Neuropeptides最新文献

Differential effects of orexin system activation on dizocilpine-induced schizophrenia-like behaviors in mice. 食欲素系统激活对二唑西平诱导的小鼠精神分裂症样行为的差异影响。

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2026-01-28 DOI: 10.1016/j.npep.2026.102587

Anna Burckhardt, Anne Rakowsky, Evelyn Kahl, Shatakshi Morchhale, Dana Mayer, Nicki Panagiotou, Lara Permien, Nadine Faesel, Markus Fendt

Schizophrenia encompasses positive, negative, and cognitive symptoms, and accumulating evidence suggests that the orexin system may modulate circuits relevant to these domains. Here, we investigated whether orexin-related interventions influence schizophrenia-like behaviors induced by the NMDA receptor antagonist dizocilpine in female and male mice. Two distinct approaches were used: nasal orexin A administration and chemogenetic activation of orexin neurons via DREADDs. Behavioral assessments included prepulse inhibition (PPI), locomotion and exploratory activity in the open field, social behavior, and working memory in the Y-maze. Overall, dizocilpine robustly induced schizophrenia-like phenotypes across these paradigms. Nasal orexin A exacerbated the dizocilpine-induced PPI deficit but attenuated the associated increase in startle reactivity, did not modify dizocilpine-induced hyperactivity, and partially rescued working memory impairments. Chemogenetic activation reproduced the PPI pattern observed with nasal orexin A, increased locomotion in both control- and dizocilpine-treated mice, induced anxiolytic-like effects in the open field, restored exploratory rearing, facilitated social recognition, and fully rescued working memory deficits. In some cases, the effects of these orexin-related interventions were differently pronounced in the two sexes. These findings indicate that activating the orexin system may worsen behavioral endophenotypes related to positive symptoms while alleviating those associated with negative and cognitive symptoms. However, substantial variability across assays, potentially related to the dosing of dizocilpine, orexin A, and CNO, as well as protocol-dependent constraints in some behavioral paradigms, limits definitive interpretation. Nevertheless, the present data reveal novel and domain-specific effects of orexin signaling in schizophrenia-relevant behavioral circuits and highlight the importance of exploring interventions with intermediate efficacy, including newly emerging orexin receptor agonists, to more precisely delineate orexin-dependent mechanisms and their therapeutic potential for negative and cognitive symptom domains.

精神分裂症包括阳性、阴性和认知症状，越来越多的证据表明，食欲素系统可能调节与这些领域相关的回路。在这里，我们研究了食欲素相关干预是否会影响NMDA受体拮抗剂二唑西平诱导的雌性和雄性小鼠的精神分裂症样行为。使用了两种不同的方法：通过鼻腔给药和通过reads化学激活食欲素神经元。行为学评估包括脉冲前抑制（PPI）、野外运动和探索活动、社会行为和y型迷宫的工作记忆。总的来说，二唑西平在这些范式中强烈地诱导了精神分裂症样表型。鼻促食欲素A加重了二唑西平诱导的PPI缺陷，但减弱了惊吓反应性的相关增加，没有改变二唑西平诱导的多动，并部分挽救了工作记忆障碍。化学发生激活重现了鼻腔食欲素A所观察到的PPI模式，增加了对照组和二唑西平治疗小鼠的运动能力，诱导了开放领域的焦虑样效应，恢复了探索性饲养，促进了社会识别，并完全恢复了工作记忆缺陷。在某些情况下，这些与食欲素相关的干预措施的效果在两性中是不同的。这些发现表明，激活食欲素系统可能会加重与阳性症状相关的行为内表型，而减轻与阴性和认知症状相关的行为内表型。然而，各试验之间的巨大差异，可能与二唑西平、食欲素A和CNO的剂量有关，以及一些行为范例中与方案相关的约束，限制了最终的解释。然而，目前的数据揭示了食欲素信号在精神分裂症相关行为回路中的新颖和特定领域的作用，并强调了探索具有中等疗效的干预措施的重要性，包括新出现的食欲素受体激动剂，以更准确地描述食欲素依赖机制及其对负面和认知症状领域的治疗潜力。

