功能障碍的发展，靶向小胶质细胞可能是改善PD认知功能的一种有希望的策略。o - glcnaclyation是一种具有认知增强作用的新型蛋白质翻译后修饰。本研究旨在探讨Thiamet-G （TMG）是一种O-GlcNAcase抑制剂，可提高细胞内O-GlcNAcase水平，对pd相关认知障碍的影响及其与小胶质细胞活化的相关机制。采用鱼藤酮（rotenone， ROT）建立PD小鼠模型，通过行为学测试观察小鼠的认知功能。在BV2小胶质细胞中检测TMG的抗炎作用。经y迷宫实验和客观识别实验证实，TMG治疗可显著改善rot诱导的PD小鼠模型的认知功能。组织学研究表明，TMG通过增加PD小鼠海马总蛋白o - glcnaclyation水平来降低反应性小胶质细胞。在体外研究中，TMG通过降低BV2小胶质细胞中促炎细胞因子TNF-α、IL-1β和IL-6来抑制rot诱导的炎症。生物信息学分析表明，作为先天免疫调控的核心蛋白，STING可能是o - glcnaclyation的新靶点。免疫沉淀实验进一步证实TMG通过增加o - glcnac酰化抑制STING磷酸化。综上所述，TMG可能通过增加小胶质细胞中STING的o - glcn酰化来改善PD相关的认知功能障碍，这为通过提高o - glcn酰化水平来抑制小胶质细胞的炎症反应可能是改善PD认知功能的有效策略提供了证据。

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引用次数: 0

Anti-inflammatory and analgesic effects of marine-derived antimicrobial peptide tilapia piscidin 3(TP3) in alleviating chronic constriction injury-induced neuropathic pain in rats 海洋来源抗菌肽Piscidin 3（TP3）对大鼠慢性收缩性损伤神经性疼痛的抗炎镇痛作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-06-20 DOI: 10.1016/j.neuint.2025.106013

Jui-Kang Tsai , Zong-Sheng Wu , San-Nan Yang , Shi-Ying Huang , Hui-Lu Chen , Wei-Ning Teng , Fu-Wei Su , Wu-Fu Chen , Zhi-Hong Wen , Chun-Sung Sung

Neuropathic pain has multiple etiologies, and many patients remain inadequately treated. The cyclic adenosine monophosphate (cAMP) signaling pathway plays a critical role in inflammatory responses, particularly through the upregulation of proinflammatory cytokines. This study aimed to investigate the anti-inflammatory and analgesic properties of the marine-derived antimicrobial peptide Tilapia Piscidin 3 (TP3), using a chronic constriction injury (CCI) model to simulate neuropathic pain. In vitro assays showed that TP3 exerted a dose-dependent inhibitory effect on lipopolysaccharide-induced proinflammatory cytokine expression in mouse BV-2 microglia and RAW 264.7 macrophages. Nociceptive behavioral tests revealed that intrathecal (IT) administration of TP3 alleviated CCI-induced mechanical allodynia and thermal hyperalgesia. Immunofluorescence analysis showed that IT TP3 significantly increased phosphodiesterase 4D (PDE4D) levels and decreased the expression of cAMP, brain-derived neurotrophic factor (BDNF), and tumor necrosis factor-α in astrocytes within the dorsal horn of the spinal cord in CCI rats. The antinociceptive effects of TP3 were abolished by the PDE4D inhibitor rolipram, highlighting the role of PDE4D-mediated modulation of the cAMP pathway in producing these effects. These findings suggest that TP3 may be a promising therapeutic agent for treating neuropathic pain by exerting anti-inflammatory and analgesic effects through regulation of the cAMP pathway.

