Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献_第6页

Mechanistic insights into the antidepressant potential of plant-derived flavonoids: A preclinical review 植物源黄酮类化合物抗抑郁潜能的机制研究：临床前综述。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-22 DOI: 10.1016/j.pnpbp.2025.111567

Yingjun Cui , Zenovia Ursuliak , H.P. Vasantha Rupasinghe

Flavonoid-based phytomedicines are emerging as promising therapies for combating various disorders, including depression. Depression is a common and serious medical illness that negatively affects the quality of life. It has become a leading cause of disability worldwide. Flavonoids are ubiquitous biologically active phytochemicals in medicinal plants, herbs, fruits, vegetables, teas, and wines. There is a negative association between total flavonoid intake and depression symptoms in humans. This review aims to discuss the recent in vivo and in vitro studies on the effects of dietary flavonoids in depression models and assays to identify the molecular pathways that underlie their actions. Here, we briefly introduce the pathophysiology of depression, the diagnosis of depression, and the models for studying depression. The discovered potential antidepressant flavonoids include flavonols (quercetin, quercitrin, kaemferol, and heptamethoxyflavone), flavones (luteolin, baicalin, apigenin, and cymaroside), isoflavones (ononin), flavanones (pinocembrin), and anthocyanins (callistephin). These plant-derived flavonoids have been shown to reduce neuronal damage in the hippocampus, decrease neurotransmitter depletion, attenuate hypothalamic-pituitary-adrenal axis hyperactivation, inhibit inflammation in the central nervous system, and regulate gut microbiota. The key signaling pathways regulated by flavonoids include brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB), and nuclear factor kappa-B (NF-κB). Clearly, there is a need to conduct human dietary intervention studies to validate the beneficial physiological functions of flavonoids on the prevention and management of depression.

以黄酮类化合物为基础的植物药物正在成为对抗包括抑郁症在内的各种疾病的有希望的治疗方法。抑郁症是一种常见的严重的医学疾病，会对生活质量产生负面影响。它已成为世界范围内致残的主要原因。类黄酮是一种普遍存在于药用植物、草药、水果、蔬菜、茶和酒中的具有生物活性的植物化学物质。人类摄入总黄酮与抑郁症状呈负相关。本文综述了近年来关于膳食类黄酮在抑郁症模型中的作用的体内和体外研究，并分析了其作用的分子途径。本文简要介绍了抑郁症的病理生理学、抑郁症的诊断以及抑郁症的研究模型。已发现的潜在抗抑郁药物黄酮类化合物包括黄酮醇（槲皮素、槲皮素、山奈酚和七甲基黄酮）、黄酮（木犀草素、黄芩苷、芹菜素和cymaroside）、异黄酮（芥子草苷）、黄酮（松皮素）和花青素（石蒜素）。这些植物衍生的类黄酮已被证明可以减少海马神经元损伤，减少神经递质耗损，减轻下丘脑-垂体-肾上腺轴过度激活，抑制中枢神经系统炎症，调节肠道微生物群。黄酮类化合物调节的关键信号通路包括脑源性神经营养因子(BDNF)/原肌球蛋白相关激酶B （TrkB）和核因子κB （NF-κB）。显然，有必要进行人类饮食干预研究，以验证黄酮类化合物在预防和管理抑郁症方面的有益生理功能。

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引用次数: 0

Spinosin ameliorates post-traumatic stress disorder-like behaviors via 5-HT1A receptor in mice Spinosin通过5-HT1A受体改善小鼠创伤后应激障碍样行为。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-06 DOI: 10.1016/j.pnpbp.2025.111559

Min Seo Kim , Ju Eun Han , Chang Hyeon Kong , Keontae Park , Hoo Sik Min , Yong Seung Lee , Won Hyung Lee , Seo Yun Jung , Soo Kyung Bae , Jae Yeol Lee , Jong Hoon Ryu

