Neuropharmacology最新文献_第6页

Chemogenetic activation of an A2 nucleus of the solitary tract to lateral parabrachial nucleus noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in male and female mice 孤立束A2核到外侧臂旁核去肾上腺素能通路的化学发生激活使嗜酒样乙醇摄入变迟钝并促进雄性和雌性小鼠的厌恶非条件反应。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-03 DOI: 10.1016/j.neuropharm.2025.110792

Caryssa R. Drinkuth , Ana Paula S. Dornellas , Sara Guarino , Montserrat Navarro , Todd E. Thiele

While there is strong evidence that the reinforcing effects of ethanol motivate seeking and consumption, ethanol produces aversive effects that limit consumption. We have previously found that in doses that support conditioned taste aversion (CTA) learning ethanol induces activity of noradrenergic (NE+) neurons of the A2 subregion of the nucleus of the solitary tract (NTS) as well as neurons within the lateral parabrachial nucleus (L-PBN), regions that have been implicated in integrating aversive responses. Here we provide evidence of a NE + circuit arising from the A2 and innervating the L-PBN in tyrosine hydroxylase (TH)-ires-cre mice. Next, we used male and female TH-ires-cre mice in tandem with an intersectional chemogenetic approach to assess the role of the NE + A2 to L-BPN circuit in modulating binge-like ethanol intake as well as unconditioned aversive behavior. Using “drinking in the dark” (DID) procedures we found that activating this circuit significantly blunted binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose solution intake. Furthermore, silencing this pathway during light cycle drinking revealed a trend of increased ethanol intake and an associated significant increase of BECs with no changes in sucrose intake. Additionally, activation of this circuit, as well as peripheral administration of the emetic agent LiCl, significantly increased the emission of mid-frequency vocalizations (MFVs) in mice, a phenotype reflecting aversive reactivity. The present findings provide novel evidence of a NE + A2 to L-PBN circuit in the modulation of binge-like ethanol intake and aversive responses.

虽然有强有力的证据表明，乙醇的强化效应激发了寻找和消费，但乙醇产生的不良效应限制了消费。我们之前已经发现，在支持条件性味觉厌恶（CTA）学习的剂量下，乙醇可诱导孤立束核（NTS） A2亚区的去甲肾上腺素能（NE+）神经元以及外侧臂旁核（L-PBN）内的神经元的活性，这些区域与整合厌恶反应有关。在这里，我们提供了在酪氨酸羟化酶(TH)-ires-cre小鼠中由A2产生并支配L-PBN的NE+回路的证据。接下来，我们将雄性和雌性TH-ires-cre小鼠串联使用交叉化学遗传学方法来评估NE+ A2到L-BPN回路在调节狂饮样乙醇摄入以及非条件厌恶行为中的作用。使用“在黑暗中饮酒”（DID）程序，我们发现激活该回路显着减弱了狂饮样乙醇摄入和相关的血液乙醇浓度（BECs），而不改变蔗糖溶液的摄入量。此外，在光循环饮酒期间，沉默这一途径揭示了乙醇摄入量增加的趋势和相关的BECs显著增加，而蔗糖摄入量没有变化。此外，该回路的激活，以及外周给药催吐剂LiCl，显著增加了小鼠中频发声（MFVs）的发射，这是一种反映厌恶反应性的表型。本研究结果提供了NE+ A2到L-PBN回路在酗酒样乙醇摄入和厌恶反应调节中的新证据。

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引用次数: 0

Exosome therapy protects the hippocampus in mice exposed to chronic methamphetamine: Insights into angiogenic and inflammatory signaling pathways 外泌体治疗保护慢性甲基苯丙胺暴露小鼠的海马：血管生成和炎症信号通路的见解

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-01 DOI: 10.1016/j.neuropharm.2025.110790

Solmaz Fallahi , Hamid Soltani Zangbar , Fariba Ghiasi , Gisou Mohaddes , Fereshteh Farajdokht