神经性疼痛有多种病因，许多患者仍未得到充分治疗。环腺苷单磷酸（cAMP）信号通路在炎症反应中起关键作用，特别是通过上调促炎细胞因子。本研究旨在通过慢性收缩损伤（CCI）模型模拟神经性疼痛，研究海洋来源抗菌肽罗非鱼Piscidin 3 （TP3）的抗炎镇痛作用。体外实验表明，TP3对脂多糖诱导的小鼠BV-2小胶质细胞和RAW 264.7巨噬细胞的促炎细胞因子表达有剂量依赖性的抑制作用。伤害性行为测试显示，鞘内给药TP3减轻了cci引起的机械异常性痛和热痛觉过敏。免疫荧光分析显示，IT TP3显著提高CCI大鼠脊髓背角星形细胞磷酸二酯酶4D （PDE4D）水平，降低cAMP、脑源性神经营养因子（BDNF）和肿瘤坏死因子-α的表达。PDE4D抑制剂罗利普兰可消除TP3的抗感知作用，这表明PDE4D介导的cAMP通路调节在产生这些作用中的作用。这些发现表明，TP3可能通过调节cAMP通路发挥抗炎和镇痛作用，成为治疗神经性疼痛的一种有前景的药物。

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引用次数: 0

Impact of NLRP6 inflammasome on neuroinflammation in temporal lobe epilepsy NLRP6炎性小体对颞叶癫痫神经炎症的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-05-19 DOI: 10.1016/j.neuint.2025.105994

Yiming Guo , Jiaqi Song , Yingxi Chen , Yang Lü , Weihua Yu

Epilepsy is one of the most common and severe chronic brain diseases, affecting up to 70 million people worldwide. Neuroinflammation plays a central role in the progression of the disease. The Nod-Like Receptor Protein 6 (NLRP6) inflammasome assembles with apoptosis-associated speck-like protein (ASC) to cleave pro-caspase-1 into caspase-1, thus forming the NLRP6 inflammasome. This process promotes the maturation and release of downstream interleukins (IL)-18 and IL-1β, exacerbating pathological processes in various diseases. In this study, we demonstrated significantly enhanced NLRP6 expression in the cortex and hippocampus of epileptic mice, suggesting a role for the inflammasome in epilepsy. Immunofluorescence staining further revealed that NLRP6 was predominantly expressed in hippocampal neurons of these mice. Additionally, knockdown of NLRP6 reduced susceptibility to epilepsy, alleviated post-seizure neuronal damage, and decreased levels of pro-inflammatory cytokines, including IL-18, IL-1β, and IL-6. Conversely, NLRP6 overexpression produced opposite effects, which were effectively reversed by treatment with the caspase-1 inhibitor VX765. To the best of our knowledge, this is the first study to demonstrate a link between NLRP6 and the activation of the caspase-1/IL-1β/IL-18 signaling pathway in a kainic acid (KA)-induced epilepsy mouse model. Administration of VX765 alleviated pathological alterations and exerted neuroprotective effects. These findings suggest that NLRP6 plays a critical role in the initiation and progression of epilepsy.

癫痫是最常见和最严重的慢性脑部疾病之一，影响全世界多达7000万人。神经炎症在疾病的发展中起着核心作用。nod样受体蛋白6 （NLRP6）炎性小体与凋亡相关斑点样蛋白（ASC）结合，将前caspase-1切割成caspase-1，从而形成NLRP6炎性小体。这一过程促进下游白细胞介素(IL)-18和IL-1β的成熟和释放，加剧了各种疾病的病理过程。在本研究中，我们发现NLRP6在癫痫小鼠的皮层和海马中的表达显著增强，提示炎症小体在癫痫中的作用。免疫荧光染色进一步显示NLRP6在小鼠海马神经元中主要表达。此外，NLRP6的敲低降低了癫痫的易感性，减轻了癫痫后的神经元损伤，降低了促炎细胞因子的水平，包括IL-18、IL-1β和IL-6。相反，NLRP6过表达产生相反的效果，用caspase-1抑制剂VX765治疗可有效逆转。据我们所知，这是第一个在kainic酸（KA）诱导的癫痫小鼠模型中证明NLRP6与caspase-1/IL-1β/IL-18信号通路激活之间存在联系的研究。VX765可减轻病理改变，发挥神经保护作用。这些发现表明NLRP6在癫痫的发生和发展中起着关键作用。

