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The neuropharmacology of kratom, a novel psychoactive natural product 一种新型精神活性天然产物——克拉托姆的神经药理学。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111215
MeShell Green , Charles A. Veltri , Walter C. Prozialeck , Oliver Grundmann
Kratom (Mitragyna speciosa, Korth.) is a tropical tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Over the past 15–20 years, kratom use has spread to Western nations including the United States, where many individuals are using kratom products for the self-management of pain, opioid use disorder, anxiety and depression. The increased use of kratom has triggered a surge in research into the biochemistry, pharmacology and behavioral effects of kratom and its active constituents, especially mitragynine and 7-hydroxymitragynine. In this review, we highlight some of the recent animal studies showing that kratom and its constituent compounds have potential beneficial effects in animal models of pain, anxiety, depression and opioid dependence. We also highlight studies showing that kratom can modulate the functioning of opioid, noradrenergic, serotonergic and dopaminergic systems. The highlighted studies strongly suggest that kratom and its constituents may form the basis for the development of novel therapeutic agents.
Kratom (Mitragyna speciosa, north .)是一种原产于东南亚的热带树木。据报道,当摄入时,苦参叶或苦参叶的煎剂会产生复杂的兴奋剂和阿片样物质。几代人以来,东南亚的土著居民一直使用kratom产品来缓解疲劳、改善情绪、缓解疼痛和控制阿片类药物戒断症状。在过去的15-20 年里,kratom的使用已经蔓延到包括美国在内的西方国家,在那里,许多人使用kratom产品来自我管理疼痛、阿片类药物使用障碍、焦虑和抑郁。kratom使用量的增加引发了对kratom及其活性成分的生物化学、药理学和行为影响的研究激增,特别是米特拉金和7-羟基米特拉金。在这篇综述中,我们重点介绍了最近的一些动物研究,这些研究表明克拉通及其成分化合物对疼痛、焦虑、抑郁和阿片类药物依赖的动物模型有潜在的有益作用。我们还强调研究表明,克拉通可以调节阿片,去甲肾上腺素能,血清素能和多巴胺能系统的功能。突出的研究强烈表明,克拉托姆及其成分可能成为开发新型治疗剂的基础。
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引用次数: 0
A two-sample study on the relationship between polygenic risk score of serotonergic polymorphisms and social phobia: Interpersonal adaptability as a mediator 血清素能多态性多基因风险评分与社交恐惧症关系的双样本研究:人际适应的中介作用。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111220
Yuting Yang , Qi Lan , Wenting Liang , Mingzhu Zhou , Wenping Zhao , Pingyuan Gong

Backgrounds

The influence of serotonin function on social phobia has been well-documented, yet the polygenic risk score of serotonergic polymorphisms for social phobia remains unclear.

Methods

We assessed two aspects of social phobia (i.e., social interaction anxiety and social phobia scrutiny fear) and created a polygenic risk score of seven serotonergic polymorphisms in two independent samples.

Results

The results from both samples indicated that a greater polygenic risk score, denoting a higher risk of anxiety, was associated with higher levels of social interaction anxiety and social phobia scrutinizing fear. Interestingly, the association between polygenic risk score and social interaction anxiety was mediated by interpersonal adaptability.