Methamphetamine (Meth) exposure leads to cognitive dysfunction and neurodegeneration in the hippocampus. Considering exosome therapy as a new treatment approach for neurological diseases, the current study proposed to investigate the effects of mesenchymal stem cell (MSC)-derived exosomes on hippocampal angiogenesis, inflammation, and cognitive function in Meth-treated mice. Meth (5 mg/kg) was injected daily for 30 days, and MSC-derived exosomes (100 μg per dose) were administered intravenously for three consecutive days after the Meth exposure. The Y-maze and Novel Object Recognition Test (NORT) evaluated spatial and recognition memory, while motor function was assessed through the Open Field Test (OFT). Results showed that exosome therapy improved both spatial and recognition memory. Additionally, the time spent in the center of the open field and the distance traveled significantly increased following treatment in Meth-exposed animals. Furthermore, exosome therapy promoted hippocampal angiogenesis and neurogenesis, as indicated by increased expression levels of HIF-1α, VEGF, and DCX, respectively, and also reduced Meth-induced hippocampal inflammation, evidenced by decreased TNF-α expression. These findings demonstrate that exosome therapy enhances cognitive function, encourages hippocampal angiogenesis, and diminishes inflammation in the hippocampus of Meth-treated mice.

甲基苯丙胺（冰毒）暴露导致认知功能障碍和海马体神经变性。考虑到外泌体治疗是神经系统疾病的一种新的治疗方法，本研究拟探讨间充质干细胞（MSC）来源的外泌体对冰毒治疗小鼠海马血管生成、炎症和认知功能的影响。每天注射甲基安非他明（5 mg/kg） 30天，甲基安非他明暴露后连续3天静脉注射msc衍生外泌体（每剂量100 μg）。y形迷宫和新物体识别测试（NORT）评估空间和识别记忆，而运动功能通过开放场测试（OFT）评估。结果表明，外泌体治疗可改善空间记忆和识别记忆。此外，暴露于冰毒的动物在开放场地中心停留的时间和行走的距离在处理后显著增加。此外，外泌体治疗促进了海马血管生成和神经发生，分别表明HIF-1α， VEGF和DCX的表达水平升高，并且还减轻了冰毒诱导的海马炎症，TNF-α表达降低。这些发现表明，外泌体治疗增强了冰毒治疗小鼠的认知功能，促进了海马血管生成，并减少了海马的炎症。

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引用次数: 0

Antisense oligonucleotide of cargo adaptor BICD2 long-term effectively alleviates neuropathic pain via activation of PSD95 in the mouse spinal dorsal horn 货物受体BICD2反义寡核苷酸通过激活小鼠脊髓背角PSD95长期有效缓解神经性疼痛。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-03 DOI: 10.1016/j.neuropharm.2025.110793

Zi-Xuan Wu , Yang Xu , Jing Xie , Gan Ma , Yu-Xia Li , Tong Yang , Jia-Hui Liang , Li Yang , Qi-Hui Wang , Ling-Yun Hao , Yang Zhang , Jing Meng , Zhi-Qiang Pan , Hong-Jun Wang

The involvement of Bicaudal D2 (BICD2), a dynein motor adaptor protein, in neuropathic pain pathogenesis remains unexplored. This study investigated the role of spinal BICD2 and its interaction with postsynaptic density protein 95 (PSD95) in neuropathic pain using Western blotting, immunofluorescence staining and reverse transcription quantitative polymerase chain reaction. We further evaluated the long-term analgesic efficacy of intrathecally (i.t.) administered Bicd2-specific antisense oligonucleotide (ASO) in male murine models of nociceptive hypersensitivity induced by spared nerve injury (SNI), cisplatin chemotherapy, and streptozotocin (STZ)-induced diabetes. Results demonstrated that BICD2 expression was selectively upregulated in the spinal dorsal horn following SNI. Both Bicd2 siRNA and Bicd2 ASO delivered via i.t. injection significantly suppressed BICD2 overexpression and attenuated mechanical/thermal hyperalgesia across all neuropathic pain etiologies (trauma, chemotherapy, diabetes). Critically, immunofluorescence staining confirmed co-expression of BICD2 and PSD95. Nerve injury-induced PSD95 elevation in the dorsal horn was abolished by Bicd2 siRNA or ASO treatment. Moreover, PSD95 inhibitor NA-1 not only alleviated SNI-induced the hyperalgesia, but also reversed mechanical/thermal hyperalgesia evoked by BICD2 overexpression. These findings reveal a novel mechanism wherein BICD2 alleviates neuropathic pain through PSD95 activation in the spinal dorsal horn, and establish the therapeutic potential of spinally targeted Bicd2 ASO for sustained pain management.

