Neuroscience Letters最新文献_第3页

Electroacupuncture at GV20 and GV24 acupoints ameliorates migraine by blocking NLRP3-mediated pyroptosis via inhibiting the Piezo1 channel 电针GV20和GV24穴位通过抑制Piezo1通道阻断nlrp3介导的热凋亡来改善偏头痛。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-06 DOI: 10.1016/j.neulet.2026.138505

Jianchang Luo , Liyao Feng , Wenbin Xu, Jiawang Lang, Luodan Wang, Zhipeng Zhao, Boxu Lang

Migraine is a complex neuro-glio-vascular disorder, and electroacupuncture (EA) have been recommended as an alternative therapy for migraine. However, the mechanism of action of EA on GV20 (Baihui) and GV24 (Shenting) acupoints in treating migraine remains unclear. Thus, this study was performed to explore the potential mechanisms underlying the therapeutic influence of EA stimulation at GV20 and GV24 acupoints in the migraine treatment. After therapeutic effects of EA stimulation at GV20 and GV24 acupoints on migraine rat model established by dural electrical stimuli (DES) stimulation exploration, numerous approaches, such as qRT-PCR, immunofluorescence, and western blot, were applied to assess the expression of Piezo1 and pyroptosis-related proteins. Finally, Piezo1 activator (Yoda1) was used to confirm the involvement of Piezo1 channel in the treatment actions of EA stimulation at GV20 and GV24 acupoints on migraine. The results showed that EA stimulation at GV20 and GV24 acupoints forcefully alleviated the mechanical allodynia and central sensitization in rat model of migraine, also downregulated the expression of pro-inflammatory cytokines, containing TNF-α, IL-6, and IL-1β. In addition, EA stimulation at GV20 and GV24 acupoints also changed the expression of Piezo1 and pyroptosis-related proteins in rat model of migraine. Interestingly, treatment with the Yoda1 could reverse the therapeutic influences of EA stimulation at GV20 and GV24 acupoints in migraine rat model. Of note, the effect of EA stimulation at GV20 and GV24 acupoints on the expression of pyroptosis-related proteins could also be reverse by Yoda1 administration. This study emphasizes the EA efficacy at GV20 and GV24 acupoints on the migraine rat model established by DES stimulation, and proposes a mechanism involving inhibition of Piezo1 channel to block NLRP3-mediated pyroptosis in migraine.

偏头痛是一种复杂的神经-胶质-血管疾病，电针（EA）已被推荐作为偏头痛的替代疗法。然而，EA对GV20（百会）和GV24（神庭）穴治疗偏头痛的作用机制尚不清楚。因此，本研究旨在探讨EA刺激GV20和GV24穴位治疗偏头痛的潜在机制。通过硬脑膜电刺激（DES）探索建立偏头痛大鼠模型，观察EA刺激GV20和GV24穴位的治疗效果，采用qRT-PCR、免疫荧光、western blot等多种方法评估Piezo1和热休克相关蛋白的表达。最后，利用Piezo1激活剂（Yoda1）证实Piezo1通道参与EA刺激GV20和GV24穴位对偏头痛的治疗作用。结果表明，EA刺激GV20和GV24穴位可有效缓解大鼠偏头痛模型的机械异常性痛和中枢致敏，并下调促炎因子TNF-α、IL-6和IL-1β的表达。此外，EA刺激GV20和GV24穴位也改变了偏头痛大鼠模型中Piezo1和焦热相关蛋白的表达。有趣的是，Yoda1可以逆转EA刺激偏头痛大鼠GV20和GV24穴位的治疗作用。值得注意的是，EA刺激GV20和GV24穴位对焦解热相关蛋白表达的影响也可以被Yoda1逆转。本研究强调了EA作用于GV20和GV24穴位对DES刺激所致偏头痛大鼠模型的影响，并提出了通过抑制Piezo1通道阻断nlrp3介导的偏头痛热凋亡的机制。

