Article
Medicine, Research & Experimental
Aoife Campbell, Gareth Morris, Albert Sanfeliu, Joana Augusto, Elena Langa, Jaideep C. Kesavan, Ngoc T. Nguyen, Ronan M. Conroy, Jesper Worm, Lukasz Kielpinski, Mads Aaboe Jensen, Meghan T. Miller, Thomas Kremer, Cristina R. Reschke, David C. Henshall
Summary: Angelman syndrome (AS) is a severe neurodevelopmental disorder. Inhibiting miR-134 and possibly other microRNAs may be beneficial in treating clinically relevant phenotypes with a later developmental window in AS.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Review
Pharmacology & Pharmacy
Yuzi Jin, Lei Ren, Xiaoqing Jing, Hongquan Wang
Summary: Epilepsy is a chronic disorder characterized by recurrent seizures, and it is a global public health issue with comorbidities in cognition, psychiatric status, and social-adaptive behaviors. The molecular mechanisms underlying epilepsy-induced neuronal damage remain unclear. Recent studies have shown that inhibiting ferroptosis, a type of regulated cell death, can mitigate neuronal damage in epilepsy. This review suggests inhibiting ferroptosis as a therapeutic target for epilepsy and associated neurobehavioral comorbidities.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Robert J. Forster, David C. Henshall, Hany El Naggar, Yann Pellegrin, Norman Delanty
Summary: This study reports the detection of a key biomarker in epilepsy, miR-134, using an environmentally sensitive electrochemiluminescent luminophore, [Ru(DPPZ)(2)PIC](2+). The ability of the sensor to quantify miR-134 in unprocessed plasma samples from healthy volunteers and people with epilepsy is demonstrated.
BIOELECTROCHEMISTRY
(2022)
Article
Neurosciences
Lars Emil Larsen, Sielke Caestecker, Latoya Stevens, Pieter van Mierlo, Evelien Carrette, Paul Boon, Kristl Vonck, Robrecht Raedt
Summary: This study assessed the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures. The results showed both inhibition and excitation of LC neurons during seizures, but a consistent release of noradrenaline was observed.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Pharmacology & Pharmacy
Lindsey Shapiro, Andrew Escayg, Jennifer C. Wong
Summary: Voltage-gated sodium channel genes are important for human epilepsy. SCN8A mutations can cause various clinical symptoms, including different types of seizures, movement disorders, intellectual disabilities, and autism. CBD treatment in RL/+ mutant mice showed dose-dependent seizure resistance and improved social behavior and reduced hyperactivity. CBD may be beneficial for patients with SCN8A-associated disease.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Martina Tallarico, Antonio Leo, Emilio Russo, Rita Citraro, Ernesto Palma, Giovambattista De Sarro
Summary: Autism spectrum disorders (ASDs) and epilepsy show a bidirectional link, possibly through common neurobiological pathways. BTBR mice have increased susceptibility to seizures induced by chemoconvulsants impairing GABA(A) neurotransmission, while there is no significant difference for seizures induced by AMPA, NMDA, and Kainate. PTZ-kindling does not affect autistic-like behavior in BTBR mice but can increase anxiety and worsen cognitive performance. This suggests a tight connection between ASD and epilepsy.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Environmental Sciences
Yan Xiong, Hui Huang, Fuli Chen, Yijia Tang
Summary: circDLGAP4 promotes autophagy and improves endothelial dysfunction in AS via the circDLGAP4/miR-134-5p/PTPN4 axis.
ENVIRONMENTAL TOXICOLOGY
(2023)
Article
Neurosciences
Rebecca Bornstein, Katerina James, Julia Stokes, Kyung Yeon Park, Ernst-Bernhard Kayser, John Snell, Angela Bard, Yihan Chen, Franck Kalume, Simon C. Johnson
Summary: Genetic mitochondrial diseases are a common cause of inherited metabolic disorders, with Leigh syndrome being the most common clinical presentation in children. While there are no proven therapies for mitochondrial diseases, a ketogenic diet has shown some success in managing mitochondrial epilepsies. mTOR inhibition is being explored as a potential therapeutic target for seizures related to primary mitochondrial dysfunction.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Chemistry, Multidisciplinary
Lin Yang, Qi Zhang, Xue-qing Wu, Xiao-yun Qiu, Fan Fei, Nan-xi Lai, Yu-yi Zheng, Meng-di Zhang, Qing-yang Zhang, Yu Wang, Fei Wang, Ceng-lin Xu, Ye-ping Ruan, Yi Wang, Zhong Chen
Summary: This study investigates the role of seizure-activated neurons in the subiculum in cognitive impairment in temporal lobe epilepsy. The results show that activation of these neurons is associated with cognitive deficits, while inhibition improves cognitive performance.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Neurosciences
Rogerio R. Gerbatin, Joana Augusto, Gareth Morris, Aoife Campbell, Jesper Worm, Elena Langa, Cristina R. Reschke, David C. Henshall
Summary: Targeting miR-134 does not have therapeutic applications in Dravet syndrome, as it does not affect hyperthermia-induced seizures and spontaneous seizures.
