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}
Pub Date : 2025-10-01DOI: 10.1016/j.neurot.2025.e00584
Csaba Szabo
Down syndrome (DS) is a genetic condition where the person affected by it is born with an additional – full or partial – copy of chromosome 21. DS presents with characteristic morphological features and is associated with a wide range of biochemical alterations and maladaptations. Cystathionine-β-synthase (CBS) – one of the key mammalian enzymes responsible for the biogenesis of the gaseous transmitter hydrogen sulfide (H2S) – is located on chromosome 21, and people with DS exhibit a significant upregulation of this enzyme in their brain and other organs. Even though 3-mercaptopyruvate sulfurtransferase – another key mammalian enzyme responsible for the biogenesis of H2S and of reactive polysulfides – is not located on chromosome 21, there is also evidence for the upregulation of this enzyme in DS cells. The hypothesis that excess H2S in DS impairs mitochondrial function and cellular bioenergetics was first proposed in the 1990s and has been substantiated and expanded upon over the past 25 years. DS cells are in a state of metabolic suppression due to H2S-induced, reversible inhibition of mitochondrial Complex IV activity. The impairment of aerobic ATP generation in DS cells is partially compensated by an upregulation of glycolysis. The DS-associated metabolic impairment can be reversed by pharmacological CBS inhibition or CBS silencing. In rodent models of DS, CBS upregulation and H2S overproduction contribute to the development of cognitive dysfunction, alter brain electrical activity, and promote reactive gliosis: pharmacological inhibition or genetic correction of CBS overactivation reverses these alterations. CBS can be considered a preclinically validated drug target for the experimental therapy of DS.
{"title":"Role of cystathionine-β-synthase and hydrogen sulfide in down syndrome","authors":"Csaba Szabo","doi":"10.1016/j.neurot.2025.e00584","DOIUrl":"10.1016/j.neurot.2025.e00584","url":null,"abstract":"<div><div>Down syndrome (DS) is a genetic condition where the person affected by it is born with an additional – full or partial – copy of chromosome 21. DS presents with characteristic morphological features and is associated with a wide range of biochemical alterations and maladaptations. Cystathionine-β-synthase (CBS) – one of the key mammalian enzymes responsible for the biogenesis of the gaseous transmitter hydrogen sulfide (H<sub>2</sub>S) – is located on chromosome 21, and people with DS exhibit a significant upregulation of this enzyme in their brain and other organs. Even though 3-mercaptopyruvate sulfurtransferase – another key mammalian enzyme responsible for the biogenesis of H<sub>2</sub>S and of reactive polysulfides – is not located on chromosome 21, there is also evidence for the upregulation of this enzyme in DS cells. The hypothesis that excess H<sub>2</sub>S in DS impairs mitochondrial function and cellular bioenergetics was first proposed in the 1990s and has been substantiated and expanded upon over the past 25 years. DS cells are in a state of metabolic suppression due to H<sub>2</sub>S-induced, reversible inhibition of mitochondrial Complex IV activity. The impairment of aerobic ATP generation in DS cells is partially compensated by an upregulation of glycolysis. The DS-associated metabolic impairment can be reversed by pharmacological CBS inhibition or CBS silencing. In rodent models of DS, CBS upregulation and H<sub>2</sub>S overproduction contribute to the development of cognitive dysfunction, alter brain electrical activity, and promote reactive gliosis: pharmacological inhibition or genetic correction of CBS overactivation reverses these alterations. CBS can be considered a preclinically validated drug target for the experimental therapy of DS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00584"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788210","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.e00711
Hideo Kimura
Hydrogen sulfide (H2S) and polysulfides including H2Sn (n = 2 or more) regulate neuronal activity, vascular tone, oxytosis/ferroptosis, oxygen sensing, cancer growth and senescence. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) produce H2S. Polysulfides are also produced by various enzymes including 3MST. In addition, transient receptor potential ankyrin 1 (TRPA1) channel-an important polysulfide target-modulates sulfur metabolism (including cysteine, H2S and polysulfides) and also affects the neurotransmitter GABA. Polysulfides persulfidate the cysteine residues of the target proteins, causing conformational changes that alter their activity. By contrast, H2S persulfidates oxidized cysteine residues (e.g., S-nitrosylated- and S-sulfinated) in its targets. H2S/polysulfides protect neurons from oxidative stress and thereby protect cells against various forms of cell death including oxytosis and ferroptosis. A deviation from normal H2S and polysulfides levels has been suggested to play a role in the pathophysiology of various neuronal- and psychiatric diseases.
