Pub Date : 2025-12-14DOI: 10.1016/j.neuropharm.2025.110808
Hao-Ran Li , Jun-Zhuo Shi , Meng-Jie Zhang , Lu-Yao Yun , Yun-Feng Zhou , Yang-Yang He , Xi Li , Guan-Hua Du , Xiao-Bin Pang , Meng-Wei Wang , Xin-Mei Xie , Jie-Jian Kou
Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ25-35-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.
{"title":"Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation","authors":"Hao-Ran Li , Jun-Zhuo Shi , Meng-Jie Zhang , Lu-Yao Yun , Yun-Feng Zhou , Yang-Yang He , Xi Li , Guan-Hua Du , Xiao-Bin Pang , Meng-Wei Wang , Xin-Mei Xie , Jie-Jian Kou","doi":"10.1016/j.neuropharm.2025.110808","DOIUrl":"10.1016/j.neuropharm.2025.110808","url":null,"abstract":"<div><div>Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including <em>C5ar1</em>, <em>Gabrg1</em>, <em>Ptger1</em>, <em>Tac1</em>, <em>Lpar2</em>, <em>Pnp2</em>, <em>Cftr</em>, and <em>Sstr3</em>. PCR-based validation in both <em>in vivo</em> and <em>in vitro</em> models confirmed Cftr as the most promising candidate for further investigation. In Aβ<sub>25</sub>-<sub>35</sub>-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110808"},"PeriodicalIF":4.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768687","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 : 2025-12-12DOI: 10.1016/j.neuropharm.2025.110806
Yanman Liu , Jimei Zhang , Wenjuan Li , Qingwen Qu , Zhengxing Shan , Chunwei Liu , Ke Jiao , Xueqin Hou
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen–cholinergic–NGF axis: E2, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.
{"title":"Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis","authors":"Yanman Liu , Jimei Zhang , Wenjuan Li , Qingwen Qu , Zhengxing Shan , Chunwei Liu , Ke Jiao , Xueqin Hou","doi":"10.1016/j.neuropharm.2025.110806","DOIUrl":"10.1016/j.neuropharm.2025.110806","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen–cholinergic–NGF axis: E<sub>2</sub>, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"286 ","pages":"Article 110806"},"PeriodicalIF":4.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757148","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 : 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":"2025-12-11","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 : 2025-12-05DOI: 10.1016/j.neuropharm.2025.110801
Anjali Chauhan , Eunyoung Angela Lee , Rakesh B. Patel , Mariia Kumskova , Enrique C. Leira , Anil K. Chauhan , Yanrong Shi , Suyi Cao , Raymond C. Koehler , Krishnan M. Dhandapani , Mohammad Badruzzaman Khan , Pradip K. Kamat , Ali Arbab , David C. Hess , Alison L. Herman , Ligia Boisserand , Lauren H. Sansing , Andreia Morais , Xuyan Jin , Sanem Aykan , Jaroslaw Aronowski
Inflammation, particularly mediated through interleukin-6 (IL-6) signaling, plays a critical role in stroke pathophysiology. High levels of IL-6 are associated with poor outcomes in stroke patients. Therapeutic inhibition of IL-6 signaling may offer a novel strategy to mitigate post-stroke damage and improve recovery. This study evaluated the efficacy of tocilizumab (TCZ), a clinically approved monoclonal antibody that blocks IL-6 receptor signaling, using data from the Stroke Preclinical Assessment Network (SPAN), a multi-center, randomized, blinded, placebo-controlled trial in preclinical stroke models.
Methods
We analyzed behavioral and MRI morphometry data from 701 rodents (both males and females; 1:1), including healthy young mice, diet-induced obese mice, aging mice, and spontaneously hypertensive rats (SHR) treated with saline (N = 348) or TCZ (N = 353) at a dose of 100 mg/kg for mice, 10 mg/kg for rats after middle cerebral artery occlusion (MCAO).