Bicaudal D2 （BICD2）是一种动力蛋白运动接头蛋白，其在神经性疼痛发病机制中的作用尚不清楚。本研究采用Western blotting、免疫荧光染色和逆转录定量聚合酶链反应研究脊髓BICD2及其与突触后密度蛋白95 （PSD95）在神经性疼痛中的作用。我们进一步评估了鞘内注射bicd2特异性反义寡核苷酸（ASO）对残神经损伤（SNI）、顺铂化疗和链脲佐菌素（STZ）诱导的糖尿病雄性小鼠伤害性超敏反应模型的长期镇痛效果。结果表明，SNI后，BICD2在脊髓背角的表达选择性上调。通过静脉注射给药Bicd2 siRNA和Bicd2 ASO均可显著抑制Bicd2过表达，并减轻所有神经性疼痛病因（创伤、化疗、糖尿病）的机械/热痛觉过敏。重要的是，免疫荧光染色证实了BICD2和PSD95的共表达。Bicd2 siRNA或ASO治疗可消除神经损伤引起的背角PSD95升高。此外，PSD95抑制剂NA-1不仅可以缓解sni诱导的痛觉过敏，还可以逆转BICD2过表达引起的机械/热痛觉过敏。这些发现揭示了BICD2通过激活脊髓背角的PSD95减轻神经性疼痛的新机制，并确立了脊髓靶向BICD2 ASO治疗持续性疼痛的潜力。

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引用次数: 0

Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy CK1δ蛋白激酶抑制剂IGS2.7联合利鲁唑治疗als相关TDP-43蛋白病变的疗效评估

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-11 DOI: 10.1016/j.neuropharm.2025.110804

Marta Gomez-Almeria , Loreto Martinez-Gonzalez , Ana Teresa Matos , Carmen Rodriguez-Cueto , Ana Rita Vaz , Raquel Martín-Baquero , Carmen Pérez de la Lastra , Rafael Infantes , Javier Fernández-Ruiz , Valle Palomo , Carmen Gil , Dora Brites , Ana Martinez , Eva de Lago

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3–18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.

肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，目前尚无有效的治疗方法。FDA和EMA只批准了利鲁唑，这种药物可以将患者的生存期适度延长3到18个月。在我们的研究中，我们发现了一种新的CK1δ抑制剂IGS2.7，它在患者源性细胞模型和TgTDP-43小鼠中调节TDP-43蛋白病变，这是ALS的主要病理标志。为了评估IGS2.7作为治疗候选药物的潜力，并考虑到利鲁唑仍然是ALS患者的标准治疗，我们评估了其与利鲁唑联合使用的效果。我们的研究结果表明，IGS2.7和利鲁唑在有效剂量下共同给药不会引起不良反应。然而，除了IGS2.7单药治疗外，没有观察到额外的治疗益处，这表明IGS2.7可能是可行的，既可以作为单独治疗，也可以作为利鲁唑的辅助治疗。值得注意的是，当给予两种药物的次优剂量时，观察到联合效应。这表明，一旦IGS2.7达到临床试验，它与低剂量的利鲁唑一起使用可能会提高治疗效果，同时潜在地减少副作用。尽管只有临床试验才能最终确定其临床相关性，但仍需要进一步的体内临床前研究来进一步评估这种可能性。

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引用次数: 0

Downregulation of SNORD20 promotes ferroptosis in corpus cavernosum smooth muscle cells from diabetic rats through inducing the mitochondrial dysfunction 下调SNORD20通过诱导线粒体功能障碍促进糖尿病大鼠海绵体平滑肌细胞的铁下垂。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-15 DOI: 10.1016/j.neuropharm.2025.110805

Yiyu Qin , Wenjie Huang , Yang Zhou , Yuping Chen , Jian Li , Zhiyue Wu

Erectile dysfunction (ED) disturbs the life of elderly men, and ferroptosis may be associated with the progression of ED. Small nucleolar RNAs (snoRNAs, 60–300 nucleotides) are non-coding regulatory RNAs mainly located in cell nucleolus, and SNORD20 was found to participate in the function of smooth muscle cells. However, the function of SNORD20 in ED remains unexplored. In the current research, protein and mRNA levels were examined using Western blot and RT-qPCR, respectively. Flow cytometry was employed to investigate apoptosis in cells. Mitochondrial function was examined using JC-1 and MitoSOX staining. Moreover, Fe²⁺ levels were examined using iron kits and an erectile function study in rats was conducted to further explore the function of SNORD20 in diabetic ED. It was revealed that SNORD20 level was reduced in cells obtained from diabetic ED rats. Notably, SNORD20 overexpression increased the proliferation in corpus cavernosum smooth muscle cells from diabetic rats, and SNORD20 small interfering RNA exerted the opposite effect. SNORD20 knockdown markedly promoted cell apoptosis and ferroptosis, and induced mitochondrial dysfunction. In addition, silencing of SNORD20 induces mitochondrial dysfunction and induced ferroptosis via downregulating Nrf2 and GPX4 expressions in corpus cavernosum smooth muscle cells. Moreover, SNORD20 overexpression alleviated the erectile function of diabetic rats in vivo. Collectively, SNORD20 knockdown may promote ferroptosis in corpus cavernosum smooth muscle cells obtained from diabetic ED rats through inducing mitochondrial dysfunction, highlighting that this snoRNA may acts as a key player in ED.