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引用次数: 0

Targeting the brain through the nose: Advances in polymeric nanoparticle delivery for schizophrenia 通过鼻子靶向大脑：聚合物纳米颗粒治疗精神分裂症的进展

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2026-01-18 DOI: 10.1016/j.npep.2026.102585

Teja Kumar Ponduri , G.S.N. Koteswara Rao

Intranasal delivery of polymeric nanoparticles (PNPs) offers a promising approach for improving drug delivery to the central nervous system (CNS), particularly for treating schizophrenia. This delivery method enables direct nose-to-brain transport via olfactory and trigeminal pathways, bypassing the blood-brain barrier (BBB) and increasing therapeutic agent bioavailability in brain tissue while reducing systemic exposure and adverse effects. PNPs fabricated from natural polymers (chitosan, alginate, gelatin) and synthetic polymers (PLGA, polycaprolactone) provide controlled and sustained drug release, enhanced stability, and prolonged nasal residence time. Surface modifications with targeting ligands such as transferrin and lactoferrin have demonstrated 3.2 to 5.8 fold increases in brain accumulation compared to non-functionalized systems. Coating agents including polysorbate 80 and PEG further enhance nanoparticle transport efficiency and stability, with documented improvements of up to 10.86-fold in brain uptake. Beyond traditional antipsychotics, these nanocarrier platforms show significant potential for delivering neuropeptides (oxytocin, vasopressin) that address negative symptoms and cognitive deficits in schizophrenia. Novel nanoparticle-based delivery systems, including dendrimers, nanoemulsions, and lipid-based carriers, complement polymeric approaches to overcome limitations of conventional drug therapies. Despite robust preclinical efficacy data, clinical translation faces substantial challenges including interspecies anatomical differences (human olfactory epithelium represents only 3–5% of nasal surface area versus 50% in rodents), limited nasal cavity dose capacity, device-dependent delivery variability, absence of standardized assessment protocols, and insufficient long-term safety data for chronic administration. Future research must prioritize nanoparticle design optimization for enhanced mucoadhesion and mucopenetration, improved brain targeting through ligand engineering, validation in physiologically relevant models including ex vivo human tissue, comprehensive chronic toxicity evaluation, and alignment with evolving regulatory frameworks. Intranasal PNPs represent a paradigm shift in treating schizophrenia and other neuropsychiatric disorders, offering a non-invasive, patient-friendly, and potentially more effective therapeutic modality.

聚合物纳米颗粒（PNPs）鼻内给药为改善中枢神经系统（CNS）的药物递送提供了一种有希望的方法，特别是用于治疗精神分裂症。这种给药方法可以通过嗅觉和三叉神经通路直接从鼻到脑运输，绕过血脑屏障（BBB），提高治疗药物在脑组织中的生物利用度，同时减少全身暴露和不良反应。由天然聚合物（壳聚糖、海藻酸盐、明胶）和合成聚合物（PLGA、聚己内酯）制备的pnp提供可控和持续的药物释放，增强稳定性和延长鼻腔停留时间。与非功能化系统相比，靶向配体（如转铁蛋白和乳铁蛋白）的表面修饰表明，脑蓄积增加了3.2至5.8倍。包括聚山梨酸酯80和聚乙二醇在内的涂层剂进一步提高了纳米颗粒的运输效率和稳定性，记录的大脑摄取提高了10.86倍。除了传统的抗精神病药物外，这些纳米载体平台显示出递送神经肽（催产素、加压素）的巨大潜力，可以解决精神分裂症的阴性症状和认知缺陷。新型纳米颗粒为基础的递送系统，包括树状大分子、纳米乳剂和基于脂质的载体，补充了聚合物方法，克服了传统药物治疗的局限性。尽管有可靠的临床前疗效数据，但临床转化面临着巨大的挑战，包括物种间解剖差异（人类嗅觉上皮仅占鼻表面积的3-5%，而啮齿动物为50%），有限的鼻腔剂量容量，设备依赖的递送可变性，缺乏标准化评估方案，以及长期给药的长期安全性数据不足。未来的研究必须优先考虑优化纳米颗粒设计，以增强黏液粘附和黏液渗透，通过配体工程改善大脑靶向性，在生理相关模型（包括离体人体组织）中验证，全面的慢性毒性评估，并与不断发展的调节框架保持一致。鼻内PNPs代表了治疗精神分裂症和其他神经精神疾病的范式转变，提供了一种非侵入性的、对患者友好的、可能更有效的治疗方式。