Results
In the overall mouse cohort, TCZ did not significantly improve long-term sensorimotor recovery or reduce brain tissue loss measured by MRI. However, aging mice exhibited modest motor function improvements. In SHRs, TCZ treatment resulted in improved sensory-motor function, particularly in male rats, as demonstrated by enhanced corner test scores on days 7 and 28 post-MCAO. While TCZ in SHRs provided early (day 2) cerebroprotection with reduced lesion volume, it did not alter subsequent tissue loss, as measured by tissue atrophy at day 30.
Conclusions
These results suggest that IL-6R blockade with TCZ was associated with functional improvement in aging mice (modest) and hypertensive rats (notably males), without durable effect of brain tissue loss. No benefit was observed in the overall mouse cohort. These findings support IL-6 signaling as a viable therapeutic target and warrant further investigation into IL-6 receptor inhibition as a potential treatment strategy for stroke recovery.
{"title":"Evaluating tocilizumab in ischemic stroke: Findings from the SPAN multicenter trial","authors":"Anjali Chauhan , Eunyoung Angela Lee , Rakesh B. Patel , Mariia Kumskova , Enrique C. Leira , Anil K. Chauhan , Yanrong Shi , Suyi Cao , Raymond C. Koehler , Krishnan M. Dhandapani , Mohammad Badruzzaman Khan , Pradip K. Kamat , Ali Arbab , David C. Hess , Alison L. Herman , Ligia Boisserand , Lauren H. Sansing , Andreia Morais , Xuyan Jin , Sanem Aykan , Jaroslaw Aronowski","doi":"10.1016/j.neuropharm.2025.110801","DOIUrl":"10.1016/j.neuropharm.2025.110801","url":null,"abstract":"<div><div>Inflammation, particularly mediated through interleukin-6 (IL-6) signaling, plays a critical role in stroke pathophysiology. High levels of IL-6 are associated with poor outcomes in stroke patients. Therapeutic inhibition of IL-6 signaling may offer a novel strategy to mitigate post-stroke damage and improve recovery. This study evaluated the efficacy of tocilizumab (TCZ), a clinically approved monoclonal antibody that blocks IL-6 receptor signaling, using data from the Stroke Preclinical Assessment Network (SPAN), a multi-center, randomized, blinded, placebo-controlled trial in preclinical stroke models.</div></div><div><h3>Methods</h3><div>We analyzed behavioral and MRI morphometry data from 701 rodents (both males and females; 1:1), including healthy young mice, diet-induced obese mice, aging mice, and spontaneously hypertensive rats (SHR) treated with saline (N = 348) or TCZ (N = 353) at a dose of 100 mg/kg for mice, 10 mg/kg for rats after middle cerebral artery occlusion (MCAO).</div></div><div><h3>Results</h3><div>In the overall mouse cohort, TCZ did not significantly improve long-term sensorimotor recovery or reduce brain tissue loss measured by MRI. However, aging mice exhibited modest motor function improvements. In SHRs, TCZ treatment resulted in improved sensory-motor function, particularly in male rats, as demonstrated by enhanced corner test scores on days 7 and 28 post-MCAO. While TCZ in SHRs provided early (day 2) cerebroprotection with reduced lesion volume, it did not alter subsequent tissue loss, as measured by tissue atrophy at day 30.</div></div><div><h3>Conclusions</h3><div>These results suggest that IL-6R blockade with TCZ was associated with functional improvement in aging mice (modest) and hypertensive rats (notably males), without durable effect of brain tissue loss. No benefit was observed in the overall mouse cohort. These findings support IL-6 signaling as a viable therapeutic target and warrant further investigation into IL-6 receptor inhibition as a potential treatment strategy for stroke recovery.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110801"},"PeriodicalIF":4.6,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701436","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 : 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":"2025-12-04","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 : 2025-12-03DOI: 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.
