دورية أكاديمية
Systemic delivery of antagomirs during blood-brain barrier disruption is disease-modifying in experimental epilepsy.
| العنوان: | Systemic delivery of antagomirs during blood-brain barrier disruption is disease-modifying in experimental epilepsy. |
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| المؤلفون: | Reschke CR; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Silva LFA; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Vangoor VR; Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands., Rosso M; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., David B; Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany., Cavanagh BL; Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Connolly NMC; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Brennan GP; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Sanz-Rodriguez A; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Mooney C; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; School of Computer Science, University College Dublin, Dublin 4, Ireland., Batool A; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Greene C; Department of Genetics, Trinity College Dublin, Dublin 2, Ireland., Brennan M; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Conroy RM; Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Rüber T; Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, 60528 Frankfurt am Main, Germany., Prehn JHM; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Campbell M; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; Department of Genetics, Trinity College Dublin, Dublin 2, Ireland., Pasterkamp RJ; Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands., Henshall DC; Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland. Electronic address: dhenshall@rcsi.ie. |
| المصدر: | Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Jun 02; Vol. 29 (6), pp. 2041-2052. Date of Electronic Publication: 2021 Feb 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : Cambridge, MA : Cell Press Original Publication: San Diego, CA : Academic Press, 2000- |
| مواضيع طبية MeSH: | Antagomirs/*genetics , Blood-Brain Barrier/*metabolism , Epilepsy/*genetics , Epilepsy/*therapy, Animals ; Antagomirs/administration & dosage ; Blood-Brain Barrier/pathology ; Disease Management ; Disease Models, Animal ; Disease Susceptibility ; Gene Expression Regulation ; Gene Silencing ; Gene Transfer Techniques ; Genetic Predisposition to Disease ; Genetic Therapy ; Mice ; MicroRNAs/genetics ; RNA Interference ; Treatment Outcome |
| مستخلص: | Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies. Competing Interests: Declaration of interests D.C.H. reports patent US9803200 B2 “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries,” and D.C.H. and C.R.R. report patent WO2019219723A1 “Pharmaceutical compositions for treatment of microRNA related diseases.” The remaining authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) |
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| فهرسة مساهمة: | Keywords: antagomirs; antiepileptic drug; antisense oligonucleotides; chemoconvulsant; epileptogenesis; hippocampal sclerosis; noncoding RNA; status epilepticus |
| المشرفين على المادة: | 0 (Antagomirs) 0 (MicroRNAs) |
| تواريخ الأحداث: | Date Created: 20210220 Date Completed: 20220331 Latest Revision: 20220716 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8178478 |
| DOI: | 10.1016/j.ymthe.2021.02.021 |
| PMID: | 33609732 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1525-0024 |
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| DOI: | 10.1016/j.ymthe.2021.02.021 |