Neurochemistry international最新文献_第10页

Acute ketamine enhances social behavior and dendritic plasticity in the amygdala by increasing BDNF, GAP43, and TRKB presence following excitotoxic neonatal ibotenic acid lesion 急性氯胺酮通过增加BDNF、GAP43和TRKB的存在，增强兴奋性新生儿伊博滕酸损伤后杏仁核的社交行为和树突可塑性。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-01 DOI: 10.1016/j.neuint.2025.106016

Nestor I. Martínez-Torres , Jhonathan Cárdenas-Bedoya , Blanca Miriam Torres-Mendoza

Schizophrenia is a highly disabling psychopathology that is a significant burden on public health systems and is characterized by both positive and negative symptoms. One of these negative symptoms is social isolation, which responds poorly to available treatments. Ketamine (KET) has been shown to enhance social behavior in various preclinical models, accompanied by neurobiological changes. In this study, we used a preclinical model of schizophrenia involving neonatal ventral hippocampal (NVHL) bilateral lesions induced by excitotoxicity with ibotenic acid (IA) at postnatal day 7 (PD). Thirty male Sprague-Dawley rats, aged 7 PD, were assigned to one of the following groups: Intact, Sham, Intact + KET, IA + Saline, and IA + KET, with n = 6 per group. Rats in the Sham, IA + Saline, and IA + KET groups underwent stereotaxic surgery and were administered with either 0.3 % saline or IA at 7 PD. At 35 PD, the rats received either saline or ketamine (15 mg/kg) and were assessed using the three-chamber social test. A Golgi-modified technique was then employed to evaluate neuronal changes in the amygdala with Sholl analysis. Also, immunohistochemistry was conducted to measure brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TRKB), and growth-associated protein 43 (GAP43). Acute KET treatment rescued social behavior, increased dendritic tree complexity, and elevated BDNF, TRKB, and GAP43 protein presence. Our results suggest that acute sub-anesthetic administration of KET may help alleviate social isolation symptoms. This dose could provide a window of opportunity to encourage individuals with schizophrenia to initiate and continue their treatment.

精神分裂症是一种高度致残的精神病理学，是公共卫生系统的重大负担，其特征是阳性和阴性症状。这些负面症状之一是社会孤立，对现有治疗效果不佳。氯胺酮（KET）已被证明在各种临床前模型中增强社会行为，并伴有神经生物学变化。在这项研究中，我们使用了一个临床前精神分裂症模型，该模型涉及出生后第7天（PD）由伊博tenic酸（IA）兴奋性毒性引起的新生儿腹侧海马（NVHL）双侧病变。30只雄性sd - dawley大鼠，年龄7 PD，随机分为：完整组、假手术组、完整+KET组、IA+生理盐水组和IA+KET组，每组n = 6。Sham， IA+Saline和IA+KET组的大鼠进行立体定向手术，并在7 PD时给予0.3%生理盐水或IA。在35 PD时，大鼠接受生理盐水或氯胺酮（15 mg/kg），并使用三室社会测试进行评估。然后采用高尔基改良技术与Sholl分析来评估杏仁核中的神经元变化。免疫组化检测脑源性神经营养因子（BDNF）、酪氨酸受体激酶B （TRKB）和生长相关蛋白43 （GAP43）。急性KET治疗挽救了社会行为，增加了树突树的复杂性，并提高了BDNF、TRKB和GAP43蛋白的存在。我们的研究结果表明，急性亚麻醉给药可以帮助减轻社会隔离症状。这个剂量可以提供一个机会窗口，鼓励精神分裂症患者开始并继续他们的治疗。

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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 : 2025-06-26 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 : 2025-06-20 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

Pathway-specific regulation of amphetamine-induced conditioned place preference by chemogenetic modulation of basolateral amygdala projections to prelimbic cortex and nucleus accumbens subregions 安非他明诱导的条件位置偏好的通路特异性调控：杏仁核基底外侧向前边缘皮层和伏隔核亚区投射的化学发生调节

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-18 DOI: 10.1016/j.neuint.2025.106012

