Pub Date : 2026-03-01Epub Date: 2025-12-11DOI: 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.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-12-15DOI: 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.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-12-02DOI: 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 GABAB receptor (GABABR) expression, but not GABAAR, expression in the DG. Administration of the GABABR 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 GABABR and CaMKII. GABABR blockade enhanced CaMKII phosphorylation and activated downstream effectors, including p-CREB and BDNF, indicating re-engagement of plasticity-related signaling. These findings demonstrate that GABABR 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 GABABR may thus offer a promising strategy to restore E/I balance and cognitive performance in a sAD-like rat model.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-11-21DOI: 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.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-12-04DOI: 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.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-12-16DOI: 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.
{"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}
Pub Date : 2026-03-01Epub Date: 2025-12-18DOI: 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.
{"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}
Pub Date : 2026-02-27DOI: 10.1016/j.neuropharm.2026.110893
Tao Zhu, Minxiu Ye, Chao Huang, Yilong Jiang, Yiming Gu, Ziwei Cao, Feng Xu, Jianbin Su, Rongrong Yang
High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previous studies have reported that a decline in microglia in the dentate gyrus, following initial microglial activation under stress, is an important mechanism mediating the pathogenesis of depression. As HFD can activate microglia, we hypothesize that dynamic changes in dentate gyrus microglia also mediate the development of depression-like behaviors under chronic HFD exposure. Our results showed that a 12-week HFD induced depression-like behaviors in mice, accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus. The reduction in microglia in the dentate gyrus of mice treated with a 12-week HFD was mediated by initial microglial activation and subsequent microglial damage. Suppressing initial microglial activation with minocycline prevented HFD-induced dentate gyrus microglial damage and decline, as well as the development of depression-like behaviors in HFD-treated mice. Furthermore, administration of lipopolysaccharide (LPS), a classical microglial stimulant that restored the number of microglia in the dentate gyrus of HFD mice, reversed the depression-like behaviors in mice given a 12-week HFD. These findings reveal a dynamic microglial response in the dentate gyrus underlying HFD-induced depression-like behaviors and suggest that modulating microglial dynamics may offer a potential strategy for preventing or treating depression caused by factors associated with high fat intake.
{"title":"Dentate gyrus microglial dynamics contributes to high-fat diet-induced depression-like behaviors in mice.","authors":"Tao Zhu, Minxiu Ye, Chao Huang, Yilong Jiang, Yiming Gu, Ziwei Cao, Feng Xu, Jianbin Su, Rongrong Yang","doi":"10.1016/j.neuropharm.2026.110893","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2026.110893","url":null,"abstract":"<p><p>High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previous studies have reported that a decline in microglia in the dentate gyrus, following initial microglial activation under stress, is an important mechanism mediating the pathogenesis of depression. As HFD can activate microglia, we hypothesize that dynamic changes in dentate gyrus microglia also mediate the development of depression-like behaviors under chronic HFD exposure. Our results showed that a 12-week HFD induced depression-like behaviors in mice, accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus. The reduction in microglia in the dentate gyrus of mice treated with a 12-week HFD was mediated by initial microglial activation and subsequent microglial damage. Suppressing initial microglial activation with minocycline prevented HFD-induced dentate gyrus microglial damage and decline, as well as the development of depression-like behaviors in HFD-treated mice. Furthermore, administration of lipopolysaccharide (LPS), a classical microglial stimulant that restored the number of microglia in the dentate gyrus of HFD mice, reversed the depression-like behaviors in mice given a 12-week HFD. These findings reveal a dynamic microglial response in the dentate gyrus underlying HFD-induced depression-like behaviors and suggest that modulating microglial dynamics may offer a potential strategy for preventing or treating depression caused by factors associated with high fat intake.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110893"},"PeriodicalIF":4.6,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326714","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}
Pub Date : 2026-02-15Epub Date: 2025-11-26DOI: 10.1016/j.neuropharm.2025.110785
Xiaofan Li , Guang Shi , Wanshu Guo , Kaishu Wen , Yifei Liu , Jiayue Cheng , Meichi Liu , Yuehui Yang , Xinyu Fan
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.