Conclusion

These findings demonstrate the importance of serotonergic polymorphisms in social phobia and unveil a psychological pathway whereby interpersonal adaptability mediates the effect of serotonergic polymorphisms on social phobia.
背景:血清素功能对社交恐惧症的影响已得到充分证实,但血清素能多态性对社交恐惧症的多基因风险评分仍不清楚:方法:我们评估了社交恐惧症的两个方面(即社交互动焦虑和社交恐惧症审视恐惧),并在两个独立样本中建立了七个血清素能多态性的多基因风险评分:结果:两个样本的结果表明,多基因风险得分越高,表示焦虑风险越高,则社交互动焦虑和社交恐惧症的程度越高。有趣的是,多基因风险得分与社交互动焦虑之间的关联是由人际适应性介导的:这些研究结果证明了血清素能多态性在社交恐惧症中的重要性,并揭示了人际适应性介导血清素能多态性对社交恐惧症影响的心理途径。
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引用次数: 0
Prenatal exposure to valproic acid induces sex-specific alterations in rat cortical and hippocampal neuronal structure and function in vitro 产前暴露于丙戊酸诱导大鼠皮质和海马神经元结构和功能的性别特异性改变。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111222
Olivia O.F. Williams , Madeleine Coppolino , Cecilia B. Micelli , Ryan T. McCallum , Paula T. Henry-Duru , Joshua D. Manduca , Jasmin Lalonde , Melissa L. Perreault
There are substantial differences in the characteristics of males and females with an autism spectrum disorder (ASD), yet there is little knowledge surrounding the mechanistic underpinnings of these differences. The valproic acid (VPA) rodent model is based upon the human fetal valproate spectrum disorder, which is associated with increased risk of developing ASD. This model, which displays significant social, learning, and memory alterations, has therefore been widely used to further our understanding of specific biological features of ASD. However, to date, almost all of the studies employing this model have used male rodents. To fill this knowledge gap, we evaluated sex differences for neuronal activity, morphology, and glycogen synthase kinase-3 (GSK-3) signaling in primary cortical (CTX) and hippocampal (HIP) neurons prepared from rats exposed to VPA in utero. In vivo, sex-specific VPA-induced alterations in the frontal CTX transcriptome at birth were also determined. Overall, VPA induced more robust changes in neuronal function and structure in the CTX than in the HIP. Male- and female-derived primary CTX neurons from rats exposed to prenatal VPA had elevated activity and showed more disorganized firing. In the HIP, only the female VPA neurons showed elevated firing, while the male VPA neurons exhibited disorganized activity. Dendritic arborization of CTX neurons from VPA rats was less complex in both sexes, though this was more pronounced in the females. Conversely, both female and male HIP neurons from VPA rats showed elevated complexity distal to the soma. Female VPA CTX neurons also had an elevated number of dendritic spines. The relative activity of the α and β isoforms of GSK-3 were suppressed in both female and male VPA CTX neurons, with no changes in the HIP neurons. On postnatal day 0, alterations in CTX genes associated with neuropeptides (e.g., penk, pdyn) and receptors (e.g., drd1, adora2a) were seen in both sexes, though they were downregulated in females and upregulated in males. Together these findings suggest that substantial sex differences in neuronal structure and function in the VPA model may have relevance to the reported sex differences in idiopathic ASD.
患有自闭症谱系障碍(ASD)的男性和女性在特征上有很大的差异,但对这些差异的机制基础知之甚少。丙戊酸(VPA)啮齿动物模型是基于人类胎儿丙戊酸谱系障碍,这与发展为ASD的风险增加有关。该模型显示了显著的社交、学习和记忆改变,因此被广泛用于进一步了解ASD的特定生物学特征。然而,到目前为止,几乎所有采用这种模型的研究都使用了雄性啮齿动物。为了填补这一知识空白,我们评估了在子宫内暴露于VPA的大鼠制备的初级皮质(CTX)和海马(HIP)神经元中神经元活性、形态和糖原合成酶激酶3 (GSK-3)信号传导的性别差异。在体内,还确定了出生时vpa诱导的额叶CTX转录组的性别特异性改变。总的来说,VPA在CTX中诱导的神经元功能和结构的变化比在HIP中更强大。暴露于产前VPA的大鼠的雄性和雌性原始CTX神经元活性升高,表现出更多的无组织放电。在HIP中,只有雌性VPA神经元表现出升高的放电,而雄性VPA神经元表现出紊乱的活动。VPA大鼠CTX神经元的树突树突化在两性中都不那么复杂,尽管这在雌性中更为明显。相反,雌性和雄性VPA大鼠的HIP神经元在远端胞体处都表现出更高的复杂性。雌性VPA CTX神经元的树突棘数量也有所增加。GSK-3 α和β亚型的相对活性在雌性和雄性VPA CTX神经元中均受到抑制,而在HIP神经元中无变化。在出生后第0天,与神经肽(例如,penk, pdyn)和受体(例如,drd1, adora2a)相关的CTX基因在两性中都发生了变化,尽管它们在雌性中下调,在雄性中上调。总之,这些发现表明,VPA模型中神经元结构和功能的实质性性别差异可能与报道的特发性ASD的性别差异有关。
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引用次数: 0
Multi-omics data integration reveals novel genes related to autoimmune hypothyroidism in the brain: A molecular basis for the brain–thyroid axis 多组学数据整合揭示了大脑中与自身免疫性甲状腺功能减退症有关的新基因:脑-甲状腺轴的分子基础
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111239
Hong Yu , Zuoxi Li , Xiao Gao , Xuehuan Liu , Weiwei Cui , Ningjun Li , Xinying Lian , Can Li , Jun Liu