Post-traumatic stress disorder (PTSD) is a severe mental illness characterized by increased arousal, intrusion, avoidance, and negative cognitive alterations following exposure to fatal stresses or psychological trauma. In this study, we explored the ameliorating effects of spinosin on PTSD-like behaviors in PTSD model mice induced by single prolonged stress (SPS). A single dose of spinosin (3 mg/kg, p.o.) ameliorated PTSD-like behaviors as assessed using the elevated plus-maze test, marble burying test, Y-maze test, tail suspension test, and fear extinction test. Furthermore, we discovered that spinosin promotes fear extinction through 5-HT_1A receptor activation. We also verified that spinosin normalizes the increased phosphorylation levels of PKA and CREB, which are downstream signaling pathways of the 5-HT_1A receptor, in the amygdala of mice modeling PTSD. Our findings suggest that spinosin could be an effective treatment for PTSD via 5-HT_1A receptor activation, addressing the limitations of current PTSD medications.

创伤后应激障碍（PTSD）是一种严重的精神疾病，其特征是暴露于致命的压力或心理创伤后，唤醒、入侵、逃避和负面认知改变增加。在本研究中，我们探讨了脊髓肽对单次长时间应激（SPS）诱导的PTSD模型小鼠PTSD样行为的改善作用。单剂量spinosin（3 mg/kg, p.o.）改善ptsd样行为，通过升高的正迷宫测试、弹珠掩埋测试、y迷宫测试、悬尾测试和恐惧消除测试进行评估。此外，我们发现spinosin通过5-HT1A受体激活促进恐惧消退。我们还证实，脊髓球蛋白使PKA和CREB磷酸化水平升高正常化，这是5-HT1A受体的下游信号通路，在创伤后应激障碍小鼠的杏仁核中。我们的研究结果表明，spinosin可能通过5-HT1A受体激活有效治疗PTSD，解决了目前PTSD药物的局限性。

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引用次数: 0

Mitochondrial metabolic reprogramming of microglia in neuroinflammation: Implications for major depressive disorder 神经炎症中小胶质细胞的线粒体代谢重编程：对重度抑郁症的影响

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-26 DOI: 10.1016/j.pnpbp.2025.111566

Yu-Fei Wang, Cong-Ya Chen, Xuan Yang, Lan Lei, Yi Zhang

Major depressive disorder (MDD) is a recurrent episodic mood disorder characterized by persistent low mood and loss of interest. The pathogenesis of major depressive disorder (MDD) involves a neuroinflammatory response, neurotransmitter dysfunction, blood-brain barrier disruption, oxidative stress, and mitochondrial dysfunction. Neuroinflammation, caused by the overactivation of microglia, is considered a key factor in the development of the disease. Metabolic reprogramming has been shown to play a crucial role in microglial activation and executive function. In MDD, microglia have the potential to become activated and transform into either pro-inflammatory or anti-inflammatory phenotypes. These variations in cellular phenotypes lead to differences in cellular energy metabolism. Mitochondria are involved in the energy metabolism of microglia and have intricate connections with microglia-mediated metabolic reprogramming and neuroinflammation. However, the specific changes in the metabolic reprogramming of microglia in depression, the numerous signaling pathways and cytokines involved, and the mechanisms by which they mediate phenotypic transitions remain unclear. Therefore, this review summarizes the metabolic reprogramming of microglia in MDD, as well as the involved signaling pathways, mitochondrial involvement and cytokines, and elaborates on their interaction with phenotypic transformation. The effects of drugs on regulating immune metabolic reprogramming to suppress neuroinflammation were summarized, providing potential for new research approaches in the treatment of MDD.

