Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00492
Andrés de la Rosa , Nicole G. Metzendorf , Jonathan Efverström , Ana Godec , Dag Sehlin , Jamie Morrison , Greta Hultqvist
Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, in silico protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery.
{"title":"Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration","authors":"Andrés de la Rosa , Nicole G. Metzendorf , Jonathan Efverström , Ana Godec , Dag Sehlin , Jamie Morrison , Greta Hultqvist","doi":"10.1016/j.neurot.2024.e00492","DOIUrl":"10.1016/j.neurot.2024.e00492","url":null,"abstract":"<div><div>Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, <em>in silico</em> protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00492"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00516
Sarvin Sasannia , Richard Leigh , Pouya B. Bastani , Hyeong-Geol Shin , Peter van Zijl , Linda Knutsson , Paul Nyquist
Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia. Ischemic events can cause blood-brain barrier (BBB) disruption and, ultimately, white matter alterations, contributing to neurological deficits and long-term functional impairments. Hence, understanding the mechanisms of BBB breakdown and white matter injury across various ischemic conditions is critical for developing effective interventions and improving patient outcomes. This review discusses the proposed mechanisms of ischemia-related BBB breakdown. Moreover, magnetic resonance imaging (MRI) based perfusion-weighted imaging (PWI) techniques sensitive to BBB permeability changes are described, including dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI), two perfusion-weighted imaging (PWI). These PWI techniques provide valuable insights that improve our understanding of the complex early pathophysiology of brain ischemia, which can lead to better assessment and management. Finally, in this review, we explore the implications of the mentioned neuroimaging findings, which emphasize the potential of neuroimaging biomarkers to guide personalized treatment and inform novel neuroprotective strategies. This review highlights the importance of investigating BBB changes in brain ischemia and the critical role of advanced neuroimaging in improving patient care and advancing stroke research.
{"title":"Blood-brain barrier breakdown in brain ischemia: Insights from MRI perfusion imaging","authors":"Sarvin Sasannia , Richard Leigh , Pouya B. Bastani , Hyeong-Geol Shin , Peter van Zijl , Linda Knutsson , Paul Nyquist","doi":"10.1016/j.neurot.2024.e00516","DOIUrl":"10.1016/j.neurot.2024.e00516","url":null,"abstract":"<div><div>Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia. Ischemic events can cause blood-brain barrier (BBB) disruption and, ultimately, white matter alterations, contributing to neurological deficits and long-term functional impairments. Hence, understanding the mechanisms of BBB breakdown and white matter injury across various ischemic conditions is critical for developing effective interventions and improving patient outcomes. This review discusses the proposed mechanisms of ischemia-related BBB breakdown. Moreover, magnetic resonance imaging (MRI) based perfusion-weighted imaging (PWI) techniques sensitive to BBB permeability changes are described, including dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI), two perfusion-weighted imaging (PWI). These PWI techniques provide valuable insights that improve our understanding of the complex early pathophysiology of brain ischemia, which can lead to better assessment and management. Finally, in this review, we explore the implications of the mentioned neuroimaging findings, which emphasize the potential of neuroimaging biomarkers to guide personalized treatment and inform novel neuroprotective strategies. This review highlights the importance of investigating BBB changes in brain ischemia and the critical role of advanced neuroimaging in improving patient care and advancing stroke research.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00516"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00480
Ding Quan Ng , Casey Hudson , Tracy Nguyen , Sukesh Kumar Gupta , Yong Qin Koh , Munjal M. Acharya , Alexandre Chan
Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 % lower (P = 0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 % lower DNM1 levels than those without impairment (P = 0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 % decline (P < 0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P < 0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.
{"title":"Dynamin-1 is a potential mediator in cancer-related cognitive impairment","authors":"Ding Quan Ng , Casey Hudson , Tracy Nguyen , Sukesh Kumar Gupta , Yong Qin Koh , Munjal M. Acharya , Alexandre Chan","doi":"10.1016/j.neurot.2024.e00480","DOIUrl":"10.1016/j.neurot.2024.e00480","url":null,"abstract":"<div><div>Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 % lower (P = 0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 % lower DNM1 levels than those without impairment (P = 0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 % decline (P < 0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P < 0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00480"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 mg/kg) 30 min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.