Background

The mechanisms underlying the complex relationship between autoimmune hypothyroidism and neurological disorders remain unclear. We conducted a comprehensive analysis of associations between alternative splicing, transcriptomics, and proteomics data and autoimmune hypothyroidism.

Methods

Splicing-wide association studies (SWAS), proteome-wide association studies (PWAS), and transcriptome-wide association studies (TWAS) were used to identify genes and proteins that regulate autoimmune hypothyroidism within the brain axis. We performed TWAS on GTEx V8 thyroid tissue data to identify autoimmune hypothyroidism-associated thyroid axis genes. A FUSION analysis of overlapping genes in the brain and thyroid axes and brain splicing weights was conducted to determine the influence of alternative splicing in the brain on thyroid tissue gene expression.

Results

SWAS identified 223 alternative splicing events, TWAS identified 270 genes, and PWAS revealed five genes (FDPS, PPIL3, PEX6, MMAB, and ALDH2) encoding proteins associated with autoimmune hypothyroidism. Neuroimaging analyses revealed distinct brain-imaging phenotypes associated with these five genes. TWAS of thyroid tissue identified four genes (FDPS, PPIL3, MMAB, and ALDH2) associated with the brain axis related to thyroid tissue. A FUSION analysis indicated that alternative splicing changes in ALDH2 in brain tissue influenced its expression in thyroid tissue.

Conclusion

Integrating brain splicing, proteomic, and transcriptomic data supports the association between specific genes and proteins in the brain and autoimmune hypothyroidism. Additionally, ALDH2 alternative splicing in brain tissue influences its thyroid tissue expression. These findings provide new insights into the molecular basis of autoimmune hypothyroidism, facilitating future pathogenesis research.
背景:自身免疫性甲状腺功能减退与神经系统疾病之间复杂关系的机制尚不清楚。我们对选择性剪接、转录组学和蛋白质组学数据与自身免疫性甲状腺功能减退症之间的关联进行了全面分析。方法:采用剪接全关联研究(SWAS)、蛋白质组全关联研究(PWAS)和转录组全关联研究(TWAS)来鉴定脑轴内调节自身免疫性甲状腺功能减退症的基因和蛋白质。我们对GTEx V8甲状腺组织数据进行TWAS,以鉴定自身免疫性甲状腺功能减退相关的甲状腺轴基因。我们对脑和甲状腺轴的重叠基因和脑剪接权重进行了融合分析,以确定脑选择性剪接对甲状腺组织基因表达的影响。结果:SWAS鉴定了223个备选剪接事件,TWAS鉴定了270个基因,PWAS发现了5个基因(FDPS、PPIL3、PEX6、MMAB和ALDH2)编码与自身免疫性甲状腺功能减退症相关的蛋白。神经影像学分析揭示了与这五个基因相关的不同的脑成像表型。甲状腺组织TWAS鉴定出与甲状腺组织相关的脑轴相关的4个基因(FDPS、PPIL3、MMAB和ALDH2)。一项FUSION分析表明,脑组织中ALDH2的选择性剪接变化影响其在甲状腺组织中的表达。结论:整合脑剪接、蛋白质组学和转录组学数据支持脑中特定基因和蛋白质与自身免疫性甲状腺功能减退症之间的关联。此外,ALDH2在脑组织中的选择性剪接影响其在甲状腺组织中的表达。这些发现为自身免疫性甲状腺功能减退症的分子基础提供了新的见解,为未来的发病机制研究提供了便利。
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引用次数: 0
Structural alterations of thalamic nuclei and their associations with leptin levels in patients with anorexia nervosa 神经性厌食症患者丘脑核的结构改变及其与瘦素水平的关系。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2025.111248
Marie-Louis Wronski , Franziska Gronow , John Schlömer , Fabio Bernardoni , Daniel Geisler , Arne Doose , Dominic Arold , Nadine Schwanke , Franziska Ludwicki , Veit Roessner , Joseph A. King , Stefan Ehrlich