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引用次数: 0

The role of galanin/GALR2 signaling in the link between type 2 diabetes and Alzheimer's disease 甘丙肽/GALR2信号在2型糖尿病和阿尔茨海默病之间的作用

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2026-01-18 DOI: 10.1016/j.npep.2026.102586

Mengfan Xu , Jia Wang , Yuqing She , Junbo He , Mei Yu , Zhenwen Zhang , Penghua Fang

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two major healthcare problems among the elderly worldwide. Several epidemiological studies suggest that T2DM is associated with an increased risk of developing AD, leading to cognitive decline and loss of behavioral abilities. Despite many studies probing into the insulin resistance that serves as a pivotal etiopathology link between T2DM and AD, the precise mechanism for this association of both diseases is still poorly understood. Emerging evidence suggests that galanin and galanin receptor 2 (GALR2) are broadly described in the early steps of T2DM and AD and play the crucial role in the intersection between both two diseases in preclinical models. The dysregulation of the galanin-GALR2 axis plays a major role in the development of both diseases based on animal and cellular studies and has emerged as a plausible molecular pathogenesis link between them. In this review article, we mainly summarize our and other recent studies to provide a new insight into the multivariate relationship among galanin-GALR2, T2DM and AD, highlighting the beneficial effect of galanin/GALR2 signaling on the comorbid state of both diseases in preclinical models, and explain the underlying molecular mechanism in T2DM and AD pathogenesis. These may strengthen our knowledge of the pathophysiology of AD and T2DM based on preclinical studies and provide helpful hints for future research, such as whether GALR2 agonists might be determined as a potential therapeutic approach to treat both conditions.

2型糖尿病（T2DM）和阿尔茨海默病（AD）是全球老年人的两大健康问题。一些流行病学研究表明，2型糖尿病与AD发病风险增加有关，导致认知能力下降和行为能力丧失。尽管许多研究探讨了胰岛素抵抗作为T2DM和AD之间的关键病因病理学联系，但这两种疾病之间联系的确切机制仍然知之甚少。新出现的证据表明，甘丙肽和甘丙肽受体2 （GALR2）在T2DM和AD的早期阶段被广泛描述，并在临床前模型中在两种疾病的交叉中发挥关键作用。基于动物和细胞研究，galanine - galr2轴的失调在这两种疾病的发展中起着重要作用，并已成为两者之间似是而非的分子发病机制联系。在这篇综述文章中，我们主要总结了我们和其他最近的研究，为甘丙肽-GALR2、T2DM和AD之间的多因素关系提供了新的视角，强调了甘丙肽/GALR2信号在临床前模型中对两种疾病的合并症状态的有益作用，并解释了T2DM和AD发病的潜在分子机制。这可能会加强我们在临床前研究的基础上对AD和T2DM病理生理的认识，并为未来的研究提供有用的提示，例如GALR2激动剂是否可能被确定为治疗这两种疾病的潜在治疗方法。

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引用次数: 0

Modulating neuropeptide Y pathways to combat nicotine addiction through emerging evidence and future directions 通过新出现的证据和未来的方向调节神经肽Y通路对抗尼古丁成瘾。

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-12-30 DOI: 10.1016/j.npep.2025.102584

Sameer Khidkikar , Divya Malode , Brijesh Taksande , Mayur Kale , Jayshree Taksande , Mohammad Qutub , Amol Tatode , Milind Umekar