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引用次数: 0

The role of childhood trauma in hippocampal subfield alterations in lithium-treated type I bipolar disorder and healthy controls: A subfield volumetry MRI study 儿童创伤在锂治疗的I型双相情感障碍和健康对照者海马亚区改变中的作用：一项亚区容量MRI研究

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-04 DOI: 10.1016/j.neulet.2026.138503

Júnior Aparecido-de-Almeida , Marcio Gerhardt Soeiro-de-Souza

Background

Type I bipolar disorder (BD-I) affects approximately 1% of the global population, and alterations in the morphology of the hippocampus, a cerebral region critical for memory and emotional regulation, may play an important role in its pathophysiology. Childhood Adversity (CA), including abuse and neglect, has been linked to structural hippocampal changes and elevated psychiatric risk, yet the impact of CA on hippocampal subfields in BD remains poorly understood.

Methods

Eighty‑five euthymic patients with BD-I on stable lithium therapy (age 18–40), and 59 healthy controls were assessed (both groups trauma-exposed with score of Childhood Trauma Questionnaire (CTQ) > 25). Volumes of 12 hippocampal subfields were measured using FreeSurfer v6.0.0 and ENIGMA protocols. Partial correlations between CTQ subscale scores and subfield volumes were identified, controlling for age, sex, lithium use, and intracranial volume.

Results

In the BD-I group, higher physical neglect scores correlated with larger right hippocampal volumes: total hippocampus, CA1, hippocampal fissure, and presubiculum, whereas high emotional abuse scores were associated with increased left hippocampal fissure and subiculum volume. No significant associations were observed in controls, indicating specificity of trauma‑related alterations in BD-I.

Conclusion

Different CA subtypes yield distinct volumetric signatures in BD-I: physical neglect seems to drive expansion especially in right‑hemisphere subfields, while emotional abuse appears to enlarge the left subiculum. These findings highlight potential neuroplasticity biomarkers and may help inform early and targeted interventions.

背景： I型双相情感障碍（BD）影响全球约1%的人口，海马（记忆和情绪调节的关键大脑区域）形态的改变可能在其病理生理中发挥重要作用。童年逆境（CA），包括虐待和忽视，与海马结构变化和精神风险升高有关，但CA对双相障碍海马亚区的影响尚不清楚。方法：对85例接受稳定锂治疗的 I型BD患者（年龄 18-40岁）和59名健康对照者（两组均有创伤暴露，儿童创伤问卷（CTQ）得分 > 25）进行评估。使用FreeSurfer v6.0.0和ENIGMA协议测量12个海马子区体积。在控制了年龄、性别、锂离子使用和颅内容积的情况下，CTQ子量表得分与子场容积之间存在部分相关性。结果：在BD组中，较高的身体忽视得分与较大的右侧海马体积相关：海马总体积、CA1、海马裂和耻骨下体积，而较高的情绪虐待得分与较大的左侧海马裂和耻骨下体积相关。在对照组中未观察到显著相关性，表明BD-I中创伤相关改变的特异性。结论：不同的CA亚型在BD-I中产生不同的体积特征：身体忽视似乎驱动扩张，尤其是在右半球亚区，而情绪虐待似乎扩大了左肩带下。这些发现突出了潜在的神经可塑性生物标志物，可能有助于告知早期和有针对性的干预措施。

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引用次数: 0

Prolonged exposure of cerebrocortical neurons to diazepam induces downregulation of surface α1-containing GABAA receptors and uncoupling of GABA/benzodiazepine site interactions through different mechanisms 脑皮质神经元长时间暴露于地西泮可通过不同机制下调表面含α1的GABAA受体，并使GABA/苯二氮卓位点相互作用解偶联。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-23 DOI: 10.1016/j.neulet.2025.138495