{"title":"Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury","authors":"Georgios Michalettos , Fredrik Clausen , Elham Rostami , Niklas Marklund","doi":"10.1016/j.neurot.2024.e00472","DOIUrl":"10.1016/j.neurot.2024.e00472","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 mg/kg) 30 min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00472"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00504
Bosco Seong Kyu Yang , Spiros L. Blackburn , Philip L. Lorenzi , Huimahn A. Choi , Aaron M. Gusdon
Aneurysmal subarachnoid hemorrhage (aSAH) results in a complex systemic response that is critical to the pathophysiology of late complications and has important effects on outcomes. Omics techniques have expanded our investigational scope and depth into this phenomenon. In particular, metabolomics—the study of small molecules, such as blood products, carbohydrates, amino acids, and lipids—can provide a snapshot of dynamic subcellular processes and thus broaden our understanding of molecular-level pathologic changes that lead to the systemic response after aSAH. Lipids are especially important due to their abundance in the circulating blood and numerous physiological roles. They are comprised of a wide variety of subspecies and are critical for cellular energy metabolism, the integrity of the blood-brain barrier, the formation of cell membranes, and intercellular signaling including neuroinflammation and ferroptosis. In this review, metabolomic and lipidomic pathways associated with aSAH are summarized, centering on key metabolites from each metabolomic domain.
{"title":"Metabolomic and lipidomic pathways in aneurysmal subarachnoid hemorrhage","authors":"Bosco Seong Kyu Yang , Spiros L. Blackburn , Philip L. Lorenzi , Huimahn A. Choi , Aaron M. Gusdon","doi":"10.1016/j.neurot.2024.e00504","DOIUrl":"10.1016/j.neurot.2024.e00504","url":null,"abstract":"<div><div>Aneurysmal subarachnoid hemorrhage (aSAH) results in a complex systemic response that is critical to the pathophysiology of late complications and has important effects on outcomes. Omics techniques have expanded our investigational scope and depth into this phenomenon. In particular, metabolomics—the study of small molecules, such as blood products, carbohydrates, amino acids, and lipids—can provide a snapshot of dynamic subcellular processes and thus broaden our understanding of molecular-level pathologic changes that lead to the systemic response after aSAH. Lipids are especially important due to their abundance in the circulating blood and numerous physiological roles. They are comprised of a wide variety of subspecies and are critical for cellular energy metabolism, the integrity of the blood-brain barrier, the formation of cell membranes, and intercellular signaling including neuroinflammation and ferroptosis. In this review, metabolomic and lipidomic pathways associated with aSAH are summarized, centering on key metabolites from each metabolomic domain.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00504"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2025.e00533
Sung-Min Cho , Jose I. Suarez
{"title":"Advancing neurocritical care: Bridging molecular mechanisms and physiological monitoring to neurotherapeutics","authors":"Sung-Min Cho , Jose I. Suarez","doi":"10.1016/j.neurot.2025.e00533","DOIUrl":"10.1016/j.neurot.2025.e00533","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00533"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00459
James Feghali, Christopher M. Jackson
Since the discovery and characterization of the PD-1/PD-L pathway, mounting evidence has emerged regarding its role in regulating neuroinflammation following cerebrovascular injury. Classically, PD-L1 on antigen-presenting cells or tissues binds PD-1 on T cell surfaces resulting in T cell inhibition. In myeloid cells, PD-1 stimulation induces polarization of microglia and macrophages into an anti-inflammatory, restorative phenotype. The therapeutic potential of PD-1 agonism in ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage-related vasospasm, and traumatic brain injury rests on the notion of harnessing the immunomodulatory function of immune checkpoint pathways to temper the harmful effects of immune overactivation and secondary injury while promoting repair and recovery. Immune checkpoint agonism has greater specificity than the wider and non-specific anti-inflammatory effects of other agents, such as steroids. PD-1 agonism has already demonstrated success in clinical trials for rheumatoid arthritis and is being tested in other chronic inflammatory diseases. Further investigation of PD-1 agonism as a therapeutic strategy in cerebrovascular injury can help clarify the mechanisms underlying clinical benefit, develop drugs with optimal pharmacodynamic and pharmacokinetic properties, and mitigate unwanted side effects.