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引用次数: 0

Repetitive transcranial magnetic stimulation as a universal modulator of synaptic plasticity: Bridging the gap between functional and structural plasticity 重复经颅磁刺激作为突触可塑性的普遍调节剂：弥合功能和结构可塑性之间的差距

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-07-08 DOI: 10.1016/j.neuint.2025.106021

Danica Popovic , Milorad Dragic

Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive technique for neuromodulation that has shown great potential in therapy of several neurodegenerative and neuropsychiatric disorders both in patients and animal models. In addition to its non-invasiveness, the main rationale for using it for these disorders is that the positive effects extend beyond the stimulation period and can last up to several minutes, hours or even days after the last application. While the mechanisms underlying these long-lasting positive effects have not yet been fully deciphered, current literature supports hypothesis of modulation of both functional and structural plasticity. Dendritic spines are structures on dendritic branches that regulate synaptic transmission at the level of postsynapse and represent one of the structural and functional carriers of synaptic plasticity. Since rTMS has been proposed to induce long-term potentiation/long-term depression-like effects, based on the existing literature in animal studies, we suggest several molecular mechanisms which could underpin rTMS-induced structural plasticity manifested at the level of dendritic spines that include processes starting from spinogenesis to gradual spine maturation and eventual spine shrinkage and loss. The results gathered in this review postulate rTMS as a universal modulator of synaptic plasticity, which could guide future research and help in optimizing appropriate protocols of transcranial magnetic stimulation for adequate disorders and pathologies.

重复经颅磁刺激（rTMS）是一种无痛、无创的神经调节技术，在多种神经退行性疾病和神经精神疾病的治疗中显示出巨大的潜力，无论是在患者还是动物模型中。除了它的非侵入性之外，使用它治疗这些疾病的主要理由是，积极的效果超出了刺激期，可以在最后一次应用后持续几分钟、几小时甚至几天。虽然这些长期积极影响的机制尚未完全破译，但目前的文献支持功能和结构可塑性调节的假设。树突棘是树突分支上在突触后水平调节突触传递的结构，是突触可塑性的结构和功能载体之一。由于rTMS已被提出诱导长期增强/长期抑郁样效应，基于现有的动物研究文献，我们提出了几种支持rTMS诱导树突棘水平结构可塑性的分子机制，包括从脊柱形成到逐渐脊柱成熟和最终脊柱萎缩和丧失的过程。本综述的结果表明，rTMS是突触可塑性的一种普遍调节剂，可以指导未来的研究，并有助于优化经颅磁刺激治疗适当疾病和病理的方案。

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引用次数: 0

Refinement of TSLP expression mediates chronic allodynia associated with IL22/STAT3 axis TSLP表达的改善介导与IL22/STAT3轴相关的慢性异常性痛

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-07-10 DOI: 10.1016/j.neuint.2025.106022

Chun-Ching Lu , Ying-Yi Lu , Hung-Pei Tsai , Chieh-Hsin Wu

Chronic allodynia is a painful response to an innocuous stimulus because of maladaptive neuroplasticity within the central nervous system. IL22 is a pleiotropic mediator owing to its proinflammatory and immunosuppressive effects. In this study, we aimed to investigate the potential of modulating TSLP expressions to treat chronic allodynia and elucidate the underlying mechanisms associated with IL22. TSLP^−/− mice were generated, and four mouse groups were created as follows: wild-type (WT) + PBS, TSLP knockout (KO) + PBS, WT + bleomycin, and TSLP KO + bleomycin. Repeated bleomycin administration reduced the IL22/STAT3 pathway to trigger chronic allodynia in C57BL/6 mice. The degree of gliosis and neuron loss were significantly greater in the somatosensory cortex and spinal cord dorsal horn of the bleomycin-treated mice compared with those in the PBS-treated mice. Compared with those in WT mice treated with bleomycin, in TSLP-deficient mice, the degree of gliosis and neuron loss were significantly lower in the somatosensory cortex and spinal cord dorsal horn and the mechanical withdrawal threshold was altered. Differentiated human SH-SY5Y cells were created to investigate the neuroprotective effects of TSLP refinement against hydrogen peroxide (H₂O₂)-induced neurotoxicity. The deficiency of TSLP protected differentiated SH-SY5Y cells against H₂O₂-induced neurotoxicity. IL22 stimulator not only rescued the H₂O₂-induced neurotoxicity but augmented the protective effect of si-TSLP on differentiated SH-SY5Y cells. Our data confirmed that a lack of TSLP decreased the expression of TSLPR/STAT5, the bleomycin-induced chronic allodynia and the H₂O₂-induced neurotoxicity. In addition, inhibiting TSLP rescued the IL22/STAT3-mediated effect, which regulated neuroglial interactions to relieve chronic allodynia. Targeting TSLP/TSLPR is a potential therapeutic approach for relieving chronic allodynia by regulating gliosis, neuron loss, and the IL22/STAT3 axis.

