Pub Date : 2025-10-01DOI: 10.1016/j.neurot.2025.e00742
Sarah E. Hocevar , Brian C. Ross , Samantha R. Schwartz , Brooke M. Smiley , Brian J. Cummings , Aileen J. Anderson , Lonnie D. Shea
Spinal cord injury (SCI) causes the loss of motor function below the site of injury due to neuron loss and the severing of spinal tracts. The injury leads to the recruitment of circulating myeloid cells that create an inflammatory microenvironment and exacerbate cell death, with subsequent migration of fibroblasts and astrocytes that contribute to scar tissue that inhibits regeneration. Herein, we investigated a combinatorial treatment in a chronic cervical hemisection model involving cargo-less nanoparticles (NPs) administered acutely, and a multichannel bridge and microtubule stabilizer delivered chronically. NPs administration acutely for one-week post-injury contributed to improved paw placement on a ladder beam relative to vehicle control. Four weeks after injury, damaged tissue was resected, and a microporous, multichannel PLG bridge was inserted to reduce scar tissue and provide a substrate for axon regrowth. Epothilone D (epoD), a microtubule stabilizer, was also administered to further decrease fibrotic scar formation and improve axon elongation. Mice receiving a scaffold with NP treatment or epoD treatment had improved motor performance, but the combination of NP and epoD maximally improved function. In conjunction with this improved performance, mice that received NPs or epoD exhibited increased neuromuscular junction innervation, robust axon growth into the bridge, and both oligodendrocyte and Schwann-cell myelination of regenerating axons. Collectively, these results suggest that a combinatorial treatment plan targeting inflammation and scarring, a substrate for growth, and growth-promoting factors can improve motor performance following SCI.
脊髓损伤（SCI）是由于神经元丧失和脊髓束切断而导致损伤部位以下运动功能丧失。损伤导致循环骨髓细胞的募集，形成炎症微环境，加剧细胞死亡，随后成纤维细胞和星形胶质细胞迁移，形成疤痕组织，抑制再生。在此，我们研究了慢性颈椎半切模型的组合治疗，包括急性给药无货物纳米颗粒（NPs）和慢性给药多通道桥和微管稳定剂。相对于车辆控制，损伤后一周内急性给予NPs有助于改善脚爪在梯梁上的放置。损伤后4周，切除受损组织，插入微孔多通道PLG桥以减少疤痕组织并为轴突再生提供基质。微管稳定剂Epothilone D （epoD）也可进一步减少纤维化瘢痕形成并改善轴突伸长。接受NP处理或epoD处理的支架小鼠的运动性能得到改善，但NP和epoD的组合最大程度地改善了功能。与此同时，接受NPs或epoD的小鼠表现出神经肌肉连接处神经支配增加，轴突向桥内生长强劲，再生轴突的少突胶质细胞和雪旺细胞髓鞘形成。总之，这些结果表明，针对炎症和瘢痕形成、生长基质和生长促进因子的组合治疗方案可以改善脊髓损伤后的运动表现。
{"title":"Nanoparticle and epothilone D combinatorial intervention improves motor performance and regeneration in chronic cervical spinal cord injury","authors":"Sarah E. Hocevar , Brian C. Ross , Samantha R. Schwartz , Brooke M. Smiley , Brian J. Cummings , Aileen J. Anderson , Lonnie D. Shea","doi":"10.1016/j.neurot.2025.e00742","DOIUrl":"10.1016/j.neurot.2025.e00742","url":null,"abstract":"<div><div>Spinal cord injury (SCI) causes the loss of motor function below the site of injury due to neuron loss and the severing of spinal tracts. The injury leads to the recruitment of circulating myeloid cells that create an inflammatory microenvironment and exacerbate cell death, with subsequent migration of fibroblasts and astrocytes that contribute to scar tissue that inhibits regeneration. Herein, we investigated a combinatorial treatment in a chronic cervical hemisection model involving cargo-less nanoparticles (NPs) administered acutely, and a multichannel bridge and microtubule stabilizer delivered chronically. NPs administration acutely for one-week post-injury contributed to improved paw placement on a ladder beam relative to vehicle control. Four weeks after injury, damaged tissue was resected, and a microporous, multichannel PLG bridge was inserted to reduce scar tissue and provide a substrate for axon regrowth. Epothilone D (epoD), a microtubule stabilizer, was also administered to further decrease fibrotic scar formation and improve axon elongation. Mice receiving a scaffold with NP treatment or epoD treatment had improved motor performance, but the combination of NP and epoD maximally improved function. In conjunction with this improved performance, mice that received NPs or epoD exhibited increased neuromuscular junction innervation, robust axon growth into the bridge, and both oligodendrocyte and Schwann-cell myelination of regenerating axons. Collectively, these results suggest that a combinatorial treatment plan targeting inflammation and scarring, a substrate for growth, and growth-promoting factors can improve motor performance following SCI.