自 PD-1/PD-L 通路被发现和描述以来，越来越多的证据表明它在脑血管损伤后调节神经炎症中的作用。通常，抗原递呈细胞或组织上的 PD-L1 与 T 细胞表面的 PD-1 结合，导致 T 细胞抑制。在骨髓细胞中，PD-1 刺激可诱导小胶质细胞和巨噬细胞极化为抗炎和恢复表型。PD-1 激动剂对缺血性中风、脑出血、蛛网膜下腔出血相关血管痉挛和创伤性脑损伤的治疗潜力在于利用免疫检查点通路的免疫调节功能来抑制免疫过度激活和二次损伤的有害影响，同时促进修复和恢复。与类固醇等其他药物广泛的非特异性抗炎作用相比，免疫检查点激动剂具有更强的特异性。PD-1 激动剂已在治疗类风湿性关节炎的临床试验中取得成功，目前正在对其他慢性炎症性疾病进行测试。进一步研究 PD-1 激动剂作为脑血管损伤的治疗策略，有助于阐明临床获益的机制，开发具有最佳药效学和药代动力学特性的药物，并减轻不必要的副作用。
{"title":"Therapeutic implications for the PD-1 axis in cerebrovascular injury","authors":"James Feghali, Christopher M. Jackson","doi":"10.1016/j.neurot.2024.e00459","DOIUrl":"10.1016/j.neurot.2024.e00459","url":null,"abstract":"<div><div>Since the discovery and characterization of the PD-1/PD-L pathway, mounting evidence has emerged regarding its role in regulating neuroinflammation following cerebrovascular injury. Classically, PD-L1 on antigen-presenting cells or tissues binds PD-1 on T cell surfaces resulting in T cell inhibition. In myeloid cells, PD-1 stimulation induces polarization of microglia and macrophages into an anti-inflammatory, restorative phenotype. The therapeutic potential of PD-1 agonism in ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage-related vasospasm, and traumatic brain injury rests on the notion of harnessing the immunomodulatory function of immune checkpoint pathways to temper the harmful effects of immune overactivation and secondary injury while promoting repair and recovery. Immune checkpoint agonism has greater specificity than the wider and non-specific anti-inflammatory effects of other agents, such as steroids. PD-1 agonism has already demonstrated success in clinical trials for rheumatoid arthritis and is being tested in other chronic inflammatory diseases. Further investigation of PD-1 agonism as a therapeutic strategy in cerebrovascular injury can help clarify the mechanisms underlying clinical benefit, develop drugs with optimal pharmacodynamic and pharmacokinetic properties, and mitigate unwanted side effects.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00459"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00493
Cheng-Yuan Lai , Ming-Chun Hsieh , Chou-Ming Yeh , Tzer-Bin Lin , Dylan Chou , Hsueh-Hsiao Wang , Kuan-Hung Lin , Jen-Kun Cheng , Po-Sheng Yang , Hsien-Yu Peng
Neuropathic pain poses a significant public health challenge, greatly impacting patients' quality of life. Emerging evidence underscores the involvement of epigenetics in dorsal root ganglion (DRG) neurons relevant to pain modulation. C-terminal binding protein 1 (CtBP1) has emerged as a crucial epigenetic transcriptional coregulator. However, the underlying molecular mechanisms of CtBP1-mediated epigenetic regulation in DRG neurons in neuropathic pain remain poorly elucidated. Here, we employed a Sprague‒Dawley rat model of spinal nerve ligation (SNL) to establish a neuropathic pain model. CtBP1 expression in the ipsilateral DRG gradually increased over a three-week period post-SNL. Immunohistochemistry revealed a significant elevation in CtBP1 levels specifically in NeuN-positive neuronal cells in the ipsilateral DRG following SNL. Further characterization demonstrated CtBP1 expression across various subtypes of DRG neurons in SNL rats. Silencing CtBP1 expression with siRNA reversed tactile allodynia in SNL rats and restored both CtBP1 and μ-opioid receptor expression in the DRG in SNL rats. Moreover, Foxp1 was identified to recruit CtBP1 for mediating μ-opioid receptor gene silencing in the DRG in SNL rats. Subsequent investigation unveiled that Foxp1 recruits CtBP1 and associates with HDAC2 to regulate H3K9Ac binding to μ-opioid receptor chromatin regions in the DRG in SNL rats, implicating epigenetic mechanisms in neuropathic pain. Targeting the Foxp1/CtBP1/HDAC2/μ-opioid receptor signaling pathway in the DRG holds promise as a potential therapeutic strategy for managing neuropathic pain.