Nicotine addiction constitutes a significant global health burden, primarily driven by the substance's capacity to dysregulate the brain's reward and stress systems. This chronic relapsing disorder is characterized by robust dependence and high rates of relapse, underscoring the limitations of current therapeutic strategies. Neuropeptide Y (NPY), a 36-amino acid neuromodulator abundantly expressed in the central nervous system, has emerged as a critical regulator of emotional behavior, stress responses, and reward pathways. Its role in the pathophysiology of nicotine addiction is of increasing interest. NPY exerts its pleiotropic effects via G-protein-coupled receptors (Y1, Y2, and Y5), which are strategically positioned to modulate stress-related circuits and attenuate the hyper-dopaminergic state induced by nicotine in the mesolimbic system. Chronic nicotine exposure disrupts endogenous NPYergic signaling in key neuroanatomical loci such as the amygdala and prefrontal cortex, a neuroadaptation that heightens stress sensitivity and addiction vulnerability. The consequent reduction in NPY tone during withdrawal exacerbates the negative affective states of anxiety and stress, precipitating relapse. Preclinical evidence indicates that therapeutic strategies targeting NPY pathways including receptor-specific agonists, gene therapy for region-specific overexpression, and advanced peptide delivery systems show considerable promise for mitigating withdrawal symptomatology and reducing nicotine-seeking behavior. This review synthesizes the compelling preclinical and emerging human evidence supporting the NPY system as a therapeutic target, highlighting the critical need to develop novel, brain-penetrant NPY receptor agonists and biomarkers to bridge the translational gap and improve clinical outcomes for nicotine dependence.

尼古丁成瘾构成了一个重大的全球健康负担，主要是由于这种物质能够失调大脑的奖励和压力系统。这种慢性复发性疾病的特点是强烈的依赖性和高复发率，强调了当前治疗策略的局限性。神经肽Y （NPY）是一种由36个氨基酸组成的神经调节剂，在中枢神经系统中大量表达，是情绪行为、应激反应和奖励通路的重要调节因子。它在尼古丁成瘾的病理生理中的作用越来越引起人们的兴趣。NPY通过g蛋白偶联受体（Y1， Y2和Y5）发挥其多效性作用，这些受体被战略性地定位于调节应激相关回路，并减弱尼古丁在中脑边缘系统中诱导的高多巴胺能状态。慢性尼古丁暴露会破坏关键神经解剖位点（如杏仁核和前额皮质）的内源性NPYergic信号，这是一种神经适应性，可增强应激敏感性和成瘾脆弱性。戒断期间NPY张力随之降低，加剧了焦虑和压力的负面情感状态，加速复发。临床前证据表明，针对NPY通路的治疗策略，包括受体特异性激动剂、针对区域特异性过表达的基因治疗和先进的肽递送系统，在减轻戒断症状和减少尼古丁寻求行为方面显示出相当大的希望。本综述综合了支持NPY系统作为治疗靶点的令人信服的临床前和新出现的人类证据，强调了开发新型脑渗透NPY受体激动剂和生物标志物的迫切需要，以弥合翻译差距并改善尼古丁依赖的临床结果。

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引用次数: 0

Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies 神经肽Y在神经变性的十字路口：机制的见解和新兴的治疗策略。

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-12-24 DOI: 10.1016/j.npep.2025.102583

Viswanthram Palanivel , Akanksha Salkar , Avinash Shenoy , Taslima Akter Eva , Rumandee Perera , Nitin Chitranshi , Veer Gupta , Yuyi You , Mehdi Mirzaei , Stuart L. Graham , Vivek Gupta , Devaraj Basavarajappa

Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.

神经肽Y （NPY）是一种分布广泛且高度保守的神经肽，通过激活其受体亚型，在多种生理过程的调节中发挥核心作用，包括应激反应、能量稳态、血管张力和免疫调节。除了其生理作用外，NPY表达失调已在几种神经退行性疾病中得到证实，包括阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性侧索硬化症、Machado-Joseph病和视网膜疾病，如糖尿病视网膜病变和青光眼。这些NPY水平和受体活性的改变突出了它不仅作为疾病进展的生物标志物，而且作为有希望的治疗靶点的潜力。先前的证据表明，NPY通过减轻兴奋性毒性、氧化应激、线粒体功能障碍和神经炎症发挥神经保护作用，同时促进神经发生、突触可塑性和细胞弹性。NPY激活受体介导的细胞内信号级联，如PI3K/Akt、MAPK/ERK和p38K，控制细胞存活、蛋白酶抑制和炎症，从而影响疾病轨迹。了解NPY手术的这些机制可以为靶向治疗开辟新的途径。这篇综述讨论了NPY在神经退行性疾病中的复杂作用，以及它们在诊断和治疗策略中的意义。