Leydi Carolina González Gómez, María Clara Gravielle

GABA_A receptors play a crucial role in mediating fast inhibitory neurotransmission in the central nervous system. These receptors are targets of numerous pharmacological agents used clinically to control neuronal excitability in different neurological disorders. Sustained stimulation of GABA_A receptors by endogenous or exogenous modulators leads to adaptive homeostatic alterations in the receptor function. In particular, chronic benzodiazepine administration results in tolerance to most of the behavioral effects, limiting the clinical use of these drugs for long-term treatments. In previous studies, we found that prolonged exposure of rat cerebrocortical neurons to diazepam produces uncoupling of GABA/benzodiazepine site interactions and decreased expression of the GABA_A receptor α1 subunit gene, mediated by a mechanism involving the activation of L-type voltage-gated calcium channels (L-VGCCs). This work aimed to further explore the molecular basis of GABA_A receptor regulation induced by prolonged benzodiazepine stimulation. Our findings indicate that diazepam increases intracellular calcium levels, confirming the dependence of benzodiazepine-induced GABA_A receptor regulation on calcium entry through L-VGCCs. Immunocytochemical analyses revealed that sustained diazepam treatment reduces the expression of α1-containing GABA_A receptors on the cell surface, which likely impacts functional receptors. By knocking-down α1 subunit expression, we demonstrated that α1 downregulation alone results in minor, non-significant uncoupling, suggesting that additional GABA_A receptor modifications contribute to the observed uncoupling. Altogether, our results suggest that persistent exposure of GABA_A receptors to benzodiazepines produces uncoupling and downregulation of functional α1-containing GABA_A receptors through two distinct mechanisms, both initiated by calcium influx through L-VGCCs.

GABAA受体在中枢神经系统的快速抑制性神经传递中起着至关重要的作用。这些受体是临床上用于控制不同神经系统疾病中神经元兴奋性的许多药理学药物的靶点。内源性或外源性调节剂对GABAA受体的持续刺激可导致受体功能的适应性稳态改变。特别是，长期服用苯二氮卓类药物导致对大多数行为影响的耐受性，限制了这些药物用于长期治疗的临床使用。在之前的研究中，我们发现长时间暴露于地西平的大鼠大脑皮质神经元会导致GABA/苯二氮卓位点相互作用的解耦，GABAA受体α1亚基基因的表达降低，其机制涉及l型电压门控钙通道（L-VGCCs）的激活。本工作旨在进一步探讨长时间苯二氮卓类药物刺激诱导GABAA受体调控的分子基础。我们的研究结果表明，地西泮增加细胞内钙水平，证实了苯二氮卓诱导的GABAA受体对钙通过l - vgc进入的依赖性。免疫细胞化学分析显示，持续地西泮治疗降低了细胞表面含α1的GABAA受体的表达，这可能影响了功能受体。通过下调α1亚基的表达，我们发现α1的下调只会导致轻微的、不显著的解偶联，这表明额外的GABAA受体修饰有助于观察到的解偶联。总之，我们的研究结果表明，GABAA受体持续暴露于苯二氮卓类药物会通过两种不同的机制产生含有α1的功能性GABAA受体的解偶联和下调，这两种机制都是由钙通过l - vgc内流引发的。

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引用次数: 0

Recovery from cuprizone induced incontinence is not dependent upon remyelination 铜酮引起的尿失禁的恢复不依赖于髓鞘再生。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-21 DOI: 10.1016/j.neulet.2025.138494

Anirudhya Lahiri, Lucille E Papile, Zaenab Dhari, Jake T Lustig, Evan T Lombardo, Erica R Lavoie, Pearl A Sutter, Stephen J Crocker