重度抑郁障碍（MDD）是一种复发性发作性情绪障碍，其特征是持续的情绪低落和兴趣丧失。重度抑郁症（MDD）的发病机制涉及神经炎症反应、神经递质功能障碍、血脑屏障破坏、氧化应激和线粒体功能障碍。由小胶质细胞过度激活引起的神经炎症被认为是该疾病发展的关键因素。代谢重编程已被证明在小胶质细胞激活和执行功能中起着至关重要的作用。在MDD中，小胶质细胞有可能被激活并转化为促炎或抗炎表型。这些细胞表型的变化导致细胞能量代谢的差异。线粒体参与小胶质细胞的能量代谢，并与小胶质细胞介导的代谢重编程和神经炎症有复杂的联系。然而，抑郁症中小胶质细胞代谢重编程的具体变化，所涉及的众多信号通路和细胞因子，以及它们介导表型转变的机制尚不清楚。因此，本文综述了MDD中小胶质细胞的代谢重编程，以及相关的信号通路、线粒体参与和细胞因子，并阐述了它们与表型转化的相互作用。综述了药物调节免疫代谢重编程抑制神经炎症的作用，为MDD治疗提供了新的研究途径。

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引用次数: 0

Targeting neurochemical and immune dysregulation in schizophrenia: From molecular mechanisms to emerging therapeutic strategies 针对精神分裂症的神经化学和免疫失调：从分子机制到新兴的治疗策略。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-10-24 DOI: 10.1016/j.pnpbp.2025.111535

Aastha Datta , Himani Rana, Shareen Singh , Thakur Gurjeet Singh

Schizophrenia is a multifaceted neuropsychiatric condition marked by a diverse array of symptoms, which can be categorized into positive, negative, and cognitive deficits. The underlying pathophysiology of this disorder is complex, involving a variety of mechanisms such as the dysregulation of neurotransmitter systems, neuroinflammatory responses, and neuronal dysfunction induced by oxidative stress. These interrelated processes lead to synaptic and neuronal impairments, which ultimately result in the clinical manifestations observed in patients with schizophrenia. The challenge of elucidating the molecular mechanisms that contribute to schizophrenia is significant, given the disorder's intricate and multifactorial characteristics. Neuroinflammatory pathways, such as those involving NF-κB, MAPK/ERK, kynurenine pathway and the activation of the NLRP3 inflammasome, play a significant role in promoting oxidative stress, synaptic dysfunction, and neuronal injury, which in turn aggravate cognitive and negative symptoms associated with schizophrenia. Although current pharmacological treatments primarily focus on dopamine and glutamate systems, their limited effectiveness in alleviating cognitive and negative symptoms highlights the necessity for a deeper mechanistic understanding of the disorder at the molecular level. Progress in neurobiological research, particularly concerning inflammatory pathways, mitochondrial dysfunction, and synaptic plasticity, is essential for the development of more targeted and effective therapeutic strategies for schizophrenia. This review underscores the critical need for a deeper understanding of molecular insights and treatment methodologies in the context of schizophrenia.

精神分裂症是一种多方面的神经精神疾病，以各种各样的症状为特征，可分为阳性、阴性和认知缺陷。这种疾病的潜在病理生理是复杂的，涉及多种机制，如神经递质系统失调、神经炎症反应和氧化应激诱导的神经元功能障碍。这些相互关联的过程导致突触和神经元损伤，最终导致在精神分裂症患者中观察到的临床表现。鉴于精神分裂症的复杂和多因素特征，阐明导致精神分裂症的分子机制的挑战是重大的。神经炎症通路，如涉及NF-κB、MAPK/ERK、犬尿氨酸通路和NLRP3炎性体激活的神经炎症通路，在促进氧化应激、突触功能障碍和神经元损伤中发挥重要作用，从而加重精神分裂症相关的认知和阴性症状。虽然目前的药物治疗主要集中在多巴胺和谷氨酸系统，但它们在缓解认知和阴性症状方面的有限效果突出了在分子水平上对该疾病进行更深入的机制理解的必要性。神经生物学研究的进展，特别是关于炎症途径、线粒体功能障碍和突触可塑性的研究，对于开发更有针对性和更有效的精神分裂症治疗策略至关重要。这篇综述强调了在精神分裂症的背景下，对分子见解和治疗方法有更深入的了解的迫切需要。

