Neurotherapeutics最新文献

{"title":"Amelioration of functional and histopathological consequences after spinal cord injury through phosphodiesterase 4D (PDE4D) inhibition","authors":"Melissa Schepers ,&nbsp;Sven Hendrix ,&nbsp;Femke Mussen ,&nbsp;Elise van Breedam ,&nbsp;Peter Ponsaerts ,&nbsp;Stefanie Lemmens ,&nbsp;Niels Hellings ,&nbsp;Roberta Ricciarelli ,&nbsp;Ernesto Fedele ,&nbsp;Olga Bruno ,&nbsp;Chiara Brullo ,&nbsp;Jos Prickaerts ,&nbsp;Jana Van Broeckhoven ,&nbsp;Tim Vanmierlo","doi":"10.1016/j.neurot.2024.e00372","DOIUrl":"10.1016/j.neurot.2024.e00372","url":null,"abstract":"<div><p>Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00372"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000588/pdfft?md5=bbb741ff9faba0ce0c7f002b0ece51cf&pid=1-s2.0-S1878747924000588-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957326","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}

{"title":"Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials","authors":"Jasna Metovic ,&nbsp;Yedda Li ,&nbsp;Yi Gong ,&nbsp;Florian Eichler","doi":"10.1016/j.neurot.2024.e00443","DOIUrl":"10.1016/j.neurot.2024.e00443","url":null,"abstract":"<div><p>Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.clinicaltrials.gov through August 2024, and the relevant preclinical studies that enabled clinical translation. Of the approximately 50 leukodystrophies described to date, only eight have existing gene therapy clinical trials: metachromatic leukodystrophy, X-linked adrenoleukodystrophy, globoid cell leukodystrophy, Canavan disease, giant axonal neuropathy, GM2 gangliosidoses, Alexander disease and Pelizaeus-Merzbacher disease. What led to the emergence of gene therapy trials for these specific disorders? What preclinical data or disease context was enabling? For each of these eight disorders, we first describe its pathophysiology and clinical presentation. We discuss the impact of gene therapy delivery route, targeted cell type, delivery modality, dosage, and timing on therapeutic efficacy. We note that use of allogeneic hematopoietic stem cell transplantation in some leukodystrophies allowed for an accelerated path to clinic even in the absence of available animal models. In other leukodystrophies, small and large animal model studies enabled clinical translation of experimental gene therapies. Human clinical trials for the leukodystrophies include <em>ex vivo</em> lentiviral gene delivery, <em>in vivo</em> AAV-mediated gene delivery, and intrathecal antisense oligonucleotide approaches. We outline adverse events associated with each modality focusing specifically on genotoxicity and immunotoxicity. We review monitoring and management of events related to insertional mutagenesis and immune responses. The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00443"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924001302/pdfft?md5=c685829836d31414b77785d7a30a5443&pid=1-s2.0-S1878747924001302-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228538","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}

{"title":"Hematopoietic stem cell gene therapy to halt neurodegeneration","authors":"Alessandra Biffi","doi":"10.1016/j.neurot.2024.e00440","DOIUrl":"10.1016/j.neurot.2024.e00440","url":null,"abstract":"<div><p>Microglia play fundamental roles in multiple pathological primary and secondary processes affecting the central nervous system that ultimately result in neurodegeneration and for this reason they are considered as a key therapeutic target in several neurodegenerative diseases. Microglia-targeted therapies are directed at either restoring or modulating microglia function, to redirect their functional features toward neuroprotection. Among these strategies, hematopoietic stem cell gene therapy have proven to be endowed with a unique potential for replacing diseased microglia with engineered, transplant progeny cells that can integrate and exert relevant beneficial effects in the central nervous system of patients affected by inherited and acquired neurodegenerative conditions.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924001272/pdfft?md5=6224d3b2e9d4d159fc4f8ea2aa2de4b7&pid=1-s2.0-S1878747924001272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228539","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}

{"title":"AlzPED: An Open Science Tool Raising the Standards for Preclinical Testing of Candidate Therapeutics in Alzheimer’s Disease Animal Models","authors":"Jaya Viswanathan Ph.D.,&nbsp;Maria Fe Lanfranco Gallofre Ph.D.,&nbsp;Zane Martin Ph.D.,&nbsp;Suzana Petanceska Ph.D.,&nbsp;Shreaya Chakroborty Ph.D.,&nbsp;Lorenzo Refolo Ph.D.","doi":"10.1016/j.neurot.2024.e00407","DOIUrl":"10.1016/j.neurot.2024.e00407","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00407"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S187874792400093X/pdfft?md5=e4e7e157ba6bc3666d942cf5795b8852&pid=1-s2.0-S187874792400093X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142310246","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}

{"title":"Positive Allosteric Modulation of GABAA α5 Receptors Improves Memory performance of rats with Conditions of Hippocampal Hyperactivity","authors":"Ming Teng Koh Ph.D. ,&nbsp;Sharon Rosenzweig-Lipson Ph.D. ,&nbsp;Michela Gallagher Ph.D.","doi":"10.1016/j.neurot.2024.e00395","DOIUrl":"10.1016/j.neurot.2024.e00395","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00395"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000813/pdfft?md5=1b3ff82be7f0d163b7db9e1ce18c1ab3&pid=1-s2.0-S1878747924000813-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142312911","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}