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00742"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150277","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00757
Andrew A. Pieper , Bindu D. Paul
{"title":"Synergistic mitochondrial impairment by endogenously elevated cyanide and hydrogen sulfide in Down syndrome; commentary on: Cyanide overproduction impairs cellular bioenergetics in Down syndrome","authors":"Andrew A. Pieper , Bindu D. Paul","doi":"10.1016/j.neurot.2025.e00757","DOIUrl":"10.1016/j.neurot.2025.e00757","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00757"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177012","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}
Neuropathic pain poses a significant societal and clinical burden and is closely linked to neuroinflammation of the central nervous system. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of inflammatory processes and has been implicated in the development of nociceptive hypersensitivity. In this study, we aimed to elucidate the therapeutic potential and underlying mechanisms of STAT3 inhibition in a rodent model of neuropathic pain. Using behavioral assessments of nociceptive sensitivity and immunofluorescence analysis, we investigated the analgesic mechanisms of the intrathecal STAT3 inhibitor, Bt354, in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. Cellular and molecular markers of glial activation and inflammation were examined to assess the effects of Bt354 on neuroinflammatory pathways. Intrathecal administration of Bt354 significantly reduced CCI-induced mechanical allodynia and thermal hyperalgesia, accompanied by a marked decrease in phosphorylated STAT3 (pSTAT3) expression in spinal neurons. Bt354 treatment attenuated the polarization of M1-type microglia and A1-type astrocytes, suppressed inflammasome-related signaling, and mitigated neuroinflammatory responses. Importantly, Bt354 inhibited the nuclear translocation of neuronal pSTAT3, which is a critical step in regulating pro-inflammatory gene transcription. Moreover, CCI-induced angiogenesis and microglial phosphorylation of CREB and P38 were mitigated by pSTAT3 inhibition. These findings suggest that STAT3 plays a central role in the pathogenesis of neuropathic pain by regulating glial cell polarization and neuroinflammation. Targeting STAT3 with Bt354 may represent a promising therapeutic strategy for treating neuropathic pain.
{"title":"Intrathecal STAT3 inhibitor Bt354 ameliorates chronic constriction injury-induced nociceptive sensitization by modulating neuroinflammation","authors":"Hao-Jung Cheng , Nan-Fu Chen , Yueh-Chiao Tang , Po-Chang Shih , Wu-Fu Chen , Ya-Jen Chiu , Chun-Sung Sung , Zhi-Hong Wen","doi":"10.1016/j.neurot.2025.e00763","DOIUrl":"10.1016/j.neurot.2025.e00763","url":null,"abstract":"<div><div>Neuropathic pain poses a significant societal and clinical burden and is closely linked to neuroinflammation of the central nervous system. