Neuropharmacology最新文献_第6页

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

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

{"title":"Exosome therapy protects the hippocampus in mice exposed to chronic methamphetamine: Insights into angiogenic and inflammatory signaling pathways","authors":"Solmaz Fallahi , Hamid Soltani Zangbar , Fariba Ghiasi , Gisou Mohaddes , Fereshteh Farajdokht","doi":"10.1016/j.neuropharm.2025.110790","DOIUrl":"10.1016/j.neuropharm.2025.110790","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110790"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658874","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

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

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

{"title":"Antisense oligonucleotide of cargo adaptor BICD2 long-term effectively alleviates neuropathic pain via activation of PSD95 in the mouse spinal dorsal horn","authors":"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","doi":"10.1016/j.neuropharm.2025.110793","DOIUrl":"10.1016/j.neuropharm.2025.110793","url":null,"abstract":"<div><div>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 (<em>i.t.</em>) administered <em>Bicd2</em>-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 <em>Bicd2</em> siRNA and <em>Bicd2</em> ASO delivered via <em>i.t.</em> 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 <em>Bicd2</em> 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 <em>Bicd2</em> ASO for sustained pain management.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110793"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687757","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

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

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

{"title":"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","authors":"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","doi":"10.1016/j.neuropharm.2025.110804","DOIUrl":"10.1016/j.neuropharm.2025.110804","url":null,"abstract":"<div><div>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 <em>in vivo</em> pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110804"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752014","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

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

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

{"title":"Downregulation of SNORD20 promotes ferroptosis in corpus cavernosum smooth muscle cells from diabetic rats through inducing the mitochondrial dysfunction","authors":"Yiyu Qin , Wenjie Huang , Yang Zhou , Yuping Chen , Jian Li , Zhiyue Wu","doi":"10.1016/j.neuropharm.2025.110805","DOIUrl":"10.1016/j.neuropharm.2025.110805","url":null,"abstract":"<div><div>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, Fe<sup>2+</sup> 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 <em>in vivo</em>. 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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110805"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775129","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

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

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

{"title":"GABAB receptor blockade in the dentate gyrus restores glutamatergic synaptic plasticity and hippocampus dependent memory in an AD-like rat model","authors":"Jianzhou Chen , Yuening Tian , Linping Wang , Zihan Zhang , Qinghua Jin , Bin Xiao","doi":"10.1016/j.neuropharm.2025.110789","DOIUrl":"10.1016/j.neuropharm.2025.110789","url":null,"abstract":"<div><div>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 (<sub>S</sub>AD)-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. <em>In vivo</em> microdialysis combined with HPLC during MWM training revealed decreased GABA levels and selective upregulation of GABA<sub>B</sub> receptor (GABA<sub>B</sub>R) expression, but not GABA<sub>A</sub>R, expression in the DG. Administration of the GABA<sub>B</sub>R 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<sub>B</sub>R and CaMKII. GABA<sub>B</sub>R 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<sub>B</sub>R upregulation in the DG impairs glutamatergic synaptic plasticity and memory function in sAD like rats, likely <em>via</em> direct suppression of the CaMKII/CREB/BDNF pathway. Targeting GABA<sub>B</sub>R may thus offer a promising strategy to restore E/I balance and cognitive performance in a sAD-like rat model.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110789"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678172","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

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

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

{"title":"Emerging role of N6-methyladenosine (m6A) epitranscriptomic changes in adult anxiety after adolescent alcohol exposure","authors":"Emir Malovic , Jamuna Tandukar , Huaibo Zhang , Lalith K. Venkareddy , Ruixuan Gao , Subhash C. Pandey","doi":"10.1016/j.neuropharm.2025.110777","DOIUrl":"10.1016/j.neuropharm.2025.110777","url":null,"abstract":"<div><div>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 <em>Mettl3</em> 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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110777"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588132","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

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

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

{"title":"Protective effects of phosphodiesterase 5 inhibitor, mirodenafil, on traumatic brain injury-induced neuronal death","authors":"Min Kyu Park , Hyun Wook Yang , Seo Young Woo , Hyun Ho Jung , Sol Jae Shin , Bo Young Choi , Jai Jun Choung , Sang Won Suh","doi":"10.1016/j.neuropharm.2025.110787","DOIUrl":"10.1016/j.neuropharm.2025.110787","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110787"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693107","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

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

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

{"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

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

{"title":"Activation of 5-HT4 receptors reverses stress-induced dopamine system dysregulation","authors":"Olivia J. Yang , Stephanie M. Perez , Daniel J. Lodge","doi":"10.1016/j.neuropharm.2025.110810","DOIUrl":"10.1016/j.neuropharm.2025.110810","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110810"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788149","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

Oxytocin may promote hippocampal neurogenesis in ischemic stroke rats via a pathway related to DNMT1-mediated Wnt3a/β-catenin 催产素可能通过dnmt1介导的Wnt3a/β-catenin通路促进缺血性脑卒中大鼠海马神经发生

IF 4.6 2区医学

Neuropharmacology Pub Date : 2026-02-15 Epub Date: 2025-11-26 DOI: 10.1016/j.neuropharm.2025.110785

Xiaofan Li , Guang Shi , Wanshu Guo , Kaishu Wen , Yifei Liu , Jiayue Cheng , Meichi Liu , Yuehui Yang , Xinyu Fan

{"title":"Oxytocin may promote hippocampal neurogenesis in ischemic stroke rats via a pathway related to DNMT1-mediated Wnt3a/β-catenin","authors":"Xiaofan Li , Guang Shi , Wanshu Guo , Kaishu Wen , Yifei Liu , Jiayue Cheng , Meichi Liu , Yuehui Yang , Xinyu Fan","doi":"10.1016/j.neuropharm.2025.110785","DOIUrl":"10.1016/j.neuropharm.2025.110785","url":null,"abstract":"<div><div>DNA methylation plays a pivotal role in neuroprotection after ischemic stroke. Oxytocin, a neuropeptide renowned for its involvement anti-inflammatory and antioxidant activities, emerges as a promising candidate for the treatment of stroke. Here, we employed a transient middle cerebral artery occlusion (tMCAO) rat model to explore the underlying mechanisms of oxytocin's therapeutic potential. We utilized the Morris Water Maze, novel object recognition, and intruder tests to assess spatial memory, cognitive memory, and social memory abilities in rats, respectively. RNA sequencing and Western blotting were employed to detect alterations in mRNA expression and protein expression levels in the hippocampus. Daily oxytocin administration (0.1 and 1.0 mg/kg, subcutaneous) for seven days significantly reduced infarct volume, restored the expression of 1100 genes, including NQO1 and HO1, and robustly promoted hippocampal neurogenesis in tMCAO rats. These effects translated into enhanced neurological function and improved learning and memory abilities. Remarkably, our findings reveal that oxytocin-induced neurogenesis is intimately linked to the activation of the Wnt3a/β-catenin signaling pathway with Nrf2 as a key downstream target. Furthermore, it is possible that oxytocin, acting through its receptors, inhibited the tMCAO-induced binding of DNMT1 to MeCP2, thereby preventing the increase in DNA methylation at the Wnt3a gene. In summary, our study implies a possible involvement of oxytocin in the activation of the DNMT1-mediated Wnt3a/β-catenin signaling pathway. It may contribute to enhancing hippocampal neurogenesis and ameliorating memory impairments in rats with ischemic stroke. This hints that oxytocin holds great promise as a potential therapeutic agent for promoting post-stroke neurogenesis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110785"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616529","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}

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