Background

The thalamus is a complex subcortical brain structure that plays a role in various cognitive functions. Few studies have focused on thalamic nuclei-specific alterations and potential neurohormonal involvement in eating disorders including anorexia nervosa (AN).

Methods

We employed a FreeSurfer segmentation tool to compare thalamic nuclei volumes cross-sectionally between females with AN (n = 131, 12–29 years) and age-matched healthy females (HC, n = 131). Potential associations with BMI, leptin, and psychiatric symptoms were analyzed via robust linear regression.

Results

Most thalamic nuclei volumes were reduced in both hemispheres in AN versus HC. The spread of alterations ranged between −39.7 % and +3.8 % (average −9.8 %, ηp2 = 0.16). Left laterodorsal and pulvinar inferior nuclei showed positive associations with leptin in AN. Leptin mediated the effect of BMI on both thalamic nuclei volumes.

Conclusions

In AN, thalamic nuclei are altered to different degrees with laterodorsal nuclei emerging as substantially reduced. Leptin seems to be mechanistically involved in the reduction of some thalamic nuclei, further supporting the investigation of experimental leptin treatment for AN. Effect sizes observed for thalamic nuclei reductions in AN exceed other brain structures as well as other psychiatric disorders, which demonstrates the importance of the thalamus as a target structure in research on AN.
背景:丘脑是一个复杂的大脑皮层下结构,在多种认知功能中发挥作用。很少有研究关注丘脑核特异性改变和潜在的神经激素参与饮食失调,包括神经性厌食症(AN)。方法:我们采用FreeSurfer分割工具对AN女性(n = 131, 12-29岁)和年龄匹配的健康女性(n = 131)的丘脑核体积进行横断面比较。通过稳健线性回归分析BMI、瘦素和精神症状的潜在关联。结果:与HC相比,AN在两个半球的大部分丘脑核体积减小。变异的范围为- 39.7% ~ + 3.8%(平均- 9.8%,ηp2 = 0.16)。在AN中,左鼻外侧核和枕下核与瘦素呈正相关。瘦素介导BMI对丘脑核体积的影响。结论:在AN中,丘脑核有不同程度的改变,外侧核明显减少。瘦素似乎在机制上参与了一些丘脑核的减少,进一步支持实验性瘦素治疗AN的研究。在AN中观察到的丘脑核减少的效应大小超过了其他脑结构以及其他精神疾病,这表明丘脑作为AN研究的目标结构的重要性。
{"title":"Structural alterations of thalamic nuclei and their associations with leptin levels in patients with anorexia nervosa","authors":"Marie-Louis Wronski ,&nbsp;Franziska Gronow ,&nbsp;John Schlömer ,&nbsp;Fabio Bernardoni ,&nbsp;Daniel Geisler ,&nbsp;Arne Doose ,&nbsp;Dominic Arold ,&nbsp;Nadine Schwanke ,&nbsp;Franziska Ludwicki ,&nbsp;Veit Roessner ,&nbsp;Joseph A. King ,&nbsp;Stefan Ehrlich","doi":"10.1016/j.pnpbp.2025.111248","DOIUrl":"10.1016/j.pnpbp.2025.111248","url":null,"abstract":"<div><h3>Background</h3><div>The thalamus is a complex subcortical brain structure that plays a role in various cognitive functions. Few studies have focused on thalamic nuclei-specific alterations and potential neurohormonal involvement in eating disorders including anorexia nervosa (AN).</div></div><div><h3>Methods</h3><div>We employed a FreeSurfer segmentation tool to compare thalamic nuclei volumes cross-sectionally between females with AN (<em>n</em> = 131, 12–29 years) and age-matched healthy females (HC, n = 131). Potential associations with BMI, leptin, and psychiatric symptoms were analyzed via robust linear regression.</div></div><div><h3>Results</h3><div>Most thalamic nuclei volumes were reduced in both hemispheres in AN versus HC. The spread of alterations ranged between −39.7 % and +3.8 % (average −9.8 %, η<sub>p</sub><sup>2</sup> = 0.16). Left laterodorsal and pulvinar inferior nuclei showed positive associations with leptin in AN. Leptin mediated the effect of BMI on both thalamic nuclei volumes.</div></div><div><h3>Conclusions</h3><div>In AN, thalamic nuclei are altered to different degrees with laterodorsal nuclei emerging as substantially reduced. Leptin seems to be mechanistically involved in the reduction of some thalamic nuclei, further supporting the investigation of experimental leptin treatment for AN. Effect sizes observed for thalamic nuclei reductions in AN exceed other brain structures as well as other psychiatric disorders, which demonstrates the importance of the thalamus as a target structure in research on AN.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"136 ","pages":"Article 111248"},"PeriodicalIF":5.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Measuring the effects of ketogenic diet on neuropsychiatric disorder: A scoping review – Letter to the Editor 测量生酮饮食对神经精神障碍的影响:范围审查-致编辑的信。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111246