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of inflammatory processes and has been implicated in the development of nociceptive hypersensitivity. In this study, we aimed to elucidate the therapeutic potential and underlying mechanisms of STAT3 inhibition in a rodent model of neuropathic pain. Using behavioral assessments of nociceptive sensitivity and immunofluorescence analysis, we investigated the analgesic mechanisms of the intrathecal STAT3 inhibitor, Bt354, in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. Cellular and molecular markers of glial activation and inflammation were examined to assess the effects of Bt354 on neuroinflammatory pathways. Intrathecal administration of Bt354 significantly reduced CCI-induced mechanical allodynia and thermal hyperalgesia, accompanied by a marked decrease in phosphorylated STAT3 (pSTAT3) expression in spinal neurons. Bt354 treatment attenuated the polarization of M1-type microglia and A1-type astrocytes, suppressed inflammasome-related signaling, and mitigated neuroinflammatory responses. Importantly, Bt354 inhibited the nuclear translocation of neuronal pSTAT3, which is a critical step in regulating pro-inflammatory gene transcription. Moreover, CCI-induced angiogenesis and microglial phosphorylation of CREB and P38 were mitigated by pSTAT3 inhibition. These findings suggest that STAT3 plays a central role in the pathogenesis of neuropathic pain by regulating glial cell polarization and neuroinflammation. Targeting STAT3 with Bt354 may represent a promising therapeutic strategy for treating neuropathic pain.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00763"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258647","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00766
Baojie Wang , Yuxiu Xiao , Yufeng Chu , Chunjuan Wang , Hao Sun , Teng Huang , Danqing Qin , Xuetao Cao , Shuai Guo , Haotian Zhao , Xiumin Zhao , Shougang Guo
Approximately 25 %–40 % of anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) patients develop refractory disease with prolonged neurological deficits. We aim to evaluate the efficacy of B cell depletion therapy (BCDT) via CD20 antibodies versus conventional first-line immunotherapy only (intravenous methylprednisolone for 5 days, 0.4 g/kg intravenous immunoglobulin for 5 days, and ≥4 consecutive plasma exchange treatments, non-BCDT group) in treatment of severe NMDARE in the real-world setting. From multicenter cohort of severe NMDARE, 108 patients (ofatumumab group 36; rituxixmab group 36; non-BCDT group 36) were prospectively reviewed. The primary end point was the proportion of patients to achieving good outcomes (modified Rankin Scale scores ≤2) at 3 months. Secondary end points included longitudinal outcomes assessed by mRS scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores, cognitive function and adverse events (AEs). BCDT demonstrated a higher frequency of mRS scores ≤2 compared to non-BCDT at 3 months (ofatumumab 63.9 % vs. non-BCDT 36.1 %, p < 0.001; rituximab 55.6 % vs. non-BCDT 36.1 %, p = 0.007, respectively). Ofatumuamb showed superior therapeutic response at 1 month compared to both rituximab-treated patients (mean CASE score: 5.89 vs 7.91, p = 0.025) and non-BCDT treated patients (mean CASE score: 5.89 vs 9.97, p < 0.0001). All groups improved over 12 months, with significantly higher complete remission rates in BCDT groups (70.8 %–75 % vs. 55.6 %, p < 0.05). Five of 33 patients (15.2 %) experienced persistent mild cognitive impairment. AEs were mild-to moderate in severity. We calculated the probability of relapse-free as ofatumumab and rituximab reduced risk of disease relapses compared to non-BCDT (ofatumumab vs. non-BCDT: HR, 0.193; 95 % CI, 0.062–0.6; p = 0.007; rituximab vs. non-BCDT: HR, 0.265; 95 % CI, 0.089–0.787; p = 0.029). Therefore, we suggest that BCDT effectively promoted neurological recovery, and reduced relapse risk with favorable safety, while ofatumumab demonstrated superior efficacy in controlling early disease severity.