Joonyeup Han , Haeun Rim , Hanbyual Jang , Wen Ting Cai , Wha Young Kim , Jeong-Hoon Kim

Individuals with substance use disorders develop maladaptive associative memories, linking environmental contexts with drug experiences. The basolateral amygdala (BLA), prelimbic cortex (PrL), and nucleus accumbens (NAc) are central components of the neural circuitry underlying these associations. However, it remains unclear how specific BLA outputs differentially regulate the expression of contextual drug memories. Using designer receptors exclusively activated by designer drugs, we selectively modulated neuronal activity with deschloroclozapine as the activating agent during the expression of amphetamine-induced conditioned place preference (CPP) in the BLA pathways to the PrL, NAc core, and NAc shell. Our findings revealed a dissociation between these pathways: the BLA-to-PrL circuit exerted bidirectional control over CPP expression, with inhibition significantly enhancing and activation attenuating drug-context associations. In contrast, BLA-to-NAc core manipulations selectively modulated locomotor aspects of conditioned responses without affecting place preference, while BLA-to-NAc shell manipulations produced no significant effects on CPP expression. These results demonstrate that the BLA has a distinctive pathway-specific roles in the expression of contextual drug memory.

有物质使用障碍的个体会发展出适应性不良的联想记忆，将环境背景与药物体验联系起来。基底外侧杏仁核（BLA）、前边缘皮层（PrL）和伏隔核（NAc）是这些关联背后的神经回路的核心组成部分。然而，目前尚不清楚具体的BLA输出如何不同地调节情境药物记忆的表达。利用特异性药物激活的特异性受体，我们选择性地以去氯氯氮平作为激活剂，调节了苯丙胺诱导的条件位置偏好（CPP）在通往PrL、NAc核心和NAc外壳的BLA通路中的表达过程。我们的研究结果揭示了这些途径之间的分离：BLA-to-PrL回路对CPP表达进行双向控制，抑制显著增强，激活减弱药物环境相关性。相比之下，BLA-to-NAc核心操作选择性地调节了条件反应的运动方面，而不影响位置偏好，而BLA-to-NAc壳操作对CPP表达没有显著影响。这些结果表明，BLA在情境药物记忆的表达中具有独特的通路特异性作用。

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引用次数: 0

Differential synaptic inhibition and serotonin 5-HT7 receptor-mediated modulation in identified dorsal horn neurons 鉴定的背角神经元的差异突触抑制和血清素5-HT7受体介导的调节

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-18 DOI: 10.1016/j.neuint.2025.106011

Chiara Salio , Francesco Ferrini , Andrea Bighinati , Enza Lacivita , Marcello Leopoldo , Rita Bardoni

Serotonergic modulation of pain transmission in the spinal cord involves the activation of multiple receptor types, including 5-HT₇ receptors. Activation of spinal 5-HT₇ receptors appears to have a predominant antinociceptive effect in various animal models. Although the serotonergic modulation of dorsal horn circuits has been extensively investigated, information about the specific effects of serotonergic receptors on identified neuron types remains limited. To address this, we have employed transgenic mice expressing channelrhodopsin-2 (ChR2) in inhibitory neurons, under the control of the vesicular GABA transporter (VGAT) promoter. Postsynaptic inhibitory responses (oIPSCs) induced by optogenetic stimulation of spinal cord slices displayed distinct properties in superficial dorsal horn VGAT+ and VGAT- neurons (inhibitory and putative excitatory neurons, respectively). While oIPSCs recorded from VGAT + neurons showed GABA- and glycine-mediated components of similar amplitudes, oIPSCs from VGAT- neurons were predominantly mediated by glycine. Consistently, immunofluorescence staining for the glycine transporter GlyT2 in mice expressing dTomato in GAD2 neurons revealed that GlyT2+ boutons primarily contact putative excitatory interneurons, which are negative for GAD2. Activation of 5-HT₇ receptors by the agonist LP-211 significantly enhanced both the frequency of spontaneous inhibitory currents and the amplitude of oIPSCs in VGAT- neurons. In minimal optical stimulation experiments, application of LP-211 reduced the number of synaptic failures and increased the quantal content of oIPSCs, indicating presynaptic modulation mediated by 5-HT₇ receptors. Our results suggest that enhanced synaptic inhibition of dorsal horn excitatory interneurons may contribute to the role of 5-HT₇ receptors in suppressing pain transmission at the spinal cord level.