{"title":"CtBP1 is essential for epigenetic silencing of μ-opioid receptor genes in the dorsal root ganglion in spinal nerve ligation-induced neuropathic pain","authors":"Cheng-Yuan Lai , Ming-Chun Hsieh , Chou-Ming Yeh , Tzer-Bin Lin , Dylan Chou , Hsueh-Hsiao Wang , Kuan-Hung Lin , Jen-Kun Cheng , Po-Sheng Yang , Hsien-Yu Peng","doi":"10.1016/j.neurot.2024.e00493","DOIUrl":"10.1016/j.neurot.2024.e00493","url":null,"abstract":"<div><div>Neuropathic pain poses a significant public health challenge, greatly impacting patients' quality of life. Emerging evidence underscores the involvement of epigenetics in dorsal root ganglion (DRG) neurons relevant to pain modulation. C-terminal binding protein 1 (CtBP1) has emerged as a crucial epigenetic transcriptional coregulator. However, the underlying molecular mechanisms of CtBP1-mediated epigenetic regulation in DRG neurons in neuropathic pain remain poorly elucidated. Here, we employed a Sprague‒Dawley rat model of spinal nerve ligation (SNL) to establish a neuropathic pain model. CtBP1 expression in the ipsilateral DRG gradually increased over a three-week period post-SNL. Immunohistochemistry revealed a significant elevation in CtBP1 levels specifically in NeuN-positive neuronal cells in the ipsilateral DRG following SNL. Further characterization demonstrated CtBP1 expression across various subtypes of DRG neurons in SNL rats. Silencing CtBP1 expression with siRNA reversed tactile allodynia in SNL rats and restored both CtBP1 and μ-opioid receptor expression in the DRG in SNL rats. Moreover, Foxp1 was identified to recruit CtBP1 for mediating μ-opioid receptor gene silencing in the DRG in SNL rats. Subsequent investigation unveiled that Foxp1 recruits CtBP1 and associates with HDAC2 to regulate H3K9Ac binding to μ-opioid receptor chromatin regions in the DRG in SNL rats, implicating epigenetic mechanisms in neuropathic pain. Targeting the Foxp1/CtBP1/HDAC2/μ-opioid receptor signaling pathway in the DRG holds promise as a potential therapeutic strategy for managing neuropathic pain.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00493"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00463
Fred Kim , Padmanabh Singh , Hyunji Jo , Tianyang Xi , Dong-Keun Song , Sae Kwang Ku , Jai Jun Choung
Mirodenafil is a phosphodiesterase 5 (PDE5) inhibitor with high specificity for its target and good blood-brain barrier permeability. The drug, which is currently used for treatment of erectile dysfunction, reduces Aβ and pTau levels and improves cognitive function in mouse models of Alzheimer's disease. In the present study, we investigated the effect of mirodenafil in the transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO) models of stroke in rats. Starting 24 h after cerebral artery occlusion, mirodenafil was administered subcutaneously at doses of 0.5, 1, and 2 mg/kg per day for 9 days in the tMCAO model and for 28 days in the pMCAO model. Mirodenafil significantly increased sensorimotor and cognitive recovery of tMCAO and pMCAO rats compared to saline control rats, and significantly decreased the amount of degenerative cells and cleaved caspase-3 and cleaved PARP immunoreactive cells. Effects were seen in a dose-dependent manner up to 1 mg/kg mirodenafil. The benefits of mirodenafil treatment increased with longer treatment duration, and the largest improvements over control were typically observed on the last assessment day. There was no effect of mirodenafil on infarct volume