{"title":"Hydrogen sulfide/polysulfides signaling and neuronal diseases","authors":"Hideo Kimura","doi":"10.1016/j.neurot.2025.e00711","DOIUrl":"10.1016/j.neurot.2025.e00711","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S) and polysulfides including H<sub>2</sub>S<sub>n</sub> (n = 2 or more) regulate neuronal activity, vascular tone, oxytosis/ferroptosis, oxygen sensing, cancer growth and senescence. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) produce H<sub>2</sub>S. Polysulfides are also produced by various enzymes including 3MST. In addition, transient receptor potential ankyrin 1 (TRPA1) channel-an important polysulfide target-modulates sulfur metabolism (including cysteine, H<sub>2</sub>S and polysulfides) and also affects the neurotransmitter GABA. Polysulfides persulfidate the cysteine residues of the target proteins, causing conformational changes that alter their activity. By contrast, H<sub>2</sub>S persulfidates oxidized cysteine residues (e.g., S-nitrosylated- and S-sulfinated) in its targets. H<sub>2</sub>S/polysulfides protect neurons from oxidative stress and thereby protect cells against various forms of cell death including oxytosis and ferroptosis. A deviation from normal H<sub>2</sub>S and polysulfides levels has been suggested to play a role in the pathophysiology of various neuronal- and psychiatric diseases.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00711"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794962","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.e00736
M.A. Franssen , M.A. Tjerkstra , M. Heijink , S.A. Rotman , D. Verbaan , E. van Bavel , W.P. Vandertop , H.E. de Vries , J.M. Coutinho , M.A. Giera , I.A. Mulder , G. Kooij
Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid haemorrhage (aSAH) is a complex and acute condition with limited options for early detection and effective treatments. The plasma levels of individual polyunsaturated fatty acids (PUFA) and their bioactive metabolites (oxylipins) of aSAH patients both at admission and over time remain largely unexplored, particularly concerning the development of DCI. In this study, plasma samples of aSAH patients were collected at admission and on days 4, 10, and 21 post-admission. ASAH patients who did not develop DCI were age- and sex matched to aSAH patients who did develop DCI. Control groups included patients with an unruptured aneurysm (UA) and healthy controls (HC). PUFA and oxylipin levels in plasma were measured using liquid chromatography with tandem mass spectrometry and were analysed using non-parametric univariate tests. At admission, aSAH (n = 47) patients showed elevated levels of several PUFAs, such as linoleic acid and arachidonic acid, as well as oxylipins, including 12-HETE, 20-HETE and 19,20-DiHDPA, compared to UA (n = 24) and HC (n = 13). 12-HETE was predominantly found in the S-configuration, indicating synthesis via 12(S)-lipoxygenase. PUFA and oxylipin levels dropped significantly by day four post-admission, except for 19,20-DiHDPA. No PUFAs or oxylipins differentiated patients who developed DCI. We characterized a distinct plasma PUFA- and oxylipin profile in aSAH patients at admission and identified a significant decline in PUFA and oxylipin levels by day 4 post-admission.
{"title":"The polyunsaturated fatty acid and oxylipin plasma signature of aneurysmal subarachnoid haemorrhage, case-control study","authors":"M.A. Franssen , M.A. Tjerkstra , M. Heijink , S.A. Rotman , D. Verbaan , E. van Bavel , W.P. Vandertop , H.E. de Vries , J.M. Coutinho , M.A. Giera , I.A. Mulder , G. Kooij","doi":"10.1016/j.neurot.2025.e00736","DOIUrl":"10.1016/j.neurot.2025.e00736","url":null,"abstract":"<div><div>Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid haemorrhage (aSAH) is a complex and acute condition with limited options for early detection and effective treatments. The plasma levels of individual polyunsaturated fatty acids (PUFA) and their bioactive metabolites (oxylipins) of aSAH patients both at admission and over time remain largely unexplored, particularly concerning the development of DCI. In this study, plasma samples of aSAH patients were collected at admission and on days 4, 10, and 21 post-admission. ASAH patients who did not develop DCI were age- and sex matched to aSAH patients who did develop DCI. Control groups included patients with an unruptured aneurysm (UA) and healthy controls (HC). PUFA and oxylipin levels in plasma were measured using liquid chromatography with tandem mass spectrometry and were analysed using non-parametric univariate tests. At admission, aSAH (n = 47) patients showed elevated levels of several PUFAs, such as linoleic acid and arachidonic acid, as well as oxylipins, including 12-HETE, 20-HETE and 19,20-DiHDPA, compared to UA (n = 24) and HC (n = 13). 12-HETE was predominantly found in the <em>S</em>-configuration, indicating synthesis via 12(<em>S</em>)-lipoxygenase. PUFA and oxylipin levels dropped significantly by day four post-admission, except for 19,20-DiHDPA. No PUFAs or oxylipins differentiated patients who developed DCI. We characterized a distinct plasma PUFA- and oxylipin profile in aSAH patients at admission and identified a significant decline in PUFA and oxylipin levels by day 4 post-admission.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00736"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040856","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.e00755
Jordan L. Morris , Jordan J. Lee , Russell E. Morris , Jan Lj. Miljkovic