勃起功能障碍（ED）扰乱老年男性的生活，铁上落症可能与ED的进展有关。小核rna （Small nucleolar RNAs, snoRNAs， 60-300个核苷酸）是主要位于细胞核内的非编码调控rna，研究发现SNORD20参与平滑肌细胞的功能。然而，SNORD20在ED中的功能仍未被探索。本研究分别采用western blot和RT-qPCR检测蛋白和mRNA水平。流式细胞术检测细胞凋亡情况。采用JC-1和MitoSOX染色检测线粒体功能。此外，利用铁试剂盒检测Fe2+水平，并对大鼠进行勃起功能研究，进一步探讨SNORD20在糖尿病性ED中的功能。结果显示，从糖尿病性ED大鼠获得的细胞中，SNORD20水平降低。值得注意的是，SNORD20过表达增加了糖尿病大鼠海绵体平滑肌细胞的增殖，而SNORD20小干扰RNA则起到相反的作用。SNORD20敲低显著促进细胞凋亡和铁下垂，并诱导线粒体功能障碍。此外，SNORD20的沉默通过下调海肌体平滑肌细胞中Nrf2和GPX4的表达，诱导线粒体功能障碍和铁下垂。此外，SNORD20过表达可减轻糖尿病大鼠体内勃起功能。综上所述，SNORD20敲低可能通过诱导线粒体功能障碍促进糖尿病ED大鼠海肌体平滑肌细胞的铁上吊，这表明该snoRNA可能在ED中起关键作用。

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引用次数: 0

GABAB receptor blockade in the dentate gyrus restores glutamatergic synaptic plasticity and hippocampus dependent memory in an AD-like rat model 在ad样大鼠模型中，齿状回GABAB受体阻断恢复谷氨酸能突触可塑性和海马依赖记忆。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-02 DOI: 10.1016/j.neuropharm.2025.110789

Jianzhou Chen , Yuening Tian , Linping Wang , Zihan Zhang , Qinghua Jin , Bin Xiao

Synaptic dysfunction driven by glutamate-mediated excitotoxicity is a hallmark of hippocampus-dependent memory impairment in Alzheimer's disease (AD). Although GABAergic signaling is known to regulate excitatory/inhibitory (E/I) balance, the precise molecular mechanisms by which GABA and its receptors modulate glutamatergic synaptic plasticity remains incompletely understood. Here, we investigated the role of GABA and its receptors in the dentate gyrus (DG) of a streptozotocin (STZ) induced rat model with sporadic AD (_SAD)-like features. sAD rats exhibited intact emotional and motor functions but showed marked impairments in novel object recognition, Y-maze, and Morris water maze (MWM) performance. In vivo microdialysis combined with HPLC during MWM training revealed decreased GABA levels and selective upregulation of GABA_B receptor (GABA_BR) expression, but not GABA_AR, expression in the DG. Administration of the GABA_BR antagonist 2-hydroxysaclofen improved hippocampal memory performance, reduced glutamate accumulation, and restored the key excitatory synaptic markers, including vGlut1 and PSD-95. Moreover, co-immunoprecipitation and molecular docking identified a specific interaction between GABA_BR and CaMKII. GABA_BR blockade enhanced CaMKII phosphorylation and activated downstream effectors, including p-CREB and BDNF, indicating re-engagement of plasticity-related signaling. These findings demonstrate that GABA_BR upregulation in the DG impairs glutamatergic synaptic plasticity and memory function in sAD like rats, likely via direct suppression of the CaMKII/CREB/BDNF pathway. Targeting GABA_BR may thus offer a promising strategy to restore E/I balance and cognitive performance in a sAD-like rat model.