in both tMCAO and pMCAO rats. In an experiment to determine the treatment window for mirodenafil effects, a protective effect was observed when treatment was delayed 72 h after MCAO, although the most improvement was observed with shorter treatment windows. Using pMCAO and tMCAO rat models of stroke, we determined that mirodenafil improves the recovery of sensorimotor and cognitive functions after MCAO and protects cortical cells from apoptosis and degeneration. Greater benefit was observed with longer duration of treatment, and improvement was seen even when treatment was delayed.
{"title":"Therapeutic effects of mirodenafil, a phosphodiesterase 5 inhibitor, on stroke models in rats","authors":"Fred Kim , Padmanabh Singh , Hyunji Jo , Tianyang Xi , Dong-Keun Song , Sae Kwang Ku , Jai Jun Choung","doi":"10.1016/j.neurot.2024.e00463","DOIUrl":"10.1016/j.neurot.2024.e00463","url":null,"abstract":"<div><div>Mirodenafil is a phosphodiesterase 5 (PDE5) inhibitor with high specificity for its target and good blood-brain barrier permeability. The drug, which is currently used for treatment of erectile dysfunction, reduces Aβ and pTau levels and improves cognitive function in mouse models of Alzheimer's disease. In the present study, we investigated the effect of mirodenafil in the transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO) models of stroke in rats. Starting 24 h after cerebral artery occlusion, mirodenafil was administered subcutaneously at doses of 0.5, 1, and 2 mg/kg per day for 9 days in the tMCAO model and for 28 days in the pMCAO model. Mirodenafil significantly increased sensorimotor and cognitive recovery of tMCAO and pMCAO rats compared to saline control rats, and significantly decreased the amount of degenerative cells and cleaved caspase-3 and cleaved PARP immunoreactive cells. Effects were seen in a dose-dependent manner up to 1 mg/kg mirodenafil. The benefits of mirodenafil treatment increased with longer treatment duration, and the largest improvements over control were typically observed on the last assessment day. There was no effect of mirodenafil on infarct volume in both tMCAO and pMCAO rats. In an experiment to determine the treatment window for mirodenafil effects, a protective effect was observed when treatment was delayed 72 h after MCAO, although the most improvement was observed with shorter treatment windows. Using pMCAO and tMCAO rat models of stroke, we determined that mirodenafil improves the recovery of sensorimotor and cognitive functions after MCAO and protects cortical cells from apoptosis and degeneration. Greater benefit was observed with longer duration of treatment, and improvement was seen even when treatment was delayed.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00463"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neurot.2024.e00481
Idy H.T. Ho , Yidan Zou , Kele Luo , Fenfen Qin , Yanjun Jiang , Qian Li , Tingting Jin , Xinyi Zhang , Huarong Chen , Likai Tan , Lin Zhang , Tony Gin , William K.K. Wu , Matthew T.V. Chan , Changyu Jiang , Xiaodong Liu
Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain are common challenges for patients receiving oxaliplatin chemotherapy. Oxaliplatin accumulation in dorsal root ganglion (DRGs) is known to impair gene transcription by epigenetic dysregulation. We hypothesized that sodium butyrate, a pro-resolution short-chain fatty acid, inhibited histone acetylation in DRGs and abolished K+ channel dysregulation-induced neuronal hyperexcitability after oxaliplatin treatment. Mechanical allodynia and cold hyperalgesia of mice receiving an accumulation of 15 mg/kg oxaliplatin, with or without intraperitoneal sodium