Article
Pharmacology & Pharmacy
Ye Yang, Danyu Ni, Li Wang, Xiaodan Shi, Xiaolan Zhang, Lin Zhou, Juan Ji, Chun Zhao, Rong Shen, Xiufeng Ling, Xiaojiao Chen
Summary: The study found that antimicrobial triclosan (TCS) has a detrimental effect on the development of mouse embryos, leading to impaired expression of stem cell markers. The inhibition of miR-134 and overexpression of Nanog mRNA can rescue the embryos affected by TCS.
Article
Neurosciences
Priyanka Sinha, Bhupender Verma, Subramaniam Ganesh
Summary: Brain aging is characterized by a decline in cellular homeostatic processes, leading to a decreased ability to respond to physiological stress. The aged brain shows physical changes such as degenerating neurons, proteinaceous plaques and tangles, intracellular deposition of glycogen, and elevated neuroinflammation, which are also seen in neurodegenerative disorders. In this study, the authors demonstrate that the expression level of genes implicated in progressive myoclonus epilepsy (PME) decreases with age, resulting in compromised neuronal response and increased susceptibility to seizures. Furthermore, they show that suppressing neuroinflammation can improve seizure susceptibility in both aged animals and animal models of PME.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Medicine, Research & Experimental
Shuo Wang, Weicheng Tang, Lanfang Ma, Jun Yang, Kecheng Huang, Xiaofang Du, Aiyue Luo, Wei Shen, Ting Ding, Shuangmei Ye, Su Zhou, Shuhong Yang, Shixuan Wang
Summary: The study demonstrated that miR-145 targets Crkl and promotes mouse granulosa cells proliferation, differentiation, and steroidogenesis through the JNK/p38 MAPK signaling pathway. MiR-145 may play a significant role in ovarian physiology and pathology.
Article
Biochemistry & Molecular Biology
Yuya Monoe, Kentaro Jingushi, Akitaka Kawase, Takayuki Hirono, Ryo Hirose, Yoshino Nakatsuji, Kaori Kitae, Yuko Ueda, Hiroaki Hase, Yuichi Abe, Jun Adachi, Takeshi Tomonaga, Kazutake Tsujikawa
Summary: The newly designed LNA targeting the miR-130 family could inhibit the growth, invasion, and migration of bladder cancer cells by targeting protein tyrosine phosphatase non-receptor type 1 (PTPN1) and downstream signaling pathways, providing a promising approach for the treatment of bladder cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell & Tissue Engineering
Fang Zhu, Yachai Li, Xiaodan Li
Summary: miR-134 targets CTTN gene and inhibits the biological behaviors of cervical cancer cells by suppressing Cdc42/N-WASP signaling pathway, thereby suppressing cell invasion and degradation of extracellular matrix in cervical cancer.
JOURNAL OF BIOMATERIALS AND TISSUE ENGINEERING
(2022)
Review
Neurosciences
Radharani Benvenutti, Matheus Gallas-Lopes, Matheus Marcon, Cristina R. Reschke, Ana Paula Herrmann, Angelo Piato
Summary: This review integrates the major findings from zebrafish literature regarding the behavioral effects of NMDAR antagonists relevant to schizophrenia, suggesting that zebrafish is a suitable model organism for studying drug-induced behavioral phenotypes. However, more studies are needed to further understand the behavioral differences compared to mammals.
CURRENT NEUROPHARMACOLOGY
(2022)
Article
Clinical Neurology
Karen Suetterlin, Emma Matthews, Richa Sud, Samuel McCall, Doreen Fialho, James Burge, Dipa Jayaseelan, Andrea Haworth, Mary G. Sweeney, Dimitri M. Kullmann, Stephanie Schorge, Michael G. Hanna, Roope Mannikko
Summary: High-throughput DNA sequencing is widely used in the diagnosis of neurological and neuromuscular disorders. However, interpreting the clinical significance and inheritance pattern of variants remains challenging. This study focuses on the evaluation of variants in the ClC-1 channel, which is central to the diagnosis of myotonia congenita. The results show that functional characterization of variants improves the interpretation of their pathogenicity and inheritance pattern.
Article
Clinical Neurology
Andreas Brunklaus, Tony Feng, Tobias Brunger, Eduardo Perez-Palma, Henrike Heyne, Emma Matthews, Christopher Semsarian, Joseph D. Symonds, Sameer M. Zuberi, Dennis Lal, Stephanie Schorge
Summary: Pathogenic variants in the voltage-gated sodium channel gene family have diverse functional effects and can lead to various diseases. This study investigates the similarities in biophysical properties between different sodium channel genes and suggests that these similarities can be used to predict channel function and guide precision therapy. The results show that disease-associated variants cluster in specific functional domains, while population variants are more frequent in non-conserved domains.