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引用次数: 0

ATP drives the leptin inhibition of voltage-gated calcium channels via AMPK in isolated neurons of arcuate nucleus in male rats ATP通过AMPK在雄性大鼠弓形核离体神经元中驱动瘦素抑制电压门控钙通道

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-12-17 DOI: 10.1016/j.npep.2025.102582

Karina Bermeo, Margarita Jacaranda Rosendo-Pineda, Tamara Arenas, Isabel Arenas, David E. Garcia

Energy balance is controlled by multiple structures in the central nervous system. Hypothalamus, particularly arcuate nucleus, is a key region in the neuronal control of energy homeostasis. Leptin, an anorexigenic hormone, inhibits voltage-gated calcium channels via AMPK. However, the fine-tuning regulation of this inhibition is still scarcely known. The purpose of this work was to investigate whether intracellular ATP and extracellular glucose concentrations determine the calcium channel regulation by leptin. By using patch-clamp methods, immunocytochemical reagents and pharmacological manipulations, calcium channel-current inhibited by leptin was recorded in isolated neurons of arcuate nucleus. Consistently, leptin-mediated inhibition of calcium channel-current is occluded by lowering the intracellular ATP concentration. On the other hand, leptin maintains this inhibition independently of the extracellular glucose concentration. Furthermore, AMPK regulates constitutively the calcium channel-current inhibited by leptin. These results support for the first time a key role of ATP in the regulation of calcium channel-current by leptin. Remarkably, leptin inhibits calcium channel-current even under low extracellular glucose concentration supporting a calcium channel regulation hierarchically attained by ATP and leptin. Together, these results shed light to the role of ATP and AMPK in the dynamic regulation of calcium channels as critical components in the neuronal control of energy balance.

能量平衡是由中枢神经系统的多个结构控制的。下丘脑，尤其是弓状核，是神经元控制能量稳态的关键区域。瘦素，一种厌氧性激素，通过AMPK抑制电压门控钙通道。然而，这种抑制的微调调节仍然鲜为人知。本研究的目的是探讨细胞内ATP和细胞外葡萄糖浓度是否决定瘦素对钙通道的调节。采用膜片钳法、免疫细胞化学试剂和药理学方法，记录了瘦素对离体弓状核神经元钙通道电流的抑制作用。一致地，瘦素介导的钙通道电流抑制通过降低细胞内ATP浓度而被阻断。另一方面，瘦素维持这种抑制作用独立于细胞外葡萄糖浓度。此外，AMPK对瘦素抑制的钙通道电流进行组构性调节。这些结果首次支持ATP在瘦素调节钙通道电流中的关键作用。值得注意的是，即使在低细胞外葡萄糖浓度下，瘦素也能抑制钙通道电流，支持ATP和瘦素分层实现的钙通道调节。总之，这些结果揭示了ATP和AMPK在钙通道的动态调节中的作用，作为神经元控制能量平衡的关键成分。

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引用次数: 0

Evaluating the efficacy of neurotensin receptor-1 antagonist SR48692 in high-fat diet-induced neurotoxicity in mice: An in vivo study 评估神经紧张素受体-1拮抗剂SR48692在高脂肪饮食诱导的小鼠神经毒性中的作用：一项体内研究。

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-12-16 DOI: 10.1016/j.npep.2025.102581