慢性异常性疼痛是由于中枢神经系统的神经可塑性不适应而引起的对无害刺激的疼痛反应。由于其促炎和免疫抑制作用，IL22是一种多效介质。在这项研究中，我们旨在研究调节TSLP表达治疗慢性异常性疼痛的潜力，并阐明与IL22相关的潜在机制。生成TSLP−/−小鼠，并创建四组小鼠：野生型(WT) + PBS， TSLP敲除(KO) + PBS， WT +博来霉素，TSLP KO +博来霉素。在C57BL/6小鼠中，反复给予博来霉素可降低IL22/STAT3通路触发慢性异位性疼痛。与pbs组相比，博莱霉素组小鼠体感觉皮层和脊髓背角的胶质细胞增生和神经元丢失程度显著增加。与博来霉素处理的WT小鼠相比，tslp缺陷小鼠体感觉皮层和脊髓背角的胶质细胞增生程度和神经元损失明显降低，机械戒断阈值发生改变。建立分化的人SH-SY5Y细胞，研究TSLP精制对过氧化氢（H2O2）诱导的神经毒性的神经保护作用。缺乏TSLP可保护分化的SH-SY5Y细胞免受h2o2诱导的神经毒性。IL22刺激剂不仅可以挽救h2o2诱导的神经毒性，还可以增强si-TSLP对SH-SY5Y分化细胞的保护作用。我们的数据证实，缺乏TSLP会降低TSLPR/STAT5的表达、博莱霉素诱导的慢性异常性疼痛和h2o2诱导的神经毒性。此外，抑制TSLP恢复了IL22/ stat3介导的作用，其调节神经胶质相互作用以缓解慢性异常性疼痛。靶向TSLP/TSLPR是一种通过调节胶质细胞增生、神经元丢失和IL22/STAT3轴来缓解慢性异位性疼痛的潜在治疗方法。

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引用次数: 0

A multiscale atlas of Oprm1-expressing neurons in the central nervous system: Brain-wide distribution, circuit functions, and translational therapeutic implications 中枢神经系统表达oprm1神经元的多尺度图谱：全脑分布、回路功能和翻译治疗意义

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-05-28 DOI: 10.1016/j.neuint.2025.105998

Zixu Zhang , Shengru Hu , Shuyan Geng , Tianxiang Xu , Xing Liu , Zixuan Lei , Chuanyao Sun , Haoyu Sun , Wei Xie , Mingdao Mu