脊髓疼痛传递的血清素调节涉及多种受体类型的激活，包括5-HT7受体。在各种动物模型中，脊髓5-HT7受体的激活似乎具有主要的抗伤害感受作用。尽管5 -羟色胺对背角回路的调节已被广泛研究，但关于5 -羟色胺受体对确定的神经元类型的具体影响的信息仍然有限。为了解决这个问题，我们在水泡GABA转运体（VGAT）启动子的控制下，在抑制性神经元中表达通道视紫红质-2 （ChR2）的转基因小鼠。光遗传刺激脊髓片诱导的突触后抑制反应（oIPSCs）在浅表背角VGAT+和VGAT-神经元（分别为抑制性神经元和推定的兴奋性神经元）中表现出不同的特性。虽然VGAT +神经元的oIPSCs显示GABA-和甘氨酸介导的成分具有相似的振幅，但VGAT-神经元的oIPSCs主要由甘氨酸介导。与此一致的是，在GAD2神经元中表达dTomato的小鼠中，对甘氨酸转运体GlyT2的免疫荧光染色显示，GlyT2+钮扣主要与假定的兴奋性中间神经元接触，这些神经元对GAD2是阴性的。通过激动剂LP-211激活5-HT7受体，VGAT-神经元中自发抑制电流的频率和oIPSCs的幅度均显著增加。在最小光刺激实验中，LP-211的应用减少了突触失败的数量，增加了oIPSCs的量子含量，表明5-HT7受体介导了突触前调节。我们的研究结果表明，背角兴奋性中间神经元突触抑制的增强可能有助于5-HT7受体在脊髓水平抑制疼痛传递的作用。

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引用次数: 0

Antinociceptive and anti-inflammatory effects of dihydroaustrasulfone alcohol in alleviating peripheral neuropathy via Nrf2/HO-1 pathway in rats 二氢奥斯柳酮醇通过Nrf2/HO-1通路减轻大鼠周围神经病变的抗伤性和抗炎作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-17 DOI: 10.1016/j.neuint.2025.106010

Chun-Sung Sung , Hao-Jung Cheng , San-Nan Yang , Pei-Jyuan Li , Shi-Ying Huang , Wu-Fu Chen , Nan-Fu Chen , Jui-Kang Tsai , Zhi-Hong Wen

Peripheral neuropathic pain is closely associated with neuroinflammation and oxidative stress accumulation in the spinal cord dorsal horn (SCDH), but effective treatments remain limited. Dihydroaustrasulfone alcohol (WA25), a synthetic precursor of austrasulfone obtained from a Formosan soft coral, has anti-inflammatory and antioxidant properties. However, its potential therapeutic effect on neuropathic pain is yet to be established. This study aimed to elucidate the cellular mechanisms responsible for therapeutic potential of WA25 in rats with neuropathic pain. Neuropathic pain was induced in rats via chronic constriction injury (CCI), and WA25 was intrathecally administered in these rats. To evaluate the analgesic effects of WA25 and the underlying cellular mechanisms, nociceptive behavior assessment and immunofluorescence staining, respectively, were employed. WA25 significantly alleviated CCI-induced nociceptive behavior, neuroinflammation, and oxidative stress accumulation. Further, WA25 enhanced the expression of astrocytic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the ipsilateral SCDH, suggesting its role in mitigating inflammation and oxidative stress. The co-administration of the HO-1 inhibitor ZnPP abolished the analgesic, anti-inflammatory, and antioxidant effects of WA25. The findings of the study suggest that WA25 effectively attenuates nociceptive sensitization, neuroinflammation, and oxidative stress accumulation in rats via the activation of the Nrf2/HO-1 signaling pathway, highlighting its potential as a therapeutic agent for neuropathic pain management.