大约25% - 40%的抗n -甲基-d-天冬氨酸受体脑炎（NMDARE）患者发展为顽固性疾病，伴有长期的神经功能缺损。我们的目标是评估在现实世界中，通过CD20抗体的B细胞消耗疗法（BCDT）与传统的一线免疫疗法（静脉注射甲基强的松龙5天，静脉注射0.4 g/kg免疫球蛋白5天，连续≥4次血浆交换治疗，非BCDT组）治疗严重NMDARE的疗效。来自严重NMDARE多中心队列的108例患者（ofatumumab组36例；rituxxmab组36例；non-BCDT组36例）进行前瞻性回顾。主要终点是3个月时获得良好结局（修正Rankin量表评分≤2）的患者比例。次要终点包括mRS评分和自身免疫性脑炎临床评估量表（CASE）评分、认知功能和不良事件（ae）评估的纵向结局。3个月时，BCDT组mRS评分≤2的频率高于非BCDT组（ofatumumab组63.9%，非BCDT组36.1%,p < 0.001；利妥昔单抗组55.6%，非BCDT组36.1%,p = 0.007）。与利妥昔单抗治疗的患者（平均病例评分：5.89 vs 7.91, p = 0.025）和非bcdt治疗的患者（平均病例评分：5.89 vs 9.97, p < 0.0001）相比，Ofatumuamb在1个月时显示出更好的治疗反应。所有组在12个月内均有改善，BCDT组的完全缓解率明显更高（70.8% - 75% vs. 55.6%, p < 0.05）。33例患者中有5例（15.2%）出现持续性轻度认知障碍。ae的严重程度为轻度至中度。我们计算了无复发的概率，因为与非bcdt相比，ofatumumab和利妥昔单抗降低了疾病复发的风险（ofatumumab与非bcdt: HR， 0.193; 95% CI, 0.062-0.6; p = 0.007；利妥昔单抗与非bcdt: HR， 0.265; 95% CI, 0.089-0.787; p = 0.029）。因此，我们认为BCDT可有效促进神经系统恢复，降低复发风险，且安全性较好，而ofatumumab在控制早期疾病严重程度方面具有优越的疗效。
{"title":"Effectiveness of Anti-CD20 B cells depleting therapy versus conventional treatment in severe Anti-N-methyl-d-aspartate receptor encephalitis: A real-world multi-center prospective cohort study","authors":"Baojie Wang , Yuxiu Xiao , Yufeng Chu , Chunjuan Wang , Hao Sun , Teng Huang , Danqing Qin , Xuetao Cao , Shuai Guo , Haotian Zhao , Xiumin Zhao , Shougang Guo","doi":"10.1016/j.neurot.2025.e00766","DOIUrl":"10.1016/j.neurot.2025.e00766","url":null,"abstract":"<div><div>Approximately 25 %–40 % of anti-N-methyl-<span>d</span>-aspartate receptor encephalitis (NMDARE) patients develop refractory disease with prolonged neurological deficits. We aim to evaluate the efficacy of B cell depletion therapy (BCDT) via CD20 antibodies versus conventional first-line immunotherapy only (intravenous methylprednisolone for 5 days, 0.4 g/kg intravenous immunoglobulin for 5 days, and ≥4 consecutive plasma exchange treatments, non-BCDT group) in treatment of severe NMDARE in the real-world setting. From multicenter cohort of severe NMDARE, 108 patients (ofatumumab group 36; rituxixmab group 36; non-BCDT group 36) were prospectively reviewed. The primary end point was the proportion of patients to achieving good outcomes (modified Rankin Scale scores ≤2) at 3 months. Secondary end points included longitudinal outcomes assessed by mRS scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores, cognitive function and adverse events (AEs). BCDT demonstrated a higher frequency of mRS scores ≤2 compared to non-BCDT at 3 months (ofatumumab 63.9 % vs. non-BCDT 36.1 %, p < 0.001; rituximab 55.6 % vs. non-BCDT 36.1 %, p = 0.007, respectively). Ofatumuamb showed superior therapeutic response at 1 month compared to both rituximab-treated patients (mean CASE score: 5.89 vs 7.91, p = 0.025) and non-BCDT treated patients (mean CASE score: 5.89 vs 9.97, p < 0.0001). All groups improved over 12 months, with significantly higher complete remission rates in BCDT groups (70.8 %–75 % vs. 55.6 %, p < 0.05). Five of 33 patients (15.2 %) experienced persistent mild cognitive impairment. AEs were mild-to moderate in severity. We calculated the probability of relapse-free as ofatumumab and rituximab reduced risk of disease relapses compared to non-BCDT (ofatumumab vs. non-BCDT: HR, 0.193; 95 % CI, 0.062–0.6; p = 0.007; rituximab vs. non-BCDT: HR, 0.265; 95 % CI, 0.089–0.787; p = 0.029). Therefore, we suggest that BCDT effectively promoted neurological recovery, and reduced relapse risk with favorable safety, while ofatumumab demonstrated superior efficacy in controlling early disease severity.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00766"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308645","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00708
Tomohiro Nakamura , Anamika Sharma , Stuart A. Lipton
Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.
{"title":"Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases","authors":"Tomohiro Nakamura , Anamika Sharma , Stuart A. Lipton","doi":"10.1016/j.neurot.2025.e00708","DOIUrl":"10.1016/j.neurot.2025.e00708","url":null,"abstract":"<div><div>Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00708"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743323","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00735
Panxi Sun , Lili Wei , Xue Qin , Jia Luo , Dongsheng Fan , Yong Chen
Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.