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引用次数: 0

Pre-Reproductive Excessive Alcohol and Maternal Immune Activation Differentially Affect Offspring Behavior, Neurobiology, and Brain Volume in a Sex-Dependent Manner 生殖前过量酒精和母体免疫激活以性别依赖的方式对后代行为、神经生物学和脑容量产生不同的影响。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-03 DOI: 10.1016/j.pnpbp.2025.111550

Alexandra Ott , Octavio Ghirardello , Kaloyan. Tanev , Jennifer Altschüler , Asude Zülal Gül , Zoë Kruschke , Susanne Mueller , Stefan Paul Koch , Philipp Boehm-Sturm , Christine Winter , Ravit Hadar

While the harmful effects of alcohol use during pregnancy are well recognized, less is understood about how maternal alcohol consumption during adolescence, prior to reproduction, may affect offspring. This is especially concerning given the high prevalence of adolescent alcohol use, particularly in females. This study investigates how maternal pre-reproductive alcohol exposure, combined with a maternal immune activation (MIA) during pregnancy, a well-established neurodevelopmental risk factor, affects offspring. Female Wistar rats were subjected to intermittent binge-like alcohol consumption during adolescence and later mated with naïve males. On gestational day 15, dams received either saline or a mild dose of the viral mimic Poly I:C. Maternal care was monitored, and stress axis components were analyzed in both dams and their offspring. Adult offspring underwent behavioral testing, MRI, neurochemical and neuroimmune analyses, metabolic profiling, and voluntary alcohol consumption assessments. Maternal alcohol exposure prior to reproduction led to increased offspring body weight, memory impairments, altered HPA axis function, microglial reductions, and enlarged cerebellar volumes, with most outcomes showing sex-specific differences, including opposing neurochemical responses. Interestingly, MIA, but not maternal alcohol, induced elevated alcohol intake in offspring and disrupted sensorimotor gating. MIA-exposed dams also showed impaired maternal care and reproductive HPA axis dysregulation. These findings demonstrate that adolescent alcohol use before reproduction has significant intergenerational consequences and that even mild immune challenges during pregnancy can independently disrupt offspring development. Results underscore the importance of sex as a biological variable and call for targeted preventive strategies.

虽然怀孕期间饮酒的有害影响已得到充分认识，但对于母亲在生育前的青春期饮酒可能如何影响后代，了解较少。鉴于青少年、特别是女性酗酒的高发率，这一点尤其令人担忧。本研究调查了孕妇生殖前酒精暴露，结合怀孕期间孕妇免疫激活（MIA），这是一个公认的神经发育风险因素，如何影响后代。雌性Wistar大鼠在青春期间歇性狂饮，随后与naïve雄性交配。在妊娠第15天，母鼠接受生理盐水或轻度剂量的病毒模拟物Poly I:C。监测母代护理，分析母代及其后代的应力轴分量。成年后代进行了行为测试、核磁共振成像、神经化学和神经免疫分析、代谢谱分析和自愿饮酒评估。母亲在生育前的酒精暴露导致后代体重增加、记忆障碍、下丘脑轴功能改变、小胶质细胞减少和小脑体积增大，大多数结果显示性别特异性差异，包括相反的神经化学反应。有趣的是，MIA，而不是母体酒精，诱导后代酒精摄入量升高并破坏感觉运动门控。暴露于mia的水坝也表现出母性保健受损和生殖HPA轴失调。这些发现表明，青少年在生育前饮酒会产生显著的代际影响，怀孕期间即使是轻微的免疫挑战也会独立地破坏后代的发育。结果强调了性别作为一个生物学变量的重要性，并呼吁采取有针对性的预防策略。