周围神经性疼痛与脊髓背角（SCDH）的神经炎症和氧化应激积累密切相关，但有效的治疗方法仍然有限。摘要二氢奥氏磺胺醇（WA25）是从台湾软珊瑚中提取的奥氏磺胺的合成前体，具有抗炎和抗氧化的特性。然而，其对神经性疼痛的潜在治疗作用尚未确定。本研究旨在阐明WA25对神经性疼痛大鼠治疗潜力的细胞机制。通过慢性收缩损伤（CCI）诱导大鼠神经性疼痛，并在鞘内给予WA25。为了评估WA25的镇痛作用及其潜在的细胞机制，分别采用伤害性行为评估和免疫荧光染色。WA25显著减轻cci诱导的伤害性行为、神经炎症和氧化应激积累。此外，WA25增强了同侧SCDH中星形细胞核因子-红细胞2相关因子2 （Nrf2）和血红素加氧酶-1 （HO-1）的表达，提示其在减轻炎症和氧化应激中的作用。同时给药HO-1抑制剂ZnPP可消除WA25的镇痛、抗炎和抗氧化作用。研究结果表明，WA25通过激活Nrf2/HO-1信号通路，有效减轻大鼠的伤害性致敏、神经炎症和氧化应激积累，突出了其作为神经性疼痛治疗药物的潜力。

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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 : 2025-06-13 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。

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引用次数: 0

Epitranscriptomic shifts in M6A RNA methylation influencing transcriptional dynamics in the prefrontal cortex of chronic restraint stress rats 慢性限制性应激大鼠前额皮质M6A RNA甲基化的表观转录组改变影响转录动力学。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-13 DOI: 10.1016/j.neuint.2025.106008

Yu Funahashi , Bhaskar Roy , Kevin Prall , Yogesh Dwivedi

Chronic restraint stress (CRS) is a widely used model for investigating stress-induced molecular and neuronal changes. In this study, we examined transcriptome-wide m6A methylation in the prefrontal cortex of CRS rats to understand the molecular impact of stress. Elevated plasma corticosterone levels confirmed the physiological stress response in CRS rats. MeRIP-seq analysis identified 21,669 differentially methylated transcripts, with a predominant hypermethylation pattern (4,301 transcripts) compared to a smaller subset of hypomethylated transcripts (79). Chromosomal distribution revealed widespread hypermethylation across multiple chromosomes, with notable peaks on chromosomes 1, 3, and 10. Gene expression profiling indicated differential regulation of 1,424 genes, with 847 upregulated and 577 downregulated in CRS rats. Integration of m6A methylation and gene expression data revealed an inverse correlation, where hypermethylated transcripts were downregulated, suggesting a role for m6A in transcript stability and turnover. Functional analysis of hypermethylated transcripts highlighted enrichment in key neuronal processes, including synaptic plasticity, neurotransmitter signaling, and chromatin remodeling. Additionally, the 3′UTR of coding transcripts exhibited enriched m6A methylation marks, suggesting a regulatory role in mRNA stability and translation efficiency. RNA level expression analysis revealed significant downregulation of key m6A methylation-related enzymes (METTL3, METTL14, and ALKBH5), further supporting m6A dysregulation under CRS. Pathway analysis underscored the involvement of differentially methylated transcripts in RNA metabolism, chromatin remodeling, and neurobiological pathways linked to stress-related psychiatric disorders. Altogether, the study provides insight into the epitranscriptomic mechanisms underlying stress responses and their implications in neuropsychiatric disorders such as major depression.