{"title":"The GPR120 agonist TUG-891 mitigates ischemic brain injury by attenuating endoplasmic reticulum stress and apoptosis via the PI3K/AKT signaling pathway","authors":"Panxi Sun , Lili Wei , Xue Qin , Jia Luo , Dongsheng Fan , Yong Chen","doi":"10.1016/j.neurot.2025.e00735","DOIUrl":"10.1016/j.neurot.2025.e00735","url":null,"abstract":"<div><div>Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00735"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015859","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00734
Anthony T. Reder
{"title":"Two roads diverged in multiple sclerosis: When is switching therapy effective?","authors":"Anthony T. Reder","doi":"10.1016/j.neurot.2025.e00734","DOIUrl":"10.1016/j.neurot.2025.e00734","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00734"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008405","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00732
Agamjot Sangotra , Satya L. Reddy , Curtis J. Kuo , Weiguo Xiang , Diane E. Merry , Christopher Grunseich , Shaomeng Wang , Andrew P. Lieberman
Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome. We show that the AR PROTAC degrader ARD-1676 clears polyQ AR in an over-expression system, in patient iPSC-derived induced motor neurons and skeletal muscle cells, and in a gene targeted mouse model of disease. Furthermore, we demonstrate that 24-h treatment with ARD-1676 rescues transcriptional dysregulation in SBMA induced skeletal muscle cells. These data provide evidence of therapeutic efficacy and in vivo target engagement, establishing AR PROTAC degraders as potential therapeutic agents for the treatment of SBMA.
{"title":"PROTACs therapeutically target the polyglutamine androgen receptor in spinal and bulbar muscular atrophy models","authors":"Agamjot Sangotra , Satya L. Reddy , Curtis J. Kuo , Weiguo Xiang , Diane E. Merry , Christopher Grunseich , Shaomeng Wang , Andrew P. Lieberman","doi":"10.1016/j.neurot.2025.e00732","DOIUrl":"10.1016/j.neurot.2025.e00732","url":null,"abstract":"<div><div>Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome. We show that the AR PROTAC degrader ARD-1676 clears polyQ AR in an over-expression system, in patient iPSC-derived induced motor neurons and skeletal muscle cells, and in a gene targeted mouse model of disease. Furthermore, we demonstrate that 24-h treatment with ARD-1676 rescues transcriptional dysregulation in SBMA induced skeletal muscle cells. These data provide evidence of therapeutic efficacy and in vivo target engagement, establishing AR PROTAC degraders as potential therapeutic agents for the treatment of SBMA.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00732"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006399","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00724
Clara G. Chisari , Salvatore Lo Fermo , Salvatore Iacono , Giuseppe Schirò , Francesca Ruscica , Sabrina Realmuto , Sebastiano Bucello , Paolo Ragonese , Giuseppe Salemi , Francesca Matta , Simona Toscano , Salvatore Cottone , Luigi Maria Edoardo Grimaldi , Francesco Patti
Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, has shown promising efficacy in treating relapsing multiple sclerosis (RMS) by depleting B cells and reducing disease activity. This real-world, prospective, multicenter study evaluated the effectiveness and safety of OFA in treatment-naïve patients and those transitioning from other disease-modifying therapies (DMTs), including natalizumab (NTZ). RRMS patients initiating OFA at seven MS centers in Sicily and treated for at least 12 months were analyzed. Outcomes included annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS), and the percentage of patients free from relapse, MRI activity, and confirmed EDSS worsening (CEW). Of 213 patients, 66 (30.9 %) were naïve and 147 (69.1 %) were switchers. At 12 months, both groups showed comparable CEW-free (93.9 % vs. 93.8 %), relapse-free (92.4 % vs. 93.2 %), and MRI activity-free (84.8 % vs. 85.0 %) proportions. Within the high-efficacy group, NTZ-switchers showed significantly better MRI outcomes than those switching from other agents, while CEW-free and relapse-free rates remained similar. OFA was well tolerated with no serious adverse events. Predictors of non-response included high baseline MRI activity, disease duration >10 years, and prior NTZ and non-NTZ high-efficacy DMTs. These findings support OFA as a safe and effective option for RRMS across patient subtypes.