Article
Pharmacology & Pharmacy
Edward Beamer, James Morgan, Mariana Alves, Aida Menendez Mendez, Gareth Morris, Bela Zimmer, Giorgia Conte, Laura de Diego-Garcia, Cristina Alarcon-Vila, Nico Ka Yiu Ng, Stephen Madden, Francesco Calzaferri, Cristobal de los Rios, Antonio G. Garcia, Michael Hamacher, Klaus Dinkel, Pablo Pelegrin, David C. Henshall, Annette Nicke, Tobias Engel
Summary: The overexpression of ATP-gated P2X7 receptors contributed to drug-refractory status epilepticus, which was associated with neuroinflammation. Anti-inflammatory drugs and P2X7 receptor antagonists could be potential therapeutic options for drug-refractory status epilepticus.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Emma L. Clayton, Katherine Bonnycastle, Adrian M. Isaacs, Michael A. Cousin, Stephanie Schorge
Summary: Mutations in the ESCRT-III subunit CHMP2B lead to a novel synaptopathy characterized by selective retention of presynaptic SV trafficking proteins and defective SV recycling in neurons. This unique synaptic pathology may represent a key early event in various forms of FTD, as proteins associated with genetic FTD forms localize at the presynapse.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Clinical Neurology
Gareth Morris, Mona Heiland, Kai Lamottke, Haifeng Guan, Thomas D. M. Hill, Yijun Zhou, Qianjin Zhu, Stephanie Schorge, David C. Henshall
Summary: Drug-resistant epilepsy is still a major clinical and societal burden. This study evaluated the potential of BICS01, a synthetic compound, as a new anti-seizure drug. The results showed that BICS01 rapidly reduced the frequency of epileptiform bursting without affecting network excitability or short-term synaptic facilitation. It was well tolerated at high doses in animal models. However, it did not have a protective effect against acute seizures. Further studies are needed to improve its pharmacokinetics, brain accumulation, and understand its mechanism of action.
FRONTIERS IN NEUROLOGY
(2022)
Article
Clinical Neurology
Gareth Morris, Elena Langa, Conor Fearon, Karen Conboy, Kelvin Lau E-How, Amaya Sanz-Rodriguez, Donncha F. O'Brien, Kieron Sweeney, Austin Lacey, Norman Delanty, Alan Beausang, Francesca M. Brett, Jane B. Cryan, Mark O. Cunningham, David C. Henshall
Summary: This study developed a testing platform for antimiRs using human brain tissue sections and demonstrated the effects of ant-134 on miR-134 in live human brain tissues. The findings support the preclinical development of a therapy targeting miR-134 and provide a flexible platform for testing antimiRs and other antisense oligonucleotide therapeutics in human brain.
Review
Neurosciences
Gareth Morris, Stephanie Schorge
Summary: Gene therapy is showing promise in treating rare monogenetic neurological disorders and could potentially offer new treatments for common non-genetic disorders as well. However, the permanent nature of gene therapies may pose risks, and research is being conducted to develop approaches that allow for treatment to be turned on and off.
Article
Multidisciplinary Sciences
Chris Greene, Nicole Hanley, Cristina R. Reschke, Avril Reddy, Maarja A. Mae, Ruairi Connolly, Claire Behan, Eoin O'Keeffe, Isobel Bolger, Natalie Hudson, Conor Delaney, Michael A. Farrell, Donncha F. O'Brien, Jane Cryan, Francesca M. Brett, Alan Beausang, Christer Betsholtz, David C. Henshall, Colin P. Doherty, Matthew Campbell
Summary: This study identified significantly reduced levels of claudin-5 protein in the brain tissue of epilepsy patients, and disruption of claudin-5 exacerbates epilepsy symptoms and BBB dysfunction in mice. Additionally, RepSox and other drugs targeting claudin-5 expression showed potential in preventing seizure activity in experimental epilepsy.
NATURE COMMUNICATIONS
(2022)
Article
Medicine, Research & Experimental
Aoife Campbell, Gareth Morris, Albert Sanfeliu, Joana Augusto, Elena Langa, Jaideep C. Kesavan, Ngoc T. Nguyen, Ronan M. Conroy, Jesper Worm, Lukasz Kielpinski, Mads Aaboe Jensen, Meghan T. Miller, Thomas Kremer, Cristina R. Reschke, David C. Henshall
Summary: Angelman syndrome (AS) is a severe neurodevelopmental disorder. Inhibiting miR-134 and possibly other microRNAs may be beneficial in treating clinically relevant phenotypes with a later developmental window in AS.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Clinical Neurology
Tobias Brunger, Eduardo Perez-Palma, Ludovica Montanucci, Michael Nothnagel, Rikke S. Moller, Stephanie Schorge, Sameer Zuberi, Joseph Symonds, Johannes R. Lemke, Andreas Brunklaus, Stephen F. Traynelis, Patrick May, Dennis Lal
Summary: This study aimed to systematically identify biological features associated with variant pathogenicity in ion-channel genes and found that these features are correlated with clinical phenotypes and molecular measurements in patients with neurodevelopmental disorders. The results suggest the feasibility of clinical decision support algorithms that can predict variant pathogenicity and function in the future.
Review
Neurosciences
Gareth Morris
Summary: MicroRNAs