From shaping Earth's earliest anoxic seas to quietly orchestrating cellular life today, hydrogen sulfide (H2S) has journeyed from ancient toxin to modern therapeutic candidate. Once abundant in Earth's primordial environment, H2S has reemerged as a critical endogenous gasotransmitter in modern biology. Within the central nervous system, H2S regulates redox homeostasis, mitochondrial bioenergetics, inflammatory signalling, and neuronal excitability. A key mechanism involves post-translational modification of protein cysteine residues (persulfidation), reactions with metal centres, and scavenging of reactive oxygen and nitrogen species, thereby influencing diverse cellular processes. Dysregulation of H2S metabolism, whether deficient or excessive, is increasingly implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, Down syndrome, and in stroke and traumatic brain injury. This review focuses on neuronal aspects of H2S biology and therapeutic relevance in these conditions. Restoration of H2S signalling in preclinical models improves cognitive and motor function, reduces neuropathology, and preserves mitochondrial integrity. Therapeutic innovation has produced a variety of H2S donors, including slow-releasing compounds, organelle-targeted agents, and emerging nanomaterial platforms such as polymer-based and metal–organic frameworks for precision CNS delivery. Natural compounds such as ergothioneine, a sulfur-containing antioxidant, are also gaining attention as potential modulators of endogenous H2S pathways. Future directions include integration of H2S therapies with genetic targeting tools and elucidation of their interactions with other gasotransmitters and gut–brain axis signalling. Although clinical trials remain limited, the convergence of donor chemistry, molecular biology, and delivery technologies positions H2S-based therapeutics as a promising frontier for treating neurodegeneration and acute neural injuries.
{"title":"Black gas, bright future: H2S based therapeutics for neurodegenerative disorders","authors":"Jordan L. Morris , Jordan J. Lee , Russell E. Morris , Jan Lj. Miljkovic","doi":"10.1016/j.neurot.2025.e00755","DOIUrl":"10.1016/j.neurot.2025.e00755","url":null,"abstract":"<div><div>From shaping Earth's earliest anoxic seas to quietly orchestrating cellular life today, hydrogen sulfide (H<sub>2</sub>S) has journeyed from ancient toxin to modern therapeutic candidate. Once abundant in Earth's primordial environment, H<sub>2</sub>S has reemerged as a critical endogenous gasotransmitter in modern biology. Within the central nervous system, H<sub>2</sub>S regulates redox homeostasis, mitochondrial bioenergetics, inflammatory signalling, and neuronal excitability. A key mechanism involves post-translational modification of protein cysteine residues (persulfidation), reactions with metal centres, and scavenging of reactive oxygen and nitrogen species, thereby influencing diverse cellular processes. Dysregulation of H<sub>2</sub>S metabolism, whether deficient or excessive, is increasingly implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, Down syndrome, and in stroke and traumatic brain injury. This review focuses on neuronal aspects of H<sub>2</sub>S biology and therapeutic relevance in these conditions. Restoration of H<sub>2</sub>S signalling in preclinical models improves cognitive and motor function, reduces neuropathology, and preserves mitochondrial integrity. Therapeutic innovation has produced a variety of H<sub>2</sub>S donors, including slow-releasing compounds, organelle-targeted agents, and emerging nanomaterial platforms such as polymer-based and metal–organic frameworks for precision CNS delivery. Natural compounds such as ergothioneine, a sulfur-containing antioxidant, are also gaining attention as potential modulators of endogenous H<sub>2</sub>S pathways. Future directions include integration of H<sub>2</sub>S therapies with genetic targeting tools and elucidation of their interactions with other gasotransmitters and gut–brain axis signalling. Although clinical trials remain limited, the convergence of donor chemistry, molecular biology, and delivery technologies positions H<sub>2</sub>S-based therapeutics as a promising frontier for treating neurodegeneration and acute neural injuries.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00755"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150312","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.e00770
Papori Sharma , M. Farris Sawaya , Alexandru Mihai Dumitrescu , Gopi K. Kolluru , Christopher D. Schmoutz , Armando Salinas , Christopher E. Cannon , Deepak Kumbhare , Nadejda Korneeva , M. Frances Vest , Bo Jarrett Wood , Paul Bracey , Shawn McNeil , Alan D. Kaye , Sarah E. Murnane , Jason Jordan , Kelsea Keys , Ethan Brackett , Kaushik Avadhanula , Kevin S. Murnane
Substance use disorders (SUDs) are chronic disorders marked by intense and compulsive drug-seeking behavior, coupled with a high risk of relapse. Different theories have emerged over time regarding mechanisms that induce and exacerbate SUDs. This review explores new and evolving evidence on the role of reward systems and processes and aligns those conceptual frameworks with neuroplastic and neuroinflammatory mechanisms and potential therapeutic targets. As the addiction cycle progresses, substance use shifts to long-term chronic use, marked by reduced hedonic effects and intensified compulsion. Thus, a “euphoria reward” model fails to completely capture the progression and complexity of SUDs. Substantive research suggests that the brain circuits that subserve pleasure and craving are distinct, which may explain why individuals with SUDs continue to seek out substances in the absence of pleasure. Additionally, the alleviation of negative affect, anhedonia, post-acute withdrawal symptoms, or other symptoms, may play a key part in preventing relapse. Recent studies emphasize the critical roles of neuroinflammation and oxidative stress in shaping SUDs by altering neural circuitry involved in reward, motivation, negative affect, and decision-making, thereby heightening relapse risk. Molecular adaptations, neuroplasticity and neuroinflammation appear to be important mediators of these changes. This review examines toxicity across the brain, heart and liver, focusing on mechanisms of neuroinflammation, neuroplasticity and gasotransmitter systems. It is proposed that an emphasis on developing pharmacotherapies targeting these mechanisms, while also addressing interactions between the brain and peripheral systems, both as consequences of SUDs and as drivers of the progression of SUDs, may provide new success in SUD therapeutic development.