Ofatumumab （OFA）是一种全人源抗cd20单克隆抗体，通过消耗B细胞和降低疾病活动性，在治疗复发性多发性硬化症（RMS）方面显示出有希望的疗效。这项现实世界、前瞻性、多中心研究评估了OFA在treatment-naïve患者和从其他疾病改善疗法（dmt）（包括natalizumab (NTZ)）过渡的患者中的有效性和安全性。分析了在西西里岛7个MS中心开始OFA治疗且治疗至少12个月的RRMS患者。结果包括年复发率（ARR）、扩展残疾状态量表（EDSS）、无复发患者的百分比、MRI活动和确认的EDSS恶化（CEW）。213例患者中，66例（30.9%）为naïve， 147例（69.1%）为转换患者。12个月时，两组无cew （93.9% vs. 93.8%）、无复发（92.4% vs. 93.2%）和无MRI活动（84.8% vs. 85.0%）的比例相当。在高效组中，ntz转换者的MRI结果明显优于从其他药物转换者，而无cew和无复发率保持相似。OFA耐受性良好，无严重不良事件。无反应的预测因素包括高基线MRI活动，疾病持续时间bb10年，既往NTZ和非NTZ高效dmt。这些发现支持OFA作为跨患者亚型RRMS的安全有效的选择。
{"title":"Real-world effectiveness and safety of ofatumumab in relapsing-remitting multiple sclerosis: Insights from naïve and switch patients","authors":"Clara G. Chisari , Salvatore Lo Fermo , Salvatore Iacono , Giuseppe Schirò , Francesca Ruscica , Sabrina Realmuto , Sebastiano Bucello , Paolo Ragonese , Giuseppe Salemi , Francesca Matta , Simona Toscano , Salvatore Cottone , Luigi Maria Edoardo Grimaldi , Francesco Patti","doi":"10.1016/j.neurot.2025.e00724","DOIUrl":"10.1016/j.neurot.2025.e00724","url":null,"abstract":"<div><div>Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, has shown promising efficacy in treating relapsing multiple sclerosis (RMS) by depleting B cells and reducing disease activity. This real-world, prospective, multicenter study evaluated the effectiveness and safety of OFA in treatment-naïve patients and those transitioning from other disease-modifying therapies (DMTs), including natalizumab (NTZ). RRMS patients initiating OFA at seven MS centers in Sicily and treated for at least 12 months were analyzed. Outcomes included annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS), and the percentage of patients free from relapse, MRI activity, and confirmed EDSS worsening (CEW). Of 213 patients, 66 (30.9 %) were naïve and 147 (69.1 %) were switchers. At 12 months, both groups showed comparable CEW-free (93.9 % vs. 93.8 %), relapse-free (92.4 % vs. 93.2 %), and MRI activity-free (84.8 % vs. 85.0 %) proportions. Within the high-efficacy group, NTZ-switchers showed significantly better MRI outcomes than those switching from other agents, while CEW-free and relapse-free rates remained similar. OFA was well tolerated with no serious adverse events. Predictors of non-response included high baseline MRI activity, disease duration >10 years, and prior NTZ and non-NTZ high-efficacy DMTs. These findings support OFA as a safe and effective option for RRMS across patient subtypes.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00724"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075795","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 : 2025-10-01DOI: 10.1016/j.neurot.2025.e00759
Meixiang Huang , Yannan Li , Ajit G. Thomas , Anjali Sharma , Wathsala Liyanage , Tomáš Tichý , Lukáš Tenora , Yu Su , Jisu Ha , Niyada Hin , Mizuho Obayashi , Pavel Majer , Rangaramanujam M. Kannan , Takashi Tsukamoto , Gianluca Ursini , Rana Rais , Barbara S. Slusher , Xiaolei Zhu
Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.
{"title":"Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits","authors":"Meixiang Huang , Yannan Li , Ajit G. Thomas , Anjali Sharma , Wathsala Liyanage , Tomáš Tichý , Lukáš Tenora , Yu Su , Jisu Ha , Niyada Hin , Mizuho Obayashi , Pavel Majer , Rangaramanujam M. Kannan , Takashi Tsukamoto , Gianluca Ursini , Rana Rais , Barbara S. Slusher , Xiaolei Zhu","doi":"10.1016/j.neurot.2025.e00759","DOIUrl":"10.1016/j.neurot.2025.e00759","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00759"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182022","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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