由谷氨酸介导的兴奋性毒性驱动的突触功能障碍是阿尔茨海默病（AD）海马依赖性记忆障碍的一个标志。虽然已知GABA能信号调节兴奋/抑制（E/I）平衡，但GABA及其受体调节谷氨酸能突触可塑性的确切分子机制仍不完全清楚。在此，我们研究了GABA及其受体在链脲佐菌素（STZ）诱导的散发性AD （SAD）样大鼠模型齿状回（DG）中的作用。sAD大鼠的情绪和运动功能完好，但在新物体识别、y迷宫和Morris水迷宫（MWM）中表现出明显的损伤。在MWM训练期间，体内微透析联合HPLC显示GABA水平下降，GABAB受体（GABABR）表达选择性上调，但GABAAR在DG中的表达没有变化。给予GABABR拮抗剂2-羟氯芬可改善海马记忆表现，减少谷氨酸积累，并恢复关键的兴奋性突触标志物，包括vGlut1和PSD-95。此外，共免疫沉淀和分子对接发现了GABABR和CaMKII之间的特异性相互作用。GABABR阻断增强CaMKII磷酸化并激活下游效应物，包括p-CREB和BDNF，表明可塑性相关信号的重新参与。这些发现表明，GABABR在DG中的上调可能通过直接抑制CaMKII/CREB/BDNF通路，损害sAD样大鼠的谷氨酸能突触可塑性和记忆功能。因此，靶向GABABR可能为恢复sAD样大鼠模型的E/I平衡和认知表现提供了一种有希望的策略。

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引用次数: 0

Emerging role of N6-methyladenosine (m6A) epitranscriptomic changes in adult anxiety after adolescent alcohol exposure n6 -甲基腺苷（m6A）表转录组学变化在青少年酒精暴露后成人焦虑中的新作用

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-11-21 DOI: 10.1016/j.neuropharm.2025.110777

Emir Malovic , Jamuna Tandukar , Huaibo Zhang , Lalith K. Venkareddy , Ruixuan Gao , Subhash C. Pandey

Adolescent intermittent ethanol (AIE) exposure affects multiple brain regions by producing long-lasting effects on epigenetic mechanisms and behavioral phenotypes later in life. Recently, it has been shown that epigenetic switches can control epitranscriptomics, or RNA modifications. Specifically, the most abundant RNA modification, known as N6-methyladenosine (m6A), has been the subject of intense investigation in brain plasticity; however, little is known about its role in adult psychopathology after AIE. Herein, we investigated whether changes in m6A modifiers (writers, erasers, and readers) after AIE regulate phenotypes of anxiety in adulthood using an animal model. We characterized m6A regulators in the amygdala, hippocampus, medial prefrontal cortex, and the nucleus accumbens of rats after AIE in adolescence and adulthood. AIE induces differential gene expression of m6A modifiers, with some brain regions being more affected during adolescence, while other limbic brain regions show long-lasting changes in adulthood. We observed that Mettl3 mRNA levels were significantly increased in the amygdala and medial prefrontal cortex in adulthood after AIE, as measured by real-time polymerase chain reaction. We further evaluated changes in METTL3 expression and global m6A methylation in amygdala nuclei using a histochemical procedure. Indeed, protein and mRNA levels of METTL3, as well as m6A levels, were upregulated in the central and medial nucleus of the amygdala after AIE in adulthood. We pharmacologically inhibited METTL3 activity using STM2457, which significantly attenuated AIE-induced anxiety-like behaviors in adulthood. These results suggest that m6A epitranscriptomics can serve as a novel avenue in the exploration of therapeutics for AIE-induced adult psychopathology.

青少年间歇性乙醇（AIE）暴露通过对生命后期的表观遗传机制和行为表型产生持久影响，影响多个大脑区域。最近，研究表明表观遗传开关可以控制表观转录组学或RNA修饰。具体来说，最丰富的RNA修饰，被称为n6 -甲基腺苷（m6A），一直是大脑可塑性研究的重点；然而，对其在AIE后成人精神病理中的作用知之甚少。在此，我们使用动物模型研究了AIE后m6A修饰因子（书写、擦除和读取器）的变化是否会调节成年期焦虑的表型。我们研究了青春期和成年期AIE后大鼠杏仁核、海马、内侧前额叶皮层和伏隔核中的m6A调节因子。AIE诱导m6A修饰因子的差异基因表达，一些大脑区域在青春期受到的影响更大，而其他大脑边缘区域在成年期表现出持久的变化。我们观察到，通过实时聚合酶链反应（real-time polymerase chain reaction）测量，AIE后成人杏仁核和内侧前额叶皮层的Mettl3 mRNA水平显著升高。我们使用组织化学方法进一步评估了杏仁核中METTL3表达和m6A甲基化的变化。事实上，成年AIE后，杏仁核中央和内侧核的METTL3蛋白和mRNA水平以及m6A水平上调。我们使用STM2457从药理学上抑制了METTL3的活性，显著减轻了成年期aie诱导的焦虑样行为。这些结果表明，m6A表转录组学可以作为探索aie诱导的成人精神病理治疗方法的新途径。