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引用次数: 0

The cognitive and neural pathways linking psychological resilience to procrastination 将心理弹性与拖延症联系起来的认知和神经通路。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-03 DOI: 10.1016/j.pnpbp.2025.111549

Biying Zhang , Rong Zhang , Tingyong Feng

Procrastination is a problematic behavior that negatively affects both physical and mental well-being. While extant research has established a negative association between psychological resilience and procrastination, the cognitive and neural basis underlying this relationship remain poorly characterized. To address this issue, current study asked college student participants (n = 430, M_age = 19.288 years, SD = 1.675) to undergo the MRI scanning and complete the Resilience Scale for Chinese Adolescents (RSCA) and General Procrastination Scale (GPS). The network model found that the negative relationship between psychological resilience and procrastination was primarily driven by goal planning and affect control which were two subcomponents of psychological resilience. VBM results showed that the gray matter volume (GMV) of the left Inferior Frontal Gyrus (IFG) and right Middle Frontal Gyrus (MFG) were positively correlated with goal planning, while the GMV of the right Inferior Temporal Gyrus (ITG) was positively correlated with the affect control. Importantly, the structural equation modeling (SEM) results indicated that the left IFG and the right ITG were associated with procrastination via goal planning and affect control, respectively. Taken together, these findings suggest that high psychological resilience reduces procrastination primarily through brain regions supporting goal planning and affect control.

拖延症是一种有问题的行为，对身体和精神健康都有负面影响。虽然现有的研究已经建立了心理弹性和拖延症之间的负相关关系，但这种关系背后的认知和神经基础仍然缺乏特征。为了解决这一问题，本研究要求被试大学生（n = 430,Mage = 19.288 years, SD = 1.675）接受MRI扫描并完成中国青少年弹性量表（RSCA）和一般拖延量表（GPS）。网络模型发现心理弹性与拖延之间的负向关系主要由心理弹性的两个子成分目标规划和情绪控制驱动。VBM结果显示，左侧额下回（IFG）和右侧额中回（MFG）的灰质体积（GMV）与目标规划呈正相关，右侧颞下回（ITG）的GMV与情绪控制呈正相关。重要的是，结构方程模型（SEM）结果表明，左侧IFG和右侧ITG分别通过目标规划和影响控制与拖延相关。综上所述，这些发现表明，高心理弹性主要通过支持目标规划和情绪控制的大脑区域减少拖延症。

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引用次数: 0

Aging increases susceptibility to high-fat diet-induced neurobehavioral and mitochondrial dysfunction in zebrafish 衰老增加了斑马鱼对高脂肪饮食诱导的神经行为和线粒体功能障碍的易感性

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-20 DOI: 10.1016/j.pnpbp.2025.111564

Victor L. Picolo , Letícia A. Tavares , Whitney R. Santos , Nathasha P. Lopes , Ethiane R. dos Santos , Wembley R. Vilela , Angelica Amato , Paula Q. Bellozi , Jair T. Goulart , Cesar K. Grisolia , Daniel Ardisson-Araújo , Andreza F. de Bem

Aging and unhealthy eating habits independently and synergistically disrupt central nervous system (CNS) homeostasis, increasing susceptibility to neurological and behavioral disorders. Mitochondria plays a critical role in maintaining neuronal survival and activity, representing a central player in the pathogenesis of neurodegenerative diseases. Here, we used zebrafish as a model to investigate how aging and a high-fat diet (HFD) affect brain bioenergetics and behavior. Young (4–6 months) and aged (17–22 months) male zebrafish were fed either a standard diet or an HFD based on boiled chicken egg yolk for 14 days. Brain mitochondria was evaluated using high-resolution respirometry, transmission electron microscopy (TEM), and qRT-PCR. HFD impaired the metabolic health of both young and aged animals, promoting weight gain, increased abdominal length, and elevated fasting glucose levels. Aging intensified the HFD detrimental effects on behavior: aged HFD-fed zebrafish displayed increased anxiety-like behavior in the novel tank test, and impaired cognitive performance in the T-maze test. Notably, HFD had no significant effect on aggressive behavior regardless of age. Mitochondrial responses to HFD differed by age: while cerebral bioenergetic function declined in young fish, aged animals showed an opposite trend. TEM analysis revealed increased accumulation of fragmented mitochondria in HFD group, indicating potential mitochondrial dysfunction. RT-qPCR showed upregulation of genes involved in the electron transport chain, especially in aged zebrafish. In conclusion, our findings demonstrate an age-dependent vulnerability to the effects of HFD on both neurobehavioral and mitochondrial parameters.