{"title":"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","authors":"Caryssa R. Drinkuth , Ana Paula S. Dornellas , Sara Guarino , Montserrat Navarro , Todd E. Thiele","doi":"10.1016/j.neuropharm.2025.110792","DOIUrl":"10.1016/j.neuropharm.2025.110792","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110792"},"PeriodicalIF":4.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687727","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 : 2025-12-03DOI: 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.
{"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":"2025-12-03","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}
Pub 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":"2025-12-02","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}
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.
{"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":"2025-12-01","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}
Pub Date : 2025-11-30DOI: 10.1016/j.neuropharm.2025.110788
Kexin Yu , Min Li , Yuchen Jin, Miao Zhao, Zeliang Wang, Haibo Yu
Chronic pain management remains a major clinical challenge, limited by the efficacy and safety profile of existing analgesics. The P2X7 receptor (P2X7R), a key driver of neuroinflammatory signaling, represents a promising therapeutic target; however, the clinical advancement of P2X7R antagonists has been hindered by limited efficacy and marked species differences in pharmacological activity. Here, we identify cinobufagin (CBG) as a novel, human-selective allosteric antagonist of P2X7R. CBG potently inhibited human P2X7R in functional assays measuring YO-PRO-1 uptake, calcium flux, and electrophysiological responses, but exhibited minimal activity against rat P2X7R or other P2X subtypes. Structural modeling and mutagenesis confirmed CBG's engagement with the canonical allosteric pocket, with residues F103 and M105 being critical for binding. Notably, species selectivity was determined not by variations within the binding pocket itself, but by distal extracellular domains. We further identified key discriminatory residues (R126, S165, I170, R270, Y288, N303) as novel molecular determinants of this selectivity. In a murine model of complete Freund's adjuvant (CFA)-induced inflammatory pain, CBG demonstrated significant analgesic efficacy. Comprehensive electrophysiological profiling also confirmed its selectivity against other major pain-related ion channels. Collectively, our work elucidates CBG's mechanism of action and reveals a paradigm in which allosteric modulation of P2X7R can be governed by long-range conformational influences from distal extracellular domains, rather than solely by direct ligand-pocket interactions.
{"title":"Analgesic effect of cinobufagin is mediated by human-selective P2X7R antagonism governed by distinct extracellular domains","authors":"Kexin Yu , Min Li , Yuchen Jin, Miao Zhao, Zeliang Wang, Haibo Yu","doi":"10.1016/j.neuropharm.2025.110788","DOIUrl":"10.1016/j.neuropharm.2025.110788","url":null,"abstract":"<div><div>Chronic pain management remains a major clinical challenge, limited by the efficacy and safety profile of existing analgesics. The P2X7 receptor (P2X7R), a key driver of neuroinflammatory signaling, represents a promising therapeutic target; however, the clinical advancement of P2X7R antagonists has been hindered by limited efficacy and marked species differences in pharmacological activity. Here, we identify cinobufagin (CBG) as a novel, human-selective allosteric antagonist of P2X7R. CBG potently inhibited human P2X7R in functional assays measuring YO-PRO-1 uptake, calcium flux, and electrophysiological responses, but exhibited minimal activity against rat P2X7R or other P2X subtypes. Structural modeling and mutagenesis confirmed CBG's engagement with the canonical allosteric pocket, with residues F103 and M105 being critical for binding. Notably, species selectivity was determined not by variations within the binding pocket itself, but by distal extracellular domains. We further identified key discriminatory residues (R126, S165, I170, R270, Y288, N303) as novel molecular determinants of this selectivity. In a murine model of complete Freund's adjuvant (CFA)-induced inflammatory pain, CBG demonstrated significant analgesic efficacy. Comprehensive electrophysiological profiling also confirmed its selectivity against other major pain-related ion channels. Collectively, our work elucidates CBG's mechanism of action and reveals a paradigm in which allosteric modulation of P2X7R can be governed by long-range conformational influences from distal extracellular domains, rather than solely by direct ligand-pocket interactions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"285 ","pages":"Article 110788"},"PeriodicalIF":4.6,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661622","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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