慢性抑制应激（CRS）是一种广泛应用于研究应激诱导的分子和神经元变化的模型。在这项研究中，我们检测了CRS大鼠前额叶皮层转录组范围内的m6A甲基化，以了解应激的分子影响。血浆皮质酮水平升高证实了CRS大鼠的生理应激反应。MeRIP-seq分析确定了21,669个差异甲基化转录本，与较小的低甲基化转录本子集相比，主要是高甲基化模式（4301个转录本）。染色体分布显示，高甲基化在多条染色体上广泛存在，在染色体1、3和10上有显著的高峰。基因表达谱显示，CRS大鼠有1424个基因差异调控，其中847个基因上调，577个基因下调。整合m6A甲基化和基因表达数据显示出负相关，其中高甲基化转录本下调，表明m6A在转录本稳定性和周转中起作用。高甲基化转录本的功能分析强调了关键神经元过程中的富集，包括突触可塑性、神经递质信号传导和染色质重塑。此外，编码转录本的3'UTR表现出丰富的m6A甲基化标记，表明其在mRNA稳定性和翻译效率中具有调节作用。表达分析显示m6A关键甲基化相关酶（METTL3、METTL14和ALKBH5）显著下调，进一步支持CRS下m6A失调。通路分析强调了RNA代谢、染色质重塑和与压力相关精神疾病相关的神经生物学通路中差异甲基化转录物的参与。总之，该研究提供了应激反应的表转录组学机制及其在神经精神疾病（如重度抑郁症）中的意义。

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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 : 2025-06-11 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。

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Neurochemical in vivo microdialysis and postmortem tissue analysis of amygdala endocannabinoid levels after MAGL- and FAAH-inhibition in rodents MAGL-和faah抑制后啮齿动物杏仁核内源性大麻素水平的神经化学体内微透析和死后组织分析。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-08 DOI: 10.1016/j.neuint.2025.106006

Mariette S. Heins , Marc D. Ferger , Patrizia Voehringer , Thomas I.F.H. Cremers , Boris Ferger

This study is the first to investigate the target modulation of the MAGL inhibitor elcubragistat (ABX-1431; Lu-AG06466) and the FAAH inhibitor JNJ-42165279 in the amygdala, a brain region involved in stress-induced psychiatric disorders.

We aimed to assess dynamic changes in the endocannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide (AEA) following pharmacological inhibition of MAGL and FAAH, enzymes regulating their metabolism.

Freely moving rats received oral doses of elcubragistat or JNJ-42165279. Microdialysis probes in the basolateral amygdala and nucleus accumbens measured extracellular 2-AG and AEA levels over 240 min using LC-MS/MS. A supplementary mouse study analyzed postmortem endocannabinoid levels in the basolateral amygdala.

MAGL inhibition by elcubragistat selectively increased extracellular and tissue 2-AG levels in the basolateral amygdala in a dose-related manner without affecting AEA. Conversely, FAAH inhibition by JNJ-42165279 selectively elevated AEA levels without altering 2-AG. Highest endocannabinoid concentration in basolateral amygdala tissue was between 2 and 4 h after MAGL or FAAH inhibition.

In vivo microdialysis is a sensitive method to study target modulation of both MAGL and FAAH inhibitors in the amygdala of freely moving rats. The results of the microdialysis study are in general agreement with postmortem tissue analysis of both 2-AG and AEA and suitable to support the preclinical drug discovery process in concert with disease related animal models.

这项研究首次研究了MAGL抑制剂elcubragistat (ABX-1431；lug - ag06466)和FAAH抑制剂JNJ-42165279在杏仁核中的作用，杏仁核是一个涉及应激性精神疾病的大脑区域。我们旨在评估内源性大麻素配体2-花生四烯醇甘油（2-AG）和anandamide （AEA）在药物抑制MAGL和FAAH（调节其代谢的酶）后的动态变化。自由活动的大鼠口服elcubragistat或JNJ-42165279。基底外侧杏仁核和伏隔核的微透析探针在240分钟内使用LC-MS/MS测量细胞外2-AG和AEA水平。一项补充小鼠研究分析了死后杏仁核基底外侧的内源性大麻素水平。elcubragistat对MAGL的抑制作用以剂量相关的方式选择性地增加了杏仁核基底外侧细胞外和组织2-AG水平，而不影响AEA。相反，JNJ-42165279抑制FAAH选择性地提高了AEA水平，而不改变2-AG。在MAGL或FAAH抑制后2 - 4小时内，杏仁核基底外侧组织内源性大麻素浓度最高。体内微透析是一种灵敏的方法来研究MAGL和FAAH抑制剂在自由运动大鼠杏仁核中的靶调节。微透析研究的结果与2-AG和AEA的死后组织分析基本一致，适合支持与疾病相关动物模型一致的临床前药物发现过程。

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