衰老和不健康的饮食习惯独立和协同破坏中枢神经系统（CNS）稳态，增加神经和行为障碍的易感性。线粒体在维持神经元存活和活动中起着关键作用，在神经退行性疾病的发病机制中起着核心作用。在这里，我们使用斑马鱼作为模型来研究衰老和高脂肪饮食（HFD）如何影响大脑生物能量学和行为。幼龄（4-6个月）和老年（17-22个月）雄性斑马鱼分别饲喂标准饲料或以煮鸡蛋黄为基础的高热量饲料14天。使用高分辨率呼吸仪、透射电镜（TEM）和qRT-PCR评估脑线粒体。HFD损害了幼龄和老年动物的代谢健康，促进体重增加、腹部长度增加和空腹血糖水平升高。衰老加剧了HFD对行为的有害影响：喂食HFD的年老斑马鱼在新型水箱测试中表现出焦虑样行为增加，在t -迷宫测试中表现出认知能力受损。值得注意的是，无论年龄大小，高脂肪饮食对攻击行为没有显著影响。线粒体对HFD的反应因年龄而异：幼鱼的大脑生物能量功能下降，老年动物则呈现相反的趋势。透射电镜分析显示，HFD组线粒体碎片积累增加，提示可能存在线粒体功能障碍。RT-qPCR显示参与电子传递链的基因上调，尤其是在老年斑马鱼中。总之，我们的研究结果表明，HFD对神经行为和线粒体参数的影响具有年龄依赖性。

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引用次数: 0

Sirtuin 3, a mitochondrial metabolic enzyme, links the mitochondrial function to neurophysiology in depression Sirtuin 3是一种线粒体代谢酶，将线粒体功能与抑郁症的神经生理学联系起来

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-11-14 DOI: 10.1016/j.pnpbp.2025.111563

Cong-Ya Chen , Ya-Ting Wang , Ling-Jie Liu , Yi Zhang

Depression, characterized by sustained low moods and even suicidal tendencies, has been intimately linked with mitochondrial dysfunction. This dysfunction is significantly connected with various psychiatric disorders, suggesting its potential role in the pathogenesis and progression of depression. Sirtuin 3 (SIRT3), a potent deacetylase enzyme primarily located within mitochondria, orchestrates mitochondrial function and mitigates various dysfunctions, e.g., insufficient cellular energy supply and oxidative stress. Insufficient cellular energy supply and oxidative stress disrupt normal neuroplasticity and neuroinflammation in the nervous system, as well as disturbances of the hypothalamic-pituitary-adrenal axis in peripheral systems. This review aims to elucidate that SIRT3 can be a potential target for depression, thereby summarizing the mechanisms by which SIRT3 is involved in the pathogenesis and progression of depression by regulating mitochondrial function.