Dysfunction in bladder control (incontinence) is a significant comorbidity in multiple sclerosis that diminishes patients’ quality of life and is a leading cause of hospitalization. Recent evidence indicates that CNS demyelination is sufficient to induce incontinence, while bladder control is also restored following remyelination. Based on this strong association, we hypothesized that remyelination is necessary for the restoration of bladder function control after acute demyelination. To test this, we evaluated changes in bladder function in mice in which Myelin regulatory factor (Myrf) was conditionally knocked out in oligodendrocyte precursor cells (OPC)(PDGFR⍺- CreER^TM, Myrf^fl/fl (Myrf-cKO)) and compared these with control groups during and after being subjected to cuprizone treatment. Here, we report that acute demyelination leads to bladder control dysfunction which was evidenced by significantly increased voiding behavior irrespective of genotype. However, during the remyelination phase, we observed an amelioration of incontinence in all groups, including mice in which remyelination fails (e.g. Myrf-cKO mice). These data suggest that while active demyelination can initiate loss of bladder function control, failed remyelination is not an impediment to potential adaptive changes which may facilitate restoration of proper bladder function.

膀胱控制功能障碍（尿失禁）是多发性硬化症的重要合并症，它降低了患者的生活质量，是住院治疗的主要原因。最近的证据表明，中枢神经系统脱髓鞘足以引起尿失禁，而膀胱控制也恢复后，髓鞘再生。基于这种强烈的关联，我们假设在急性脱髓鞘后，再脱髓鞘对于膀胱功能控制的恢复是必要的。为了验证这一点，我们评估了髓磷脂调节因子（Myrf）在少突胶质前细胞（OPC）（PDGFR - CreERTM, Myrffl/fl (Myrf- cko)）中被有条件敲除的小鼠膀胱功能的变化，并将其与对照组进行比较。在这里，我们报道急性脱髓鞘导致膀胱控制功能障碍，这可以通过显着增加的排尿行为来证明，而与基因型无关。然而，在髓鞘再生阶段，我们观察到所有组尿失禁的改善，包括髓鞘再生失败的小鼠（如Myrf-cKO小鼠）。这些数据表明，虽然活动性脱髓鞘会导致膀胱功能失控，但脱髓鞘失败并不妨碍潜在的适应性改变，这可能有助于膀胱功能的正常恢复。

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引用次数: 0

Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway 绿原酸通过Nrf2/HO-1通路调节小胶质细胞极化，在戊四唑致癫痫小鼠模型中发挥抗炎和神经保护作用

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-19 DOI: 10.1016/j.neulet.2025.138493

Yi Sun , Jiayu Wang , Aoyuan Zhang , Ankang Hu , Lianlian Wu

Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both in vitro and in vivo. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA’s effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.

绿原酸（Chlorogenic acid， CGA）在体内体外均具有抗氧化、抗炎、抗细胞凋亡等多种生物学功能。最近的研究表明，CGA也有神经保护作用。然而，其减轻癫痫发作和减轻癫痫相关神经病理的潜力仍不清楚。本研究探讨了CGA在戊四唑（PTZ）诱导癫痫小鼠模型中的作用及其机制。CGA治疗显著减少癫痫发作。Nissl和NeuN免疫荧光染色显示，CGA还能显著减轻神经元损伤。此外，通过iNOS/IBA-1和Arg-1/IBA-1免疫荧光和RT-PCR， CGA促进小胶质细胞从促炎M1表型向抗炎M2表型极化，抑制神经炎症。BrdU染色显示CGA抑制癫痫诱导的异常神经发生。此外，行为测试显示CGA治疗后认知能力有所改善。最后，western blot分析表明Nrf2/HO-1通路激活，Nrf2敲低逆转了CGA的作用。这些发现表明，CGA通过Nrf2/HO-1途径调节小胶质细胞发挥抗癫痫和神经保护作用。

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引用次数: 0

Antinociceptive role of IL-10/STAT3 signaling in trigeminal neuropathic pain male rat model through Pomc and β-endorphin IL-10/STAT3信号通过Pomc和β-内啡肽在三叉神经性疼痛雄性大鼠模型中的抗伤害感受作用

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-18 DOI: 10.1016/j.neulet.2025.138492