Agnieszka Mechlińska, Adam Włodarczyk
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引用次数: 0
The parasubthalamic nucleus: A novel eating center in the brain 下丘脑旁核:大脑中一个新的进食中心。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2025.111250
Mingxuan Lu , Jiayao Zhang , Qi Zhang , Jiyu Sun , Danni Zou , Jinyin Huang , Weicai Liu
Eating behavior stands as a fundamental determinant of animal survival and growth, intricately regulated by an amalgamation of internal and external stimuli. Coordinated movements of facial muscles and the mandible orchestrate prey capture and food processing, propelled by the allure of taste and rewarding food properties. Conversely, satiation, pain, aversion, negative emotion or perceived threats can precipitate the cessation or avoidance of eating activities. In recent years, the parasubthalamic nucleus (PSTN), located in the lateral hypothalamic area, has emerged as a focal point in feeding research. PSTN neurons assume pivotal roles within multiple feeding circuits, bridging central feeding centers with peripheral organs. They intricately modulate regulation of oral sensorimotor functions, hedonic feeding, appetite motivation and the processing of satiation and aversive signals, thereby orchestrating the initiation or termination of feeding behaviors. This review delves into the distinctive neuronal subpopulations within the PSTN and their associated neural networks, aiming to refine our comprehension of the neural underpinnings of feeding while also seeking to unearth more efficacious therapeutic avenues for feeding and eating disorders.
进食行为是动物生存和生长的基本决定因素,受到内外刺激的复杂调节。面部肌肉和下颌骨的协调运动协调着猎物的捕捉和食物的加工,受到味道和食物特性的诱惑。相反,饱腹、痛苦、厌恶、负面情绪或感知到的威胁会促使停止或避免饮食活动。近年来,位于下丘脑外侧区的副丘脑核(PSTN)已成为进食研究的热点。PSTN神经元在多个摄食回路中扮演关键角色,将中央摄食中心与周围器官连接起来。它们复杂地调节着口腔感觉运动功能、享乐性进食、食欲动机以及饱足和厌恶信号的处理,从而协调进食行为的开始或结束。这篇综述深入研究了PSTN中独特的神经元亚群及其相关的神经网络,旨在完善我们对进食的神经基础的理解,同时也寻求发掘更有效的治疗进食障碍的途径。
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引用次数: 0
Long-term effects of antipsychotics on serum BDNF levels in patients with schizophrenia 抗精神病药物对精神分裂症患者血清BDNF水平的长期影响
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111240
F.L. Mikulic , M. Sagud , M. Nikolac Perkovic , S. Kudlek Mikulic , L. Ganoci , M. Bajs Janovic , S. Janovic , I. Filipcic Simunovic , A. Mihaljevic Peles , M. Bozicevic , Z. Bradas , N. Pivac
Brain-derived neurotrophic factor (BDNF) is implicated in the etiology of schizophrenia, and peripheral BDNF levels are affected by the short-term antipsychotic treatment. However, the data on their long-term effects on BDNF levels are scarce, and there is no information whether BDNF levels change during sustained remission in relation to values in healthy individuals. The aim of the present study was to compare serum BDNF levels in patients in long-term remission and healthy controls.
This study is an extension of our previous research on the effects of olanzapine and risperidone on serum BDNF in acute-episode patients with schizophrenia. Patients who remained in remission for at least 3 years on the same antipsychotic regimen (40 % of the initial cohort) were included. Symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured by ELISA in patients in remission (N = 20), evaluated at baseline, after 6 weeks of treatment and after 3 years of treatment, and in healthy individuals (N = 40).