抑郁症以持续的情绪低落甚至自杀倾向为特征，与线粒体功能障碍密切相关。这种功能障碍与多种精神疾病密切相关，提示其在抑郁症的发病和发展中可能起作用。Sirtuin 3 （SIRT3）是一种主要位于线粒体内的强效去乙酰酶，可调节线粒体功能并减轻各种功能障碍，如细胞能量供应不足和氧化应激。细胞能量供应不足和氧化应激破坏神经系统正常的神经可塑性和神经炎症，以及外周系统的下丘脑-垂体-肾上腺轴的紊乱。本文旨在阐明SIRT3可能是抑郁症的潜在靶点，从而总结SIRT3通过调节线粒体功能参与抑郁症发病和进展的机制。

引用次数: 0

Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression 阿戈美拉汀在慢性轻度应激大鼠抑郁症模型中使区域特异性、每日mGluR5失调正常化

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-12-03 DOI: 10.1016/j.pnpbp.2025.111572

Celine Knudsen , Majken B. Thomsen , Kristoffer Højgaard , Sofie L. Christiansen , Ove Wiborg , Heidi K. Müller , Anne M. Landau , Betina Elfving

Desynchronization of circadian rhythms is a hallmark of major depressive disorder (MDD). Agomelatine is an atypical antidepressant that acts as a melatonin receptor agonist and serotonin receptor antagonist. It has shown efficacy in alleviating symptoms of MDD with a favorable side effect profile. In the brain, agomelatine also modulates the glutamatergic system and in the present study, we investigated the effects of chronic mild stress (CMS) and agomelatine treatment on metabotropic glutamate receptor 5 (mGluR5) and synaptic vesicle glycoprotein 2 A (SV2A) binding in the medial prefrontal cortex (mPFC) and hippocampus (HP) in postmortem brain tissue derived from male rats using autoradiography. To account for diurnal influences, assessments were conducted at two time points: light-on (ZT6) and light-off (ZT18). The sucrose consumption test classified animals into four groups: Control, anhedonic-like, agomelatine responders, and non-responders.

CMS increased mGluR5 binding in the prelimbic cortex of the mPFC during the light-on phase, an effect that was normalized by agomelatine treatment in responder rats. Agomelatine also reduced mGluR5 binding in the infralimbic cortex of the mPFC. No changes in mGluR5 binding were detected during the light-off phase or in the HP at either time point. Presynaptic density, assessed by SV2A levels, remained unchanged across all groups and time points.

These findings reveal significant region-specific and diurnal alterations in mGluR5, emphasizing the role of time-of-day dependent timing in regulating mGluR5 and its association with depressive-like behaviors. Furthermore, the selective normalization of mGluR5 by agomelatine in responders reinforces its potential as a targeted therapeutic approach for MDD.

昼夜节律的不同步是重度抑郁症（MDD）的一个标志。阿戈美拉汀是一种非典型抗抑郁药，作为褪黑激素受体激动剂和血清素受体拮抗剂。它已显示出缓解重度抑郁症症状的疗效，并具有良好的副作用。在大脑中，阿戈美拉汀也调节谷氨酸能系统，在本研究中，我们研究了慢性轻度应激（CMS）和阿戈美拉汀治疗对雄性大鼠死后脑组织中内侧前额叶皮层（mPFC）和海马（HP）中代谢性谷氨酸受体5 （mGluR5）和突触囊泡糖蛋白2a （SV2A）结合的影响。为了考虑昼夜影响，在两个时间点进行评估：开灯（ZT6）和熄灯（ZT18）。蔗糖消耗试验将动物分为四组：对照组、快感缺乏症、阿戈美拉汀应答者和无应答者。在光照阶段，CMS增加了mPFC前边缘皮层的mGluR5结合，在有反应的大鼠中，阿戈美拉汀治疗使这种效果正常化。阿戈美拉汀也降低了mGluR5在mPFC边缘下皮层的结合。mGluR5结合在熄灯期和HP中均未检测到变化。通过SV2A水平评估的突触前密度在所有组和时间点保持不变。这些发现揭示了mGluR5显著的区域特异性和昼夜变化，强调了在调节mGluR5及其与抑郁样行为的关联中，时间依赖的作用。此外，阿戈美拉汀对mGluR5的选择性正常化增强了其作为重度抑郁症靶向治疗方法的潜力。