The mu-opioid receptor (MOR), encoded by the Oprm1 gene, critically modulates diverse physiological processes including pain perception, reward behaviors, emotional regulation, and autonomic control. The genetic complexity and region-specific distribution of Oprm1-expressing neurons underpin both the therapeutic actions and adverse effects of opioid drugs. In this comprehensive review, we systematically construct a multiscale atlas of Oprm1-expressing neurons throughout the central nervous system (CNS) by integrating genetic labeling, neuroanatomical mapping, functional circuit analyses, and translational perspectives. We highlight three interconnected aspects: (1) brain-wide regional distribution patterns, revealing enriched Oprm1 expression across sensory, limbic, and autonomic circuits; (2) functional heterogeneity of Oprm1-expressing neurons, elucidating their distinct roles in nociception, reward processing, emotional and neuroendocrine regulation, with a particular emphasis on sex differences and adaptive plasticity under stress; (3) translational opportunities for therapeutic interventions, focusing on innovative strategies such as circuit-specific opioid modulation and biased agonism, designed to optimize analgesic benefits while minimizing addiction liability and respiratory depression. Furthermore, we critically examine existing challenges and knowledge gaps, including receptor trafficking mechanisms, dynamic changes in Oprm1 expression under conditions such as chronic opioid exposure or stress, interspecies differences, and network-level opioid signaling dynamics. This integrative framework provides essential insights into MOR neurobiology, facilitating the development of next-generation opioid therapeutics that leverage precise modulation of neural circuits and molecular pharmacological advancements. The translational implications of understanding these aspects are emphasized throughout this review, aiming to bridge basic neurobiological findings with clinical applications.

由Oprm1基因编码的mu-阿片受体（MOR）对疼痛感知、奖励行为、情绪调节和自主控制等多种生理过程具有重要的调节作用。表达oprm1的神经元的遗传复杂性和区域特异性分布是阿片类药物治疗作用和不良反应的基础。在这篇综合综述中，我们通过整合遗传标记、神经解剖图谱、功能电路分析和翻译观点，系统地构建了整个中枢神经系统（CNS）表达oprm1神经元的多尺度图谱。我们强调了三个相互关联的方面：(1)全脑区域分布模式，揭示了在感觉、边缘和自主神经回路中丰富的Oprm1表达；(2)表达oprm1的神经元的功能异质性，阐明了它们在伤害感受、奖励加工、情绪和神经内分泌调节中的独特作用，特别强调了性别差异和应激下的适应可塑性；(3)治疗干预的转化机会，重点是创新策略，如电路特异性阿片类药物调节和偏倚激动作用，旨在优化镇痛效果，同时最大限度地减少成瘾倾向和呼吸抑制。此外，我们批判性地研究了现有的挑战和知识空白，包括受体运输机制，慢性阿片类药物暴露或应激条件下Oprm1表达的动态变化，物种间差异和网络水平阿片类药物信号动力学。这一综合框架提供了对MOR神经生物学的重要见解，促进了利用神经回路精确调节和分子药理学进步的下一代阿片类药物的发展。理解这些方面的翻译意义强调在整个审查，旨在桥梁基础神经生物学的发现与临床应用。

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引用次数: 0

Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury 去铁胺可预防缺血再灌注损伤早期血脑屏障破坏、神经炎症和细胞凋亡改变。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-01 Epub Date: 2025-06-13 DOI: 10.1016/j.neuint.2025.106009

Rajesh Ugale, Sneha Vatte, Punit Girdhar, Dinesh Anandani

Background

Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under investigation. This study aims to investigate effect of DFX on I/R damage led by BBB disruption, neuroinflammation, and apoptosis.

Methods

In adult male Wistar rats, cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Rats were treated with vehicle or DFX at 100, 200, and 300 mg/kg doses intraperitoneally (i.p.) at time intervals 1, 2, and 3 h of I/R injury. The neuroprotective effect of DFX was observed using histological staining and behavioural assessment after 24 h of I/R injury. Blood-brain barrier (BBB) integrity was evaluated by Evans blue staining & MMP9 expression. Anti-inflammatory effect of DFX was observed using immunohistochemical analysis whereas, anti-apoptotic effects via mRNA expressions of CREB, caspase-3, BDNF and Bcl-2.

Results

DFX (300 mg/kg) at 1 h of I/R injury ameliorates cerebral infarction, neurological deficits, and beam walk score. Histologically, Hoechst, hematoxylin and eosin (H & E), and cresyl violet stainings showed reduced neuronal death in DFX treated rats. It mitigates BBB disruption as observed with Evans blue staining. Additionally, DFX reduced MMP-9 expression indicative of reduced BBB disruption and improved inflammatory changes (CD86 and CD206). Besides, it inhibits mRNA expression of cleaved caspase-3 and improved expression of BDNF and Bcl-2.