{"title":"ALT100, A Designed Peptide Targeting α-sheet Amyloid-β Oligomers, Improves Behavior in an ICV Oligomeric Aβ Mouse Model","authors":"Carolyn Tallon Ph.D.,&nbsp;Chandresh Gajera Ph.D.,&nbsp;Chris Tran,&nbsp;Jeff Posakony Ph.D.,&nbsp;Charles Watt,&nbsp;Gill Block M.D., Ph.D.,&nbsp;Valerie Daggett Ph.D.","doi":"10.1016/j.neurot.2024.e00398","DOIUrl":"10.1016/j.neurot.2024.e00398","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00398"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000849/pdfft?md5=90854888f1e8ebd4c4a3d2f2768393fd&pid=1-s2.0-S1878747924000849-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142312582","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}

{"title":"In memoriam: Ira Shoulson","authors":"Robert C. Griggs ,&nbsp;M. Maral Mouradian","doi":"10.1016/j.neurot.2024.e00385","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00385","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00385"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000710/pdfft?md5=0256ae7a7424bcdfe09caa52d38e3111&pid=1-s2.0-S1878747924000710-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141478972","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}

{"title":"Carnosine ameliorates postoperative cognitive dysfunction of aged rats by limiting astrocytes pyroptosis","authors":"Jiahong Shen ,&nbsp;Jiawen Xu ,&nbsp;Yuxin Wen ,&nbsp;Zili Tang ,&nbsp;Jiaqi Li ,&nbsp;Jianliang Sun","doi":"10.1016/j.neurot.2024.e00359","DOIUrl":"10.1016/j.neurot.2024.e00359","url":null,"abstract":"<div><p>Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients, and neuroinflammation is a key hallmark. Recent studies suggest that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated astrocytes pyroptosis is involved in the regulation of neuroinflammation in many neurocognitive diseases, while its role in POCD remains obscure. Carnosine is a natural endogenous dipeptide with anti-inflammatory and neuroprotective effects. To explore the effect of carnosine on POCD and its mechanism, we established a POCD model by exploratory laparotomy in 24-month-old male Sprague-Dawley rats. We found that the administrated of carnosine notably attenuated surgery-induced NLRP3 inflammasome activation and pyroptosis in astrocytes, central inflammation, and neuronal damage in the hippocampus of aged rats. In addition, carnosine dramatically ameliorated the learning and memory deficits of surgery-induced aged rats. Then in the in vitro experiments, we stimulated primary astrocytes with lipopolysaccharide (LPS) after carnosine pretreatment. The results also showed that the application of carnosine alleviated the activation of the NLRP3 inflammasome, pyroptosis, and inflammatory response in astrocytes stimulated by LPS. Taken together, these findings suggest that carnosine improves POCD in aged rats via inhibiting NLRP3-mediated astrocytes pyroptosis and neuroinflammation.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00359"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S187874792400045X/pdfft?md5=06b3e18924bd93dd5fcad5008ec11764&pid=1-s2.0-S187874792400045X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140850538","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}

{"title":"AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury","authors":"","doi":"10.1016/j.neurot.2024.e00362","DOIUrl":"10.1016/j.neurot.2024.e00362","url":null,"abstract":"<div><p>Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00362"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000485/pdfft?md5=48397cd3b1087d7c1712a20f34509d15&pid=1-s2.0-S1878747924000485-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859065","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}

{"title":"Nurr1 overexpression in the primary motor cortex alleviates motor dysfunction induced by intracerebral hemorrhage in the striatum in mice","authors":"","doi":"10.1016/j.neurot.2024.e00370","DOIUrl":"10.1016/j.neurot.2024.e00370","url":null,"abstract":"<div><p>Hemorrhage-induced injury of the corticospinal tract (CST) in the internal capsule (IC) causes severe neurological dysfunction in both human patients and rodent models of intracerebral hemorrhage (ICH). A nuclear receptor Nurr1 (NR4A2) is known to exert anti-inflammatory and neuroprotective effects in several neurological disorders. Previously we showed that Nurr1 ligands prevented CST injury and alleviated neurological deficits after ICH in mice. To prove direct effect of Nurr1 on CST integrity, we examined the effect of Nurr1 overexpression in neurons of the primary motor cortex on pathological consequences of ICH in mice. ICH was induced by intrastriatal injection of collagenase type VII, where hematoma invaded into IC. Neuron-specific overexpression of Nurr1 was induced by microinjection of synapsin I promoter-driven adeno-associated virus (AAV) vector into the primary motor cortex. Nurr1 overexpression significantly alleviated motor dysfunction but showed only modest effect on sensorimotor dysfunction after ICH. Nurr1 overexpression also preserved axonal structures in IC, while having no effect on hematoma-associated inflammatory events, oxidative stress, and neuronal death in the striatum after ICH. Immunostaining revealed that Nurr1 overexpression increased the expression of Ret tyrosine kinase and phosphorylation of Akt and ERK1/2 in neurons in the motor cortex. Moreover, administration of Nurr1 ligands 1,1-bis(3′-indolyl)-1-(<em>p</em>-chlorophenyl)methane or amodiaquine increased phosphorylation levels of Akt and ERK1/2 as well as expression of glial cell line-derived neurotrophic factor and Ret genes in the cerebral cortex. These results suggest that the therapeutic effect of Nurr1 on striatal ICH is attributable to the preservation of CST by acting on cortical neurons.</p></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 4","pages":"Article e00370"},"PeriodicalIF":5.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878747924000564/pdfft?md5=953cba1f78adec6d4eec8115fac1d2b6&pid=1-s2.0-S1878747924000564-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865496","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}