At baseline (p = 0.046) and after 6 weeks of treatment (p = 0.028), patients had significantly lower BDNF levels than controls. However, after 3 years of continuous antipsychotic maintenance treatment, serum BDNF levels were increased compared to baseline and values after 6 weeks of treatment in remitted patients, and were also significantly higher in patients than in healthy controls (p = 0.002).
Antipsychotic medications appear to have distinct effects on serum BDNF levels in short-and long-term treatment. It remains to be determined if such finding may be related to potential neuroprotective effects of antipsychotic maintenance treatment.
脑源性神经营养因子(BDNF)与精神分裂症的病因有关,外周BDNF水平受短期抗精神病药物治疗的影响。然而,关于它们对BDNF水平的长期影响的数据很少,并且没有关于健康个体的BDNF水平在持续缓解期间是否发生变化的信息。本研究的目的是比较长期缓解患者和健康对照组的血清BDNF水平。本研究是我们之前关于奥氮平和利培酮对急性发作精神分裂症患者血清BDNF影响的研究的延伸。在相同的抗精神病治疗方案下,缓解期至少3 年的患者(占初始队列的40% %)被纳入研究。采用阳性和阴性症状量表(PANSS)评估症状。通过ELISA测定缓解期患者(N = 20)的血清BDNF水平,并在基线、治疗6 周和治疗3 年后以及健康个体(N = 40)进行评估。在基线时(p = 0.046)和治疗6 周后(p = 0.028),患者的BDNF水平显著低于对照组。然而,经过3 年的持续抗精神病维持治疗后,缓解患者的血清BDNF水平与基线和治疗6 周后的值相比有所增加,并且患者的血清BDNF水平也显著高于健康对照组(p = 0.002)。在短期和长期治疗中,抗精神病药物似乎对血清BDNF水平有不同的影响。这一发现是否与抗精神病药物维持治疗的潜在神经保护作用有关仍有待确定。
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引用次数: 0
Arketamine alleviates cognitive impairments and demyelination in mice with postoperative cognitive dysfunction via TGF-β1 activation 阿克他命通过TGF-β1激活减轻术后认知功能障碍小鼠的认知障碍和脱髓鞘。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.pnpbp.2024.111228
Ting-Ting Zhu , Ming-Ming Zhao , Dan Xu , Yi Cai , Guilin Liu , Rumi Murayama , Yong Yue , Jian-Jun Yang , Kenji Hashimoto
Postoperative cognitive dysfunction (POCD) is characterized by a decline in cognitive functions, including memory, attention, and executive abilities, following surgery, with no effective therapeutic drugs currently available. Arketamine, the (R)-enantiomer of ketamine, has shown promise in mitigating cognitive deficits in animal models. In this study, we investigated whether arketamine could ameliorate cognitive deficits in a mouse model of POCD, with a focus on the role of transforming growth factor (TGF)-β1 in its effects. POCD mice displayed cognitive impairments and demyelination in the corpus callosum. A single arketamine injection (10 mg/kg) significantly improved both cognitive function and demyelination in the corpus callosum of POCD mice. Notably, pretreatment with RepSox (10 mg/kg), a TGF-β receptor 1 inhibitor, significantly blocked the beneficial effects of arketamine on cognitive deficits and demyelination. Moreover, intranasal administration of TGF-β1 (3.0 μg/kg) markedly alleviated cognitive impairments and demyelination in POCD mice. These findings suggest that arketamine exerts its effects through a TGF-β1-dependent mechanism, positioning it as a potential therapeutic option for POCD.
术后认知功能障碍(POCD)的特点是手术后认知功能下降,包括记忆、注意力和执行能力,目前没有有效的治疗药物。阿克他命,氯胺酮的(R)-对映体,在动物模型中显示出减轻认知缺陷的希望。在本研究中,我们研究了阿克他明是否可以改善POCD小鼠模型的认知缺陷,重点研究了转化生长因子(TGF)-β1在其作用中的作用。POCD小鼠表现出认知障碍和胼胝体脱髓鞘。单次阿氯胺酮注射(10 mg/kg)可显著改善POCD小鼠的认知功能和胼胝体脱髓鞘。值得注意的是,TGF-β受体1抑制剂RepSox(10 mg/kg)预处理可显著阻断阿氯胺酮对认知缺陷和脱髓鞘的有益作用。此外,经鼻给药TGF-β1(3.0 μg/kg)可显著减轻POCD小鼠的认知障碍和脱髓鞘。这些发现表明,阿克他命通过TGF-β1依赖机制发挥其作用,将其定位为POCD的潜在治疗选择。
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引用次数: 0
Effects of 3,4-methylenedioxymethamphetamine on the gut microbiota and metabolites in the small intestine, cecum, and colon of male rats. 3,4-亚甲基二氧基甲基苯丙胺对雄性大鼠小肠、盲肠和结肠肠道微生物群和代谢物的影响。
IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 Epub Date: 2024-12-17 DOI: 10.1016/j.pnpbp.2024.111223
Dan Xu, Akifumi Eguchi, Rumi Murayama, Guilin Liu, Mingming Zhao, Tingting Zhu, Yi Cai, Yong Yue, Xiayun Wan, Yuko Fujita, Chisato Mori, Kenji Hashimoto