Lutfi Putra Perdana , Jaime Fabillar Jr , Dara Sari Arini , Swarnalakshmi Raman , Resmi Raju , Daisuke Ikutame , Masamitsu Oshima , Keiko Miyoshi , Yoshizo Matsuka

Interleukin-10 (IL-10) is a cytokine that can exert an analgesic effect on trigeminal neuropathic pain (TNP). However, its precise mechanism remains unclear. In this study, we investigated the antinociceptive effects of recombinant IL-10 (rIL-10) in a rat model of infraorbital nerve constriction. Using male Sprague-Dawley rats, we administered rIL-10 or phosphate-buffered saline to the intra-trigeminal ganglion and observed a peak analgesic effect at 4 h post-injection in the rIL-10 group. Real-time PCR demonstrated significant upregulation of the Proopiomelanocortin (Pomc) gene in rIL-10-treated rats, with immunofluorescence staining confirming increased expression of bioactive peptide β-endorphin (β-END) in the same group. In situ hybridization assay further localized Pomc expression to satellite glial cells and neurons in the trigeminal ganglion, with β-END exhibiting a similar distribution. To elucidate the signaling mechanism, we co-administered a STAT3 inhibitor, Stattic, which abolished the analgesic effect of rIL-10, suppressed Pomc upregulation, and reduced β-END expression. These findings indicate that the STAT3 pathway is a critical mediator of rIL-10-induced analgesia, with Pomc and β-END as potential molecular effectors.

白介素-10 （IL-10）是一种对三叉神经性疼痛（TNP）具有镇痛作用的细胞因子。然而，其确切机制尚不清楚。在这项研究中，我们研究了重组IL-10 （IL-10）在眶下神经收缩大鼠模型中的抗感觉作用。我们以雄性Sprague-Dawley大鼠为实验动物，在三叉神经节内注射rIL-10或磷酸盐缓冲盐水，观察il -10组在注射后4 h达到镇痛效果峰值。Real-time PCR结果显示，il -10处理大鼠的Proopiomelanocortin （Pomc）基因显著上调，免疫荧光染色证实同一组大鼠的生物活性肽β-内啡肽（β-END）表达增加。原位杂交实验进一步将Pomc的表达定位到三叉神经节的卫星胶质细胞和神经元中，β-END的表达也表现出类似的分布。为了阐明信号传导机制，我们联合使用STAT3抑制剂Stattic，该抑制剂可消除rIL-10的镇痛作用，抑制Pomc上调，并降低β-END表达。这些发现表明STAT3通路是ril -10诱导的镇痛的关键介质，Pomc和β-END是潜在的分子效应物。

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引用次数: 0

Suppression of 5-HT2 receptor signaling impairs normal eye development in zebrafish 抑制5-HT2受体信号会损害斑马鱼正常的眼睛发育。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-16 DOI: 10.1016/j.neulet.2025.138491

Zulvikar Syambani Ulhaq , Mitsuyo Kishida

Serotonin (5-HT) signaling plays essential roles in vertebrate development beyond neurotransmission, including in ocular morphogenesis. Here, we investigated the effects of Ritanserin, a non-selective 5-HT₂ receptor antagonist, on zebrafish embryonic development with a focus on eye formation. While Ritanserin exposure (0.1–10 μM) did not affect mortality or hatching rates up to 96 h post-fertilization (hpf), higher concentrations (5–10 μM) induced developmental abnormalities, such as microphthalmia, pericardial edema, blood congestion, and craniofacial malformations by 5 days post-fertilization (dpf). Ritanserin significantly reduced the expression of cyp19a1b, encoding brain aromatase (AroB) involved in local estrogen synthesis within the eye, and pax6a, a key regulator of retinal neurogenesis, without altering cyp19a1a levels. Co-treatment with exogenous 5-HT or estradiol (E₂) partially rescued eye size, optic nerve morphology, pax6a expression, and reduced retinal apoptosis. Moreover, visual deficits induced by Ritanserin, as shown by impaired visual background adaptation (VBA) and optomotor responses (OMR), were similarly reversed by 5-HT or E₂. These findings demonstrate that 5-HT₂ signaling is critical for proper eye development in zebrafish, likely through regulation of estrogen synthesis and neuroretinal gene expression, and suggest that serotonergic disruption during early development can lead to structural and functional visual deficits.