{"title":"Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems","authors":"Papori Sharma , M. Farris Sawaya , Alexandru Mihai Dumitrescu , Gopi K. Kolluru , Christopher D. Schmoutz , Armando Salinas , Christopher E. Cannon , Deepak Kumbhare , Nadejda Korneeva , M. Frances Vest , Bo Jarrett Wood , Paul Bracey , Shawn McNeil , Alan D. Kaye , Sarah E. Murnane , Jason Jordan , Kelsea Keys , Ethan Brackett , Kaushik Avadhanula , Kevin S. Murnane","doi":"10.1016/j.neurot.2025.e00770","DOIUrl":"10.1016/j.neurot.2025.e00770","url":null,"abstract":"<div><div>Substance use disorders (SUDs) are chronic disorders marked by intense and compulsive drug-seeking behavior, coupled with a high risk of relapse. Different theories have emerged over time regarding mechanisms that induce and exacerbate SUDs. This review explores new and evolving evidence on the role of reward systems and processes and aligns those conceptual frameworks with neuroplastic and neuroinflammatory mechanisms and potential therapeutic targets. As the addiction cycle progresses, substance use shifts to long-term chronic use, marked by reduced hedonic effects and intensified compulsion. Thus, a “euphoria reward” model fails to completely capture the progression and complexity of SUDs. Substantive research suggests that the brain circuits that subserve pleasure and craving are distinct, which may explain why individuals with SUDs continue to seek out substances in the absence of pleasure. Additionally, the alleviation of negative affect, anhedonia, post-acute withdrawal symptoms, or other symptoms, may play a key part in preventing relapse. Recent studies emphasize the critical roles of neuroinflammation and oxidative stress in shaping SUDs by altering neural circuitry involved in reward, motivation, negative affect, and decision-making, thereby heightening relapse risk. Molecular adaptations, neuroplasticity and neuroinflammation appear to be important mediators of these changes. This review examines toxicity across the brain, heart and liver, focusing on mechanisms of neuroinflammation, neuroplasticity and gasotransmitter systems. It is proposed that an emphasis on developing pharmacotherapies targeting these mechanisms, while also addressing interactions between the brain and peripheral systems, both as consequences of SUDs and as drivers of the progression of SUDs, may provide new success in SUD therapeutic development.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00770"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452487","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.e00729
Zifeng Huang , Hui Zhong , Yingqiong Lu , Ruoyang Yu , Muwei Zhang , Jialing Zheng , Bin Xiao , Zhidong Zhou , Yinghua Yu , Chao Deng , Kunlin Jin , Shuzhen Zhu , Chong Li , Xiaoying Cui , Karolina Poplawska-Domaszewicz , K. Ray Chaudhuri , Eng-King Tan , Qing Wang
Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein (α-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP‒ribose) (PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and α-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD + depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin α4β1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.
{"title":"Cellular fibronectin exacerbates α-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation","authors":"Zifeng Huang , Hui Zhong , Yingqiong Lu , Ruoyang Yu , Muwei Zhang , Jialing Zheng , Bin Xiao , Zhidong Zhou , Yinghua Yu , Chao Deng , Kunlin Jin , Shuzhen Zhu , Chong Li , Xiaoying Cui , Karolina Poplawska-Domaszewicz , K. Ray Chaudhuri , Eng-King Tan , Qing Wang","doi":"10.1016/j.neurot.2025.e00729","DOIUrl":"10.1016/j.neurot.2025.e00729","url":null,"abstract":"<div><div>Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein (α-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP‒ribose) (PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and α-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD + depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin α4β1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 6","pages":"Article e00729"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006370","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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