butyrate supplementation, were assessed using von Frey test and acetone evaporation test. Differential expressions of histone deacetylases (HDACs) and pain-related K+ channels were quantified with rt-qPCR and protein assays. Immunofluorescence assays of histone acetylation at H3K9/14 were performed in primary DRG cultures treated with sodium butyrate. Current clamp recording of action potentials and persistent outward current of Twik-related-spinal cord K+ (TRESK) channel were recorded in DRG neurons with small diameters extract. Accompanied by mechanical allodynia and cold hyperalgesia, HDAC1 was upregulated in mice receiving oxaliplatin treatment. Sodium butyrate enhanced global histone acetylation at H3K9/14 in DRG neurons. In vivo sodium butyrate supplementation restored oxaliplatin-induced Kcnj9 and Kcnk18 expression and pain-related behaviors in mice for at least 14 days. Oxaliplatin-induced increase in action potentials frequencies and decrease in magnitudes of KCNK18-related current were reversed in mice receiving sodium butyrate supplementation. This study suggests that sodium butyrate was a useful agent to relieve oxaliplatin-mediated neuropathic pain.
{"title":"Sodium butyrate restored TRESK current controlling neuronal hyperexcitability in a mouse model of oxaliplatin-induced peripheral neuropathic pain","authors":"Idy H.T. Ho , Yidan Zou , Kele Luo , Fenfen Qin , Yanjun Jiang , Qian Li , Tingting Jin , Xinyi Zhang , Huarong Chen , Likai Tan , Lin Zhang , Tony Gin , William K.K. Wu , Matthew T.V. Chan , Changyu Jiang , Xiaodong Liu","doi":"10.1016/j.neurot.2024.e00481","DOIUrl":"10.1016/j.neurot.2024.e00481","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain are common challenges for patients receiving oxaliplatin chemotherapy. Oxaliplatin accumulation in dorsal root ganglion (DRGs) is known to impair gene transcription by epigenetic dysregulation. We hypothesized that sodium butyrate, a pro-resolution short-chain fatty acid, inhibited histone acetylation in DRGs and abolished K<sup>+</sup> channel dysregulation-induced neuronal hyperexcitability after oxaliplatin treatment. Mechanical allodynia and cold hyperalgesia of mice receiving an accumulation of 15 mg/kg oxaliplatin, with or without intraperitoneal sodium butyrate supplementation, were assessed using von Frey test and acetone evaporation test. Differential expressions of histone deacetylases (HDACs) and pain-related K<sup>+</sup> channels were quantified with rt-qPCR and protein assays. Immunofluorescence assays of histone acetylation at H3K9/14 were performed in primary DRG cultures treated with sodium butyrate. Current clamp recording of action potentials and persistent outward current of Twik-related-spinal cord K<sup>+</sup> (TRESK) channel were recorded in DRG neurons with small diameters extract. Accompanied by mechanical allodynia and cold hyperalgesia, HDAC1 was upregulated in mice receiving oxaliplatin treatment. Sodium butyrate enhanced global histone acetylation at H3K9/14 in DRG neurons. <em>In vivo</em> sodium butyrate supplementation restored oxaliplatin-induced <em>Kcnj9</em> and <em>Kcnk18</em> expression and pain-related behaviors in mice for at least 14 days. Oxaliplatin-induced increase in action potentials frequencies and decrease in magnitudes of KCNK18-related current were reversed in mice receiving sodium butyrate supplementation. This study suggests that sodium butyrate was a useful agent to relieve oxaliplatin-mediated neuropathic pain.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 1","pages":"Article e00481"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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