Pradeep Verma, Himanshu Pal, Banalata Mohanty

Overconsumption of high-calorie foods has been linked with enhanced peripheral Neurotensin (NT) secretion. The elevated endogenous NT participates in lipid absorption in the gastrointestinal tract. An impaired neurotensinergic system leads to metabolic dysregulation, which creates systemic inflammation and oxidative stress, considered risk factors for neurodegeneration. NT receptor-1 (NTR1) antagonist, SR48692, might restrict fat absorption via inhibiting the NT signalling and, thereby, mitigating the neurotoxic effects of high-fat diet (HFD)-induced lipid dysregulation. The present study investigated the neuroprotective effect of SR48692 against HFD-induced alterations in lipid profile and imbalanced redox status. In this study, 36 male Swiss mice were randomly assigned to six groups and were injected intraperitoneally with saline or SR48692 for 4 weeks: group I/regular chow diet (CD); group II/CD + SR48692 100 μg/kg b.w. (SR_L); group III/CD + SR48692 400 μg/kg b.w. (SR_H); group IV/HFD; group V/HFD + SR_L; and group VI/HFD + SR_H. Co-treatment with SR_L showed improvements concerning lipid metabolic dysregulation and redox balance, as evidenced by decreased triglycerides, total cholesterol, low-density lipoprotein cholesterol, and leptin, and increased high-density lipoprotein cholesterol and antioxidants, observed in hippocampal histomorphometry as modulation in hippocampal cell layer thickness and density. Co-treatment with SR_H showed more detrimental effects than HFD in all studied parameters. Similarly, the CD groups treated with both doses of SR48692 showed exacerbated detrimental effects compared to the CD. Collectively, these findings suggested that only SR_L showed an ameliorating effect on HFD-induced neurodegeneration. The differential effectiveness of both doses of SR48692 co-treatment in mitigating neurodegeneration via improvement in lipid dysregulation might be due to NTR2 and/or NTR3-mediated lipid absorption.

过量食用高热量食物与周围神经紧张素（NT）分泌增加有关。内源性NT升高参与胃肠道脂质吸收。神经紧张能系统受损导致代谢失调，从而产生全身性炎症和氧化应激，被认为是神经变性的危险因素。NT受体-1 （NTR1）拮抗剂SR48692可能通过抑制NT信号传导来限制脂肪吸收，从而减轻高脂饮食（HFD）诱导的脂质失调的神经毒性作用。本研究探讨了SR48692对hfd诱导的脂质谱改变和氧化还原状态失衡的神经保护作用。本研究将36只雄性瑞士小鼠随机分为6组，连续4周腹腔注射生理盐水或SR48692：第一组/常规饲料（CD）；II组/CD + SR48692 100 μg/kg b.w (SRL)；III组/CD + SR48692 400 μg/kg b.w (SRH)；第四组/ HFD;V/HFD + SRL组；VI/HFD + SRH组。与SRL联合治疗可以改善脂质代谢失调和氧化还原平衡，如甘油三酯、总胆固醇、低密度脂蛋白胆固醇和瘦素的降低，高密度脂蛋白胆固醇和抗氧化剂的增加，海马组织形态学测量显示海马细胞层厚度和密度的调节。在所有研究参数中，与SRH联合治疗比HFD显示出更多的有害影响。同样，与CD组相比，使用两种剂量SR48692治疗的CD组显示出更严重的有害影响。总的来说，这些发现表明，只有SRL对hfd诱导的神经变性有改善作用。两种剂量的SR48692联合治疗通过改善脂质失调来减轻神经退行性变的不同效果可能是由于NTR2和/或ntr3介导的脂质吸收。

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引用次数: 0

Dual role of Kisspeptin-10 in modulating neuroinflammation: Downregulation of NLRP3 inflammasome activation and Caspase-1-mediated pyroptosis, and activation of BAG3-dependent aggrephagy in microglial cells Kisspeptin-10在调节神经炎症中的双重作用：下调NLRP3炎性体激活和caspase -1介导的焦亡，激活bag3依赖性小胶质细胞的吞噬

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-12-06 DOI: 10.1016/j.npep.2025.102580

Ömer Faruk Kalkan , Şeniz Erdem , Mehmet Erdem , Satinur Ateşer Kalkan , Zafer Şahin , Ali Yavuz Uzun , Abdullah Kaan Kurt , Süleyman Caner Karahan

Background

Microglial NLRP3 inflammasome activation plays a central role in the neuroinflammatory cascade that contributes to the pathogenesis of various neurodegenerative diseases. Activation of the canonical inflammasome pathway leads to caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cell death, along with the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Kisspeptin-10 (KP-10), a bioactive neuropeptide of the kisspeptin family, has been shown to exert regulatory effects on immune function; however, its role in neuroinflammation process remains unclear. In this study, we investigated the effects of KP-10 on LPS + ATP-induced NLRP3 inflammasome activation and pyroptotic signaling in murine microglial cells.