5-羟色胺（5-HT）信号在脊椎动物的发育中起着重要的作用，包括神经传递，包括眼形态发生。在这里，我们研究了利坦色林（一种非选择性5-HT2受体拮抗剂）对斑马鱼胚胎发育的影响，重点是眼睛的形成。在受精后96 h （hpf）内，利坦色林暴露（0.1 ~ 10  μM）对死亡率和孵化率没有影响，但在受精后5 d （dpf）内，利坦色林暴露（5 ~ 10  μM）会引起发育异常，如小眼症、心包水肿、充血和颅面畸形。利坦色林显著降低cyp19a1b的表达，cyp19a1b编码脑芳香化酶（AroB），参与眼内局部雌激素合成，pax6a是视网膜神经发生的关键调节因子，而cyp19a1a的水平没有改变。外源性5-羟色胺或雌二醇（E2）联合治疗部分恢复了眼睛大小、视神经形态、pax6a表达，并减少了视网膜凋亡。此外，利坦色林引起的视觉缺陷，如视觉背景适应（VBA）和光运动反应（OMR）受损，同样可以被5-HT或E2逆转。这些发现表明，5-HT2信号对斑马鱼正常的眼睛发育至关重要，可能通过调节雌激素合成和神经视网膜基因表达，并表明在早期发育过程中5-羟色胺能中断可能导致结构性和功能性视觉缺陷。

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引用次数: 0

The effects of lithium chloride in N-methyl-N-nitrosourea induced retinal damage in rats 氯化锂对n -甲基-n -亚硝基脲致大鼠视网膜损伤的影响。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-11 DOI: 10.1016/j.neulet.2025.138489

Canan Akdeniz İncili , Yesari Eröksüz , Hatice Eröksüz , Abdullah Aslan

The aim of the current study was to assess the potential neuroprotective effects of lithium chloride (LiCl) against retinal degeneration (RD) induced by N-methyl-N-nitrosourea (MNU) in the rats. 108 rats were assigned to 6 groups: Control, MNU (80 mg/kg), MNU + 30 mg/kg LiCI, MNU + 60 mg/kg LiCI, 30 mg/kg LiCI, and 60 mg/kg LiCI. The experimental groups comprised 18 rats each and the animals were euthanised on the 2nd, 7th and 14th days following the administration of MNU. Compared with the MNU group, both doses of LiCl significantly reduced retinal cell apoptosis and increased retinal thickness (P < 0.05). MNU group had a higher apoptotic index than the treatment groups, as evidenced by increased immunoreactivities of caspase-3, caspase-6, Bax, and 8-OHdG and decreased immunoreactivities of Bcl-2 at day 2. The outer nuclear layer (ONL) of the retina in rats treated with MNU exhibited a significant reduction in comparison the control group on both days 7 and 14 (P < 0.05). In contrast to the MNU-treated figgroup, the LiCl-injected rats exhibited a notable elevation in the expression levels of BDNF and Bcl-2 (P < 0.05). Conversely, the MNU-treated group exhibited markedly increased expression of GSK-3β, Bax, 8-OHdG, caspase-3, and caspase 6 (P < 0.05). In conclusion, LiCl demonstrated dose-dependent neuroprotective effects against MNU-induced RD in rats. These effects included a reduction in retinal cell apoptosis, an improvement in retinal thickness, and the potential involvement of anti-apoptotic mechanisms, glial activation inhibition, and neurotrophic factor modulation.