Conclusions

Our findings, demonstrate that DFX prevents I/R brain damage in early hour (1 h) of I/R injury by reducing BBB disruption, inflammation, and apoptosis. DFX may exhibit potential to act as adjuvant in management of acute ischemic stroke.

背景：铁与缺血/再灌注损伤（I/R）脑损伤有关。去铁胺（DFX）是一种铁螯合剂，在I/R动物模型中具有神经保护作用。然而，其潜在机制正在调查中。本研究旨在探讨DFX对血脑屏障破坏、神经炎症和细胞凋亡导致的I/R损伤的影响。方法：采用大脑中动脉闭塞法（MCAO）诱导成年雄性Wistar大鼠脑缺血。大鼠分别在I/R损伤后1、2和3小时腹腔注射100、200和300 mg/kg剂量的载药或DFX。I/R损伤24 h后，通过组织学染色和行为学评价观察DFX的神经保护作用。Evans蓝染色及MMP9表达评价血脑屏障（BBB）完整性。通过免疫组化分析观察DFX的抗炎作用，通过CREB、caspase-3、BDNF和Bcl-2 mRNA表达观察其抗凋亡作用。结果：DFX （300 mg/kg）在I/R损伤1小时可改善脑梗死、神经功能缺损和梁行走评分。组织学上，赫斯特、苏木精和伊红（h&e）和甲氧基紫染色显示DFX治疗大鼠神经元死亡减少。埃文斯蓝染色观察到，它减轻了血脑屏障的破坏。此外，DFX降低了MMP-9的表达，表明减少了血脑屏障破坏和改善炎症变化（CD86和CD206）。抑制cleaved caspase-3 mRNA的表达，提高BDNF和Bcl-2的表达。结论：我们的研究结果表明，DFX通过减少血脑屏障破坏、炎症和细胞凋亡，在I/R损伤早期（1小时）预防I/R脑损伤。DFX可能在急性缺血性脑卒中的治疗中显示出辅助治疗的潜力。

{"title":"Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury","authors":"Rajesh Ugale, Sneha Vatte, Punit Girdhar, Dinesh Anandani","doi":"10.1016/j.neuint.2025.106009","DOIUrl":"10.1016/j.neuint.2025.106009","url":null,"abstract":"<div><h3>Background</h3><div>Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under investigation. This study aims to investigate effect of DFX on I/R damage led by BBB disruption, neuroinflammation, and apoptosis.</div></div><div><h3>Methods</h3><div>In adult male Wistar rats, cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Rats were treated with vehicle or DFX at 100, 200, and 300 mg/kg doses intraperitoneally (<em>i.p.</em>) at time intervals 1, 2, and 3 h of I/R injury. The neuroprotective effect of DFX was observed using histological staining and behavioural assessment after 24 h of I/R injury. Blood-brain barrier (BBB) integrity was evaluated by Evans blue staining & MMP9 expression. Anti-inflammatory effect of DFX was observed using immunohistochemical analysis whereas, anti-apoptotic effects via mRNA expressions of CREB, caspase-3, BDNF and Bcl-2.</div></div><div><h3>Results</h3><div>DFX (300 mg/kg) at 1 h of I/R injury ameliorates cerebral infarction, neurological deficits, and beam walk score. Histologically, Hoechst, hematoxylin and eosin (H & E), and cresyl violet stainings showed reduced neuronal death in DFX treated rats. It mitigates BBB disruption as observed with Evans blue staining. Additionally, DFX reduced MMP-9 expression indicative of reduced BBB disruption and improved inflammatory changes (CD86 and CD206). Besides, it inhibits mRNA expression of cleaved caspase-3 and improved expression of BDNF and Bcl-2.</div></div><div><h3>Conclusions</h3><div>Our findings, demonstrate that DFX prevents I/R brain damage in early hour (1 h) of I/R injury by reducing BBB disruption, inflammation, and apoptosis. DFX may exhibit potential to act as adjuvant in management of acute ischemic stroke.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106009"},"PeriodicalIF":4.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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