Results

KP-10 treatment significantly reduced NLRP3 expression, inhibited cleavage of caspase-1 into its active p20 subunit, and decreased GSDMD cleavage into its pore-forming N-terminal fragment (GSDMD-N), indicating suppression of inflammasome-dependent pyroptosis. KP-10 also attenuated the secretion of IL-1β and IL-18, confirming functional inhibition of the inflammasome pathway. Mechanistically, KP-10 markedly upregulated Bcl-2-associated athanogene 3 (BAG3), a key co-chaperone involved in selective autophagy.

Conclusion

These findings demonstrate that KP-10 suppresses microglial pyroptosis and neuroinflammatory signaling through dual mechanisms: inhibition of the NLRP3–caspase-1–GSDMD axis and activation of BAG3-dependent selective autophagy. This study identifies KP-10 as a novel modulator of microglial inflammasome activity and highlights its therapeutic potential for treating neuroinflammatory and neurodegenerative disorders.

背景：小胶质NLRP3炎性小体的激活在神经炎症级联反应中起核心作用，参与各种神经退行性疾病的发病机制。典型炎性小体途径的激活导致caspase-1激活、气皮蛋白D （GSDMD）裂解和热亡细胞死亡，同时释放促炎细胞因子，如白细胞介素-1β (IL-1β)和白细胞介素-18 （IL-18）。kisspeptin -10 （KP-10）是kisspeptin家族的一种生物活性神经肽，已被证明对免疫功能具有调节作用；然而，其在神经炎症过程中的作用尚不清楚。在本研究中，我们研究了KP-10对LPS + atp诱导的小鼠小胶质细胞NLRP3炎性体激活和热噬信号传导的影响。结果skp -10处理显著降低NLRP3的表达，抑制caspase-1裂解成其活性p20亚基，降低GSDMD裂解成其成孔n端片段（GSDMD- n），表明抑制炎症小体依赖性焦亡。KP-10还能减弱IL-1β和IL-18的分泌，证实其具有炎性小体途径的功能抑制作用。在机制上，KP-10显著上调bcl -2相关的凋亡基因3 (BAG3)，这是一种参与选择性自噬的关键协同伴侣。结论KP-10通过抑制NLRP3-caspase-1-GSDMD轴和激活bag3依赖性选择性自噬的双重机制抑制小胶质细胞焦亡和神经炎症信号转导。本研究确定KP-10是一种新的小胶质炎性体活性调节剂，并强调其治疗神经炎症和神经退行性疾病的治疗潜力。

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引用次数: 0

Nociceptin-mediated SIRT6 downregulation drives cellular senescence in glioblastoma 损伤肽介导的SIRT6下调驱动胶质母细胞瘤细胞衰老

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-11-27 DOI: 10.1016/j.npep.2025.102570

Yankai Xu, Jiesi Zhou, Xiaobin Zhou, Yong Li, Senyuan Yang, Zebin Xue

Cellular senescence plays a crucial role in glioblastoma (GBM), influencing tumor progression and therapeutic resistance. Nociceptin (N/OFQ), an endogenous neuropeptide, and its receptor NOPr are implicated in various pathological processes, but their role in GBM remains unclear. This study investigated the effects of N/OFQ-NOPr signaling on cellular senescence in GBM. We found elevated plasma N/OFQ levels and increased NOPr expression in GBM tissues compared to normal controls. In U-251 GBM cells, N/OFQ upregulated NOPr expression, induced oxidative stress, and reduced telomerase activity and telomere length, leading to enhanced cellular senescence. Mechanistically, N/OFQ downregulated SIRT6 but not SIRT1 or HDAC, resulting in increased acetylation of p53, upregulation of p21, and suppression of p-Rb. Overexpression of SIRT6 reversed N/OFQ-induced senescence markers, restoring telomerase activity and reducing senescence-associated β-galactosidase. Notably, administration of the selective NOPr antagonist UFP-101 abolished N/OFQ-induced cellular senescence, indicating that this effect is NOPr-dependent. These findings suggest that N/OFQ-NOPr signaling promotes GBM senescence via SIRT6 downregulation, highlighting a potential therapeutic target for modulating senescence in GBM