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引用次数: 0

Protective effects of phosphodiesterase 5 inhibitor, mirodenafil, on traumatic brain injury-induced neuronal death 磷酸二酯酶5抑制剂咪洛地那非对外伤性脑损伤所致神经元死亡的保护作用

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI: 10.1016/j.neuropharm.2025.110787

Min Kyu Park , Hyun Wook Yang , Seo Young Woo , Hyun Ho Jung , Sol Jae Shin , Bo Young Choi , Jai Jun Choung , Sang Won Suh

Traumatic brain injury (TBI) is a serious neurological condition caused by external physical forces that lead to extensive brain damage. The underlying pathological processes involve complex interactions, including neuronal death driven by cerebrovascular dysfunction, inflammation, and oxidative stress. A key contributor to these processes is the enzyme phosphodiesterase 5 (PDE5), which reduces cyclic guanosine monophosphate (cGMP) levels, leading to impaired vasodilation, reduced cerebral blood flow, and disruption of protective cellular pathways.

Nitric oxide (NO) and zinc play significant roles in the progression of TBI-related damage. NO is a signaling molecule that supports cerebral blood flow and redox balance by boosting antioxidant defenses such as glutathione (GSH) levels. Zinc, an essential element for neural function, can become toxic in excess, contributing to oxidative stress and neuronal damage. During TBI, reduced NO availability and disrupted zinc homeostasis exacerbate these harmful effects, with increased PDE5 activity further depleting cGMP and limiting the activation of protective factors like Nrf2 and HO-1. This study explores the therapeutic potential of mirodenafil, a PDE5 inhibitor, in mitigating TBI-induced damage. Administered subcutaneously at 2 mg/kg, mirodenafil was evaluated through histological and biochemical techniques, including markers for neuronal degeneration, zinc accumulation, and NO synthesis. Results showed that mirodenafil reduced neuronal loss, regulated zinc levels, and restored NO signaling.

These findings suggest that mirodenafil supports neuronal survival by preserving cGMP levels, enhancing NO function, and mitigating oxidative stress related to zinc dysregulation. This study highlights mirodenafil as a potential therapeutic option for limiting TBI-induced neuronal injury and preserving brain function.

外伤性脑损伤（TBI）是一种由外部物理力引起的严重神经系统疾病，可导致广泛的脑损伤。潜在的病理过程涉及复杂的相互作用，包括由脑血管功能障碍、炎症和氧化应激驱动的神经元死亡。这些过程的一个关键因素是磷酸二酯酶5 (PDE5)，它降低环鸟苷单磷酸（cGMP）水平，导致血管舒张受损，脑血流量减少，并破坏保护性细胞通路。一氧化氮（NO）和锌在tbi相关损伤的进展中起重要作用。NO是一种信号分子，通过提高抗氧化防御如谷胱甘肽（GSH）水平来支持脑血流量和氧化还原平衡。锌是神经功能的基本元素，如果过量，会产生毒性，导致氧化应激和神经元损伤。在脑损伤期间，NO可用性降低和锌稳态破坏加剧了这些有害影响，PDE5活性增加进一步消耗cGMP并限制Nrf2和HO-1等保护因子的激活。本研究探讨了咪洛地那非（一种PDE5抑制剂）在减轻tbi引起的损伤方面的治疗潜力。以2mg /kg皮下给药，通过组织学和生化技术评估美洛地那非，包括神经元变性、锌积累和NO合成的标志物。结果表明，咪洛地那非减少神经元丢失，调节锌水平，恢复NO信号。这些发现表明，美洛地那非通过保持cGMP水平、增强NO功能和减轻锌失调相关的氧化应激来支持神经元存活。这项研究强调了咪洛地那非作为限制tbi诱导的神经元损伤和保持脑功能的潜在治疗选择。