{"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}
Pub Date : 2026-02-15Epub Date: 2025-11-21DOI: 10.1016/j.neuropharm.2025.110778
Amanda M. Acuña , Rebecca Whittington , Emma Peacock , Serena E. Rodarte , Justin L. Legg , Erin K. Nagy , Annabel Carlson , Hiba Siddiqui , Julie W. Karugu , M. Foster Olive
Methamphetamine (METH) use produces lasting elevations in peripheral and central inflammation that correspond to cognitive and behavioral deficits, which may contribute to the likelihood of relapse. Though a great deal of research over the last few decades has attempted to investigate pharmacotherapies to help facilitate long term abstinence from METH, there are still no FDA approved medications to treat METH use disorders. Our laboratory recently showed that markers of neuroinflammation persist three weeks into abstinence following prolonged (96 h/week for 3 weeks) access to METH self-administration. We also showed that medial prefrontal cortex (mPFC) mediated behavioral flexibility deficits observed at this timepoint are attenuated by the COX-2 inhibitor parecoxib. Given the role of microglia in central inflammatory processes, the current work utilized immunohistochemistry to determine whether COX-2 expression in microglia was elevated in the mPFC during abstinence from METH. We also sought to determine if METH-induced changes in microglial morphology could potentially be altered by COX-2 inhibition. We found that the number of COX-2 expressing cells was elevated in the mPFC of rats that self-administered METH compared to those that self-administered saline. Surprisingly, COX-2 immunoreactivity was absent in microglia but was predominantly observed in neurons. Most COX-2 immunoreactivity was detected in glutamatergic neurons in both sexes, while males exhibited a reduction in COX-2 expression in GABAergic neurons. COX-2 immunoreactivity was frequently absent from the infralimbic and cingulate cortices and was therefore not analyzed. Paired with our prior findings that COX-2 inhibition attenuates METH-induced behavioral deficits known to be mediated by the mPFC, these results suggest that altered neuronal COX-2 expression should be investigated for its influence on METH-induced deficits in mPFC function.
{"title":"Cyclooxygenase 2 (COX-2) expression is elevated in prefrontal cortex neurons, not microglia, following methamphetamine self-administration in male and female rats","authors":"Amanda M. Acuña , Rebecca Whittington , Emma Peacock , Serena E. Rodarte , Justin L. Legg , Erin K. Nagy , Annabel Carlson , Hiba Siddiqui , Julie W. Karugu , M. Foster Olive","doi":"10.1016/j.neuropharm.2025.110778","DOIUrl":"10.1016/j.neuropharm.2025.110778","url":null,"abstract":"<div><div>Methamphetamine (METH) use produces lasting elevations in peripheral and central inflammation that correspond to cognitive and behavioral deficits, which may contribute to the likelihood of relapse. Though a great deal of research over the last few decades has attempted to investigate pharmacotherapies to help facilitate long term abstinence from METH, there are still no FDA approved medications to treat METH use disorders. Our laboratory recently showed that markers of neuroinflammation persist three weeks into abstinence following prolonged (96 h/week for 3 weeks) access to METH self-administration. We also showed that medial prefrontal cortex (mPFC) mediated behavioral flexibility deficits observed at this timepoint are attenuated by the COX-2 inhibitor parecoxib. Given the role of microglia in central inflammatory processes, the current work utilized immunohistochemistry to determine whether COX-2 expression in microglia was elevated in the mPFC during abstinence from METH. We also sought to determine if METH-induced changes in microglial morphology could potentially be altered by COX-2 inhibition. We found that the number of COX-2 expressing cells was elevated in the mPFC of rats that self-administered METH compared to those that self-administered saline. Surprisingly, COX-2 immunoreactivity was absent in microglia but was predominantly observed in neurons. Most COX-2 immunoreactivity was detected in glutamatergic neurons in both sexes, while males exhibited a reduction in COX-2 expression in GABAergic neurons. COX-2 immunoreactivity was frequently absent from the infralimbic and cingulate cortices and was therefore not analyzed. Paired with our prior findings that COX-2 inhibition attenuates METH-induced behavioral deficits known to be mediated by the mPFC, these results suggest that altered neuronal COX-2 expression should be investigated for its influence on METH-induced deficits in mPFC function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"284 ","pages":"Article 110778"},"PeriodicalIF":4.6,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588172","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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