细胞衰老在胶质母细胞瘤（GBM）中起着至关重要的作用，影响肿瘤的进展和治疗耐药性。痛觉肽（N/OFQ）是一种内源性神经肽，它的受体NOPr与多种病理过程有关，但它们在GBM中的作用尚不清楚。本研究探讨了N/OFQ-NOPr信号在GBM细胞衰老中的作用。我们发现与正常对照相比，GBM组织中血浆N/OFQ水平升高，NOPr表达增加。在U-251 GBM细胞中，N/OFQ上调NOPr表达，诱导氧化应激，降低端粒酶活性和端粒长度，导致细胞衰老加剧。机制上，N/OFQ下调SIRT6，但不下调SIRT1或HDAC，导致p53乙酰化增加，p21上调，p-Rb抑制。过表达SIRT6逆转N/ ofq诱导的衰老标志物，恢复端粒酶活性，减少衰老相关的β-半乳糖苷酶。值得注意的是，选择性NOPr拮抗剂UFP-101可消除N/ ofq诱导的细胞衰老，表明这种作用依赖于NOPr。这些发现表明，N/OFQ-NOPr信号通过SIRT6下调促进GBM衰老，突出了调节GBM衰老的潜在治疗靶点

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引用次数: 0

Effects of vasoactive intestinal peptide on neuroexcitability of female-specific subpopulation of myelinated Ah-type neurons isolated from trigeminal ganglia of adult female rats 血管活性肠肽对成年雌性大鼠三叉神经节有髓鞘ah型神经元雌性特异性亚群神经兴奋性的影响

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-11-16 DOI: 10.1016/j.npep.2025.102569

Feng Yan , Pan Zhong-xuan , Tan Li-li , Fang Luo , Ding Hai-ying

Migraine headache remains a health issue more commonly seen in women with a complicated pathophysiology and is under debate. Vasoactive intestinal peptide (VIP) is a potential factor associated with trigeminovascular system. Here, trigeminal ganglion (TG) neurons were isolated from adult female rats and action potentials (AP) from identified myelinated Ah-type were recorded before and after treatment with VIP with or without blockers using whole-cell patch-clamp technique. The results showed that VIP 100 nM induced a significant increase in the firing frequency of repetitive discharge in these Ah-type TG neurons with dramatic narrowed AP, increased rate of derivative of down-stroke velocity, and deeper after-hyperpolarization (AHP), and these alternations could be reversed by Iberiotoxin except for AHP that was abolished by Apamin. Strikingly, VIP-mediated increase in firing frequency of AP and waveform characters of repolarization were completely blocked by PG97–269, rather that PG-99-465. Interestingly, PG97–269 alone could also slightly but markedly reduced repetitive firing of Ah-type TG neurons under control condition. Taken all these data together, we conclude that VIP upregulates the neuroexcitability of female-specific Ah-type neurons via presumable VPAC1 activation that plays a minor role in the development of basal neuroexcitation and the dataset adds valuable insights into the etiology of migraine headache.

偏头痛仍然是一个健康问题，更常见于具有复杂病理生理的女性，目前仍在争论中。血管活性肠肽（Vasoactive intestinal peptide， VIP）是一个与三叉神经血管系统相关的潜在因子。本研究从成年雌性大鼠身上分离三叉神经节（TG）神经元，利用全细胞膜片钳技术记录VIP加或不加阻断剂治疗前后确定的髓鞘ah型动作电位（AP）。结果表明，VIP 100 nM诱导ah型TG神经元重复放电频率显著增加，AP明显变窄，下行程速度导数率增加，后超极化（AHP）加深，除AHP被Apamin消除外，这些变化可被Iberiotoxin逆转。值得注意的是，vip介导的AP发射频率增加和复极波形特征被PG97-269完全阻断，而PG-99-465则完全阻断。有趣的是，PG97-269在对照条件下也能轻微但显著地减少ah型TG神经元的重复放电。综合所有这些数据，我们得出结论，VIP通过可能的VPAC1激活上调女性特异性ah型神经元的神经兴奋性，而VPAC1激活在基础神经兴奋的发展中起着次要作用，该数据集为偏头痛的病因学提供了有价值的见解。

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引用次数: 0