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引用次数: 0

Enteric gliosis induced by TRPV4 alleviates intestinal excessive-motility through Ca2+ signaling TRPV4诱导的肠胶质瘤通过Ca2+信号通路缓解肠道过度运动。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-16 DOI: 10.1016/j.neuropharm.2025.110807

Qianshan Tan , Teming Li , Huichao Xie , Yihui Chen , Shuaishuai Chen , Chenbang Xu , Feng Yang , Hui Dong , Jun Chen , WeiDong Xiao

Background

Gastrointestinal (GI) dysmotility is a fundamental clinical issue in multiple diseases such as IBS, and there is a critical requirement for drugs to precisely modulate excessive GI motility. Enteric glial cells (EGCs) are one of the major components of enteric nervous system, which is the key regulator of GI motility. EGCs undergo gliosis in response to multiple stimulation. Among them, mechanical stimulation is the most common stimulation and its motility-promoting effect been proved. However, whether mechanical stimulation could exert an motility-inhibitory effect remained to be elaborated.

Methods

GI motility was assessed by transit time, excreted/retained feces and water content. qPCR, western blotting and immunofluorescence were employed to analyze TRPV4 expression in EGCs. Furthermore, Enteric Gliosis was analyzed by proliferation, activation and neuroinflammation of EGCs. Intracellular Ca²⁺ concentration were analyzed by Ca²⁺ imaging. High-throughput sequencing was used to explore the mechanism of TRPV4.

Results

Firstly, TRPV4 activation suppressed GI motility in vivo. Secondly, TRPV4 was expressed in EGCs and activation of TRPV4 inhibited GI motility by promoting Enteric Gliosis. Furthermore, TRPV4 activation promotes EGCs Ca²⁺ signaling, and TRPV4 is required for the regulation of EGCs Ca²⁺ signaling and gliosis by CaCl₂, CaSR, and ATP. Lastly, TRPV4 activation promotes Enteric Gliosis and corrects abnormal GI motility of pathological diarrhea in vivo.

Conclusion

TRPV4 were identified as a novel accelerator of Enteric Gliosis and suppressor of GI motility. Activation of TRPV4 effectively restoring GI motility homeostasis and offering a potential drug target for gastrointestinal dysmotility.

背景：胃肠道（GI）运动障碍是肠易激综合征等多种疾病的一个基本临床问题，迫切需要药物来精确调节过度的胃肠道运动。肠胶质细胞（Enteric glial cells, EGCs）是肠神经系统的主要组成部分之一，是胃肠运动的关键调节因子。EGCs在多重刺激下发生胶质瘤。其中，机械刺激是最常见的刺激，其促进运动的作用已被证实。然而，机械刺激是否能发挥运动抑制作用仍有待阐明。方法：测定胃肠运动时间、排泄/滞留粪便及水分含量。采用qPCR、western blotting和免疫荧光法分析TRPV4在EGCs中的表达。此外，通过EGCs的增殖、活化和神经炎症分析肠胶质瘤形成。通过Ca2+成像分析细胞内Ca2+浓度。利用高通量测序技术探索TRPV4的作用机制。结果：首先，激活TRPV4可抑制体内胃肠道运动。其次，TRPV4在EGCs中表达，激活TRPV4通过促进肠胶质瘤形成抑制GI运动。此外，TRPV4激活促进EGCs Ca2+信号转导，并且TRPV4是通过CaCl2、CaSR和ATP调节EGCs Ca2+信号转导和胶质形成所必需的。最后，TRPV4的激活促进肠道胶质瘤形成，纠正体内病理性腹泻的胃肠道运动异常。结论：TRPV4是一种新的肠胶质瘤形成促进剂和胃肠道运动抑制剂。激活TRPV4可有效恢复胃肠道运动稳态，为治疗胃肠道运动障碍提供潜在的药物靶点。