本研究旨在评估氯化锂（LiCl）对n -甲基-n -亚硝基脲（MNU）所致大鼠视网膜变性（RD）的潜在神经保护作用。将108只大鼠分为6组：对照组、MNU（80 mg/kg）、MNU + 30 mg/kg LiCI、MNU + 60 mg/kg LiCI、30 mg/kg LiCI和60 mg/kg LiCI。各组大鼠18只，分别于给药后第2、7、14天实施安乐死。与MNU组比较，两种剂量的LiCl均显著降低视网膜细胞凋亡，增加视网膜厚度（P < 0.05）。MNU组细胞凋亡指数高于治疗组，表现为第2天caspase-3、caspase-6、Bax和8-OHdG的免疫反应活性升高，Bcl-2的免疫反应活性降低。与对照组相比，MNU处理大鼠视网膜外核层（ONL）在第7天和第14天均显著降低（P < 0.05）。与mnu处理的fig组相比，licl注射大鼠BDNF和Bcl-2表达水平显著升高（P < 0.05）。相反，mnu处理组GSK-3β、Bax、8-OHdG、caspase-3和caspase 6的表达显著增加（P < 0.05）。综上所述，LiCl对mnu诱导的RD具有剂量依赖性的神经保护作用。这些作用包括视网膜细胞凋亡的减少，视网膜厚度的改善，以及抗凋亡机制，神经胶质活化抑制和神经营养因子调节的潜在参与。

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引用次数: 0

Bovine lactoferrin-induced antinociception through 5-HT1A/1D receptors in formalin-induced tonic pain 牛乳铁蛋白通过5-HT1A/1D受体在福尔马林诱导的强直性疼痛中诱导抗炎反应

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-10 DOI: 10.1016/j.neulet.2025.138490

Sergio Ernesto Ávila-Morales, Maria Elisa Drago-Serrano, Beatriz Godínez-Chaparro

Bovine lactoferrin (bLF) is a multifunctional glycoprotein that displays modulatory effects on pain through pathways not fully known. Therefore, we determined the role of the serotonergic system as a potential mechanism underlying the antinociceptive effect of bLF on formalin-induced tonic nociception. The formalin test was used to assess the antinociceptive effect—pain-like behaviour (flinching) at 1 h. The bLF-induced antinociceptive effect was prevented by the intrathecal (3 µg/rat), but not the intraplantar (30 µg/rat) administration of methiothepin, a non-selective 5-hydroxytryptamine (5-HT) antagonist. Moreover, intrathecal administration of WAY-100635 (6 µg/rat; selective 5-HT_1A receptor antagonist) and BRL1555724 (4 µg/rat; selective 5-HT_1D receptor antagonist) prevented the bLF-induced antinociceptive effect. However, intrathecal administration of SB-224289 (5 µg/rat; selective 5-TH_1B receptor antagonist) and SB-699551 µg/rat; selective 5-TH_5A receptor antagonist) did not prevent the bLF-induced antinociceptive effect. The above finding suggests that bLF reduces acute nociception induced by formalin, and this antinociceptive effect is mediated, at least in part, by the serotonergic system, acting only at the spinal level and not at the peripheral level, via activation of central 5-HT_1A/1D serotonergic receptors.

牛乳铁蛋白（bLF）是一种多功能糖蛋白，通过尚不完全清楚的途径对疼痛表现出调节作用。因此，我们确定了血清素能系统的作用，作为bLF对福尔马林诱导的强直性伤害性的抗伤害性作用的潜在机制。福尔马林试验用于评估1 h时的抗痛觉效应-疼痛样行为（退缩）。鞘内注射（3µg/大鼠）可阻止blf诱导的抗痛觉效应，但足底注射（30µg/大鼠）甲氧thepin（一种非选择性5-羟色胺（5-HT）拮抗剂）不能阻止。此外，鞘内给药WAY-100635（6µg/大鼠，选择性5-HT1A受体拮抗剂）和BRL1555724（4µg/大鼠，选择性5-HT1D受体拮抗剂）可阻止blf诱导的抗伤害感受作用。然而，鞘内给药SB-224289（5µg/大鼠；选择性5- th1b受体拮抗剂）和SB-699551µg/大鼠；选择性5-TH5A受体拮抗剂)不能阻止blf诱导的抗伤害性作用。上述发现表明，bLF可减少福尔马林引起的急性伤害感受，而这种抗伤害感受作用至少部分是由血清素能系统介导的，该系统通过激活中枢5-HT1A/1D血清素能受体，仅在脊髓水平而不在外周水平起作用。