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a widely abused recreational drug that has also gained interest for potential clinical applications in mental health. With the growing recognition of gut microbiota's role in mental health, this study examined whether repeated oral MDMA administration could affect gut microbiota in the small intestine, cecum, and colon of male rats. Repeated oral MDMA administration (10 mg/kg/day for 14 days) caused significant changes in the gut microbiota across these regions, with distinct effects observed in each. PICRUSt2 analysis revealed significant alterations in several metabolic pathways in these regions, indicating potential shifts in microbial functional capabilities associated with MDMA treatment. Untargeted metabolomics analysis revealed that MDMA significantly altered levels of two metabolites-ferulic acid and methylmalonic acid-in the colon, without changes in the blood, small intestine, or cecum. Notably, methylmalonic acid levels in the colon positively correlated with Lawsonibacter and Oscillibacter. These findings suggest that repeated oral MDMA treatment can alter gut microbiota composition across intestinal regions, potentially contributing to its pharmacological effects.

3, 4-Methylenedioxymethamphetamine (MDMA;摇头丸(Ecstasy)是一种被广泛滥用的娱乐性药物,在心理健康方面的潜在临床应用也引起了人们的兴趣。随着人们越来越认识到肠道微生物群在心理健康中的作用,本研究考察了反复口服MDMA是否会影响雄性大鼠小肠、盲肠和结肠中的肠道微生物群。重复口服MDMA (10 mg/kg/天,连续14天)引起这些区域肠道微生物群的显著变化,在每个区域观察到不同的效果。PICRUSt2分析揭示了这些区域几种代谢途径的显著改变,表明与MDMA治疗相关的微生物功能能力的潜在变化。非靶向代谢组学分析显示,MDMA显著改变了结肠中两种代谢物——阿魏酸和甲基丙二酸的水平,而在血液、小肠或盲肠中没有变化。值得注意的是,结肠中的甲基丙二酸水平与Lawsonibacter和Oscillibacter呈正相关。这些发现表明,重复口服MDMA治疗可以改变肠道区域的肠道微生物群组成,可能有助于其药理作用。
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Progress in Neuro-Psychopharmacology & Biological Psychiatry
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