{"title":"Enteric gliosis induced by TRPV4 alleviates intestinal excessive-motility through Ca2+ signaling","authors":"Qianshan Tan , Teming Li , Huichao Xie , Yihui Chen , Shuaishuai Chen , Chenbang Xu , Feng Yang , Hui Dong , Jun Chen , WeiDong Xiao","doi":"10.1016/j.neuropharm.2025.110807","DOIUrl":"10.1016/j.neuropharm.2025.110807","url":null,"abstract":"<div><h3>Background</h3><div>Gastrointestinal (GI) dysmotility is a fundamental clinical issue in multiple diseases such as IBS, and there is a critical requirement for drugs to precisely modulate excessive GI motility. Enteric glial cells (EGCs) are one of the major components of enteric nervous system, which is the key regulator of GI motility. EGCs undergo gliosis in response to multiple stimulation. Among them, mechanical stimulation is the most common stimulation and its motility-promoting effect been proved. However, whether mechanical stimulation could exert an motility-inhibitory effect remained to be elaborated.</div></div><div><h3>Methods</h3><div>GI motility was assessed by transit time, excreted/retained feces and water content. qPCR, western blotting and immunofluorescence were employed to analyze TRPV4 expression in EGCs. Furthermore, Enteric Gliosis was analyzed by proliferation, activation and neuroinflammation of EGCs. Intracellular Ca<sup>2+</sup> concentration were analyzed by Ca<sup>2+</sup> imaging. High-throughput sequencing was used to explore the mechanism of TRPV4.</div></div><div><h3>Results</h3><div>Firstly, TRPV4 activation suppressed GI motility in vivo. Secondly, TRPV4 was expressed in EGCs and activation of TRPV4 inhibited GI motility by promoting Enteric Gliosis. Furthermore, TRPV4 activation promotes EGCs Ca<sup>2+</sup> signaling, and TRPV4 is required for the regulation of EGCs Ca<sup>2+</sup> signaling and gliosis by CaCl<sub>2</sub>, CaSR, and ATP. Lastly, TRPV4 activation promotes Enteric Gliosis and corrects abnormal GI motility of pathological diarrhea in vivo.</div></div><div><h3>Conclusion</h3><div>TRPV4 were identified as a novel accelerator of Enteric Gliosis and suppressor of GI motility. Activation of TRPV4 effectively restoring GI motility homeostasis and offering a potential drug target for gastrointestinal dysmotility.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110807"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of 5-HT4 receptors reverses stress-induced dopamine system dysregulation 5-HT4受体的激活可逆转应激诱导的多巴胺系统失调

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.neuropharm.2025.110810

Olivia J. Yang , Stephanie M. Perez , Daniel J. Lodge

Stress can profoundly impact brain function, particularly in circuits regulating dopamine transmission. Increased mesolimbic dopamine activity is a well-documented consequence of stress exposure, contributing to maladaptive behavioral and cognitive outcomes. Previous studies have identified a multisynaptic circuit that modulates dopamine neuron population activity in the ventral tegmental area (VTA), highlighting potential intervention points for mitigating stress-induced dopamine dysregulation. One such target is the 5-hydroxytryptamine-4 receptor (5-HT4R), which is expressed in key brain regions involved in dopamine system regulation, making it a promising candidate for pharmacological intervention. Here, we demonstrate that the 5-HT4R agonist BIMU8 effectively restores normal dopamine system function following stress exposure without altering baseline dopamine population activity in control male rats. Interestingly, in female rats, BIMU8 increased dopamine neuron population activity specifically during proestrus and estrus, suggesting that estrogen may play a role in serotoninergic modulation of mesolimbic dopamine function. Intracranial administration of BIMU8 into multiple brain regions indicates that its effects may be mediated through modulation of activity in the nucleus accumbens (NAc). These findings highlight 5-HT4R activation as a potential strategy for normalizing stress-induced alterations in dopamine system function.

压力会深刻影响大脑功能，尤其是调节多巴胺传递的回路。中脑边缘多巴胺活动的增加是压力暴露的一个充分证明的后果，导致适应不良的行为和认知结果。先前的研究已经发现了一个调节腹侧被盖区（VTA）多巴胺神经元群活动的多突触回路，强调了减轻应激性多巴胺失调的潜在干预点。其中一个目标是5-羟色胺-4受体（5-HT4R），它在参与多巴胺系统调节的关键大脑区域表达，使其成为药物干预的有希望的候选者。在这里，我们证明了5-HT4R激动剂BIMU8可以有效地恢复应激暴露后正常的多巴胺系统功能，而不会改变对照雄性大鼠的基线多巴胺群活性。有趣的是，在雌性大鼠中，BIMU8增加了多巴胺神经元群的活性，特别是在发情前和发情期间，这表明雌激素可能在5 -羟色胺能调节中脑边缘多巴胺功能中发挥作用。脑内多个脑区注射BIMU8表明其作用可能通过调节伏隔核（NAc）的活性来介导。这些发现强调了5-HT4R激活是使应激诱导的多巴胺系统功能改变正常化的潜在策略。

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引用次数: 0