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引用次数: 0

Association between long-term stimulant treatment and the functional brain response to methylphenidate in adolescents and adults with attention-deficit/hyperactivity disorder 青少年和成人注意缺陷/多动障碍患者长期兴奋剂治疗与脑功能对哌甲酯的反应之间的关系

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-20 Epub Date: 2025-10-29 DOI: 10.1016/j.pnpbp.2025.111545

Zarah van der Pal , Liesbeth Reneman , Henk J.M.M. Mutsaerts , Antonia Kaiser , Marco A. Bottelier , Hilde M. Geurts , Anouk Schrantee

Background

Stimulant medication is commonly used by children and adolescents with attention-deficit/hyperactivity disorder (ADHD), however its long-lasting effects on the developing brain remain unclear. In a previous randomized controlled trial (RCT) we found that short-term stimulant treatment influences the functional brain response to an acute methylphenidate-challenge in an age-dependent manner, in line with animal studies suggesting persisting effects on brain development.

Methods

In this 4-year naturalistic follow-up of the initial RCT, we investigated the long-term age-dependent effects of stimulant treatment on the functional brain response to methylphenidate in male children and adults with ADHD (n = 56; adolescents aged 10–17 years, adults aged 23–43 years). At baseline and 4-year follow-up, we used pharmacological MRI to estimate relative cerebral blood flow (rCBF) before a single-dose methylphenidate-challenge (resting rCBF) and the rCBF-response to a single-dose methylphenidate-challenge. Linear mixed models were constructed to evaluate the effect of stimulant medication use, age and visit on resting rCBF and rCBF-response.

Results

We found no evidence for long-term age-dependent effects of stimulant treatment, suggesting that our previously identified short-term effects may be transient. We did identify age-dependent associations between rCBF-response in the medial prefrontal cortex and stimulant treatment, which were already present before treatment initiation but were unrelated to ADHD symptom severity. Moreover, rCBF-response was associated with dopamine D1 receptor distributions in adolescents only.

Conclusions

The identified age-dependent associations may potentially be mediated by changes in dopamine- and noradrenaline-related functioning, and may hold predictive value for extent of stimulant medication use after ADHD diagnosis in children and adolescents.

兴奋剂药物通常用于患有注意力缺陷/多动障碍（ADHD）的儿童和青少年，但其对发育中的大脑的长期影响尚不清楚。在之前的一项随机对照试验（RCT）中，我们发现短期兴奋剂治疗会以年龄依赖的方式影响大脑对急性哌甲酯攻击的功能性反应，这与动物研究表明对大脑发育的持续影响一致。方法在最初的随机对照试验的4年自然随访中，我们研究了兴奋剂治疗对ADHD男性儿童和成人对哌甲酯的功能性脑反应的长期年龄依赖性影响（n = 56； 10-17岁的青少年，23-43岁的成年人）。在基线和4年随访中，我们使用药理学MRI来评估单剂量哌甲酯刺激前的相对脑血流量（rCBF）（静息rCBF）和单剂量哌甲酯刺激后的rCBF反应。建立线性混合模型评价兴奋剂使用、年龄和就诊对静息rCBF和rCBF反应的影响。结果：我们没有发现兴奋剂治疗的长期年龄依赖效应的证据，这表明我们之前确定的短期效应可能是短暂的。我们确实确定了内侧前额叶皮层rcbf反应与兴奋剂治疗之间的年龄依赖性关联，这种关联在治疗开始前就已经存在，但与ADHD症状严重程度无关。此外，rcbf反应仅与青少年的多巴胺D1受体分布有关。结论所确定的年龄依赖性关联可能由多巴胺和去甲肾上腺素相关功能的变化介导，并可能对儿童和青少年ADHD诊断后兴奋剂药物使用程度具有预测价值。

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