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引用次数: 0

The anti-epileptic mechanism of a ketogenic diet regulating the gut microbiota via SIRT2 activation of the PI3K/AKT signaling pathway 生酮饮食通过SIRT2激活PI3K/AKT信号通路调节肠道微生物群的抗癫痫机制

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2025-12-09 DOI: 10.1016/j.neulet.2025.138488

Minghua Li, Haifeng Deng, Ling Ma, Manli Sun

Purpose

Epilepsy (EP) is a disorder caused by sudden abnormal discharges of neurons in the brain. A ketogenic diet (KD) has significant anticonvulsant effects in some epileptic patients, but the signaling pathway remains unclear. This study aims to investigate the mechanisms underlying the anticonvulsant effects of a KD.

Methods

Acute epilepsy models were induced by kainic acid (KA) and pentylenetetrazol (PTZ), synaptic electrical activity in the hippocampus was measured. The effects of KD on the expression levels of postsynaptic proteins and SIRT2 was determined, as well as the phosphorylation of the PI3K and Akt-S-473 signaling pathways. Metabolomic analysis was used to investigate the effect of KD on the gut microbiota.

Results

The KD inhibited acute seizures and promoted the amplitude of induced inhibitory postsynaptic current (IPSC) transmission and the frequency of spontaneous IPSC transmission in cortical brain regions. KD upregulated the expression of PI3K, activated the phosphorylation of AKT-S-473, and increased SIRT2 expression. Metabolomic analysis indicated shifts in host metabolism, particularly involving Clostridiales(e.g., Blautia and Lachnospiraceae). Based on existing literature, we hypothesize tha KD may support gut barrier function and anti-inflammatory responses.

Conclusion

The anti-epileptic effect of KD in the prefrontal cortex is associated with the activation of the PI3K/Akt signaling pathway and an increase in SIRT2 expression. Additionally, our data are consistent with the emerging concept that the anti-seizure effects of KD may also involve modulation of the gut microbiota. This provides valuable insights for the development of new therapeutic interventions.

目的：癫痫（EP）是一种由大脑神经元突然异常放电引起的疾病。生酮饮食（KD）对一些癫痫患者具有显著的抗惊厥作用，但其信号通路尚不清楚。方法：用kainic acid （KA）和pentylenetetrazol （PTZ）诱导急性癫痫模型，测量海马突触电活动。测定KD对突触后蛋白和SIRT2表达水平的影响，以及PI3K和Akt-S-473信号通路的磷酸化。采用代谢组学分析研究KD对肠道菌群的影响。结果：KD能抑制急性发作，提高脑皮质区诱导抑制性突触后电流（IPSC）传递幅度和自发IPSC传递频率。KD上调PI3K的表达，激活AKT-S-473的磷酸化，增加SIRT2的表达。代谢组学分析表明，宿主代谢发生了变化，特别是涉及梭菌(如：，蓝藻和毛螺科)。基于现有文献，我们假设KD可能支持肠道屏障功能和抗炎反应。结论：KD在前额皮质的抗癫痫作用与激活PI3K/Akt信号通路和增加SIRT2表达有关。此外，我们的数据与新兴的概念一致，即KD的抗癫痫作用也可能涉及肠道微生物群的调节。这为开发新的治疗干预措施提供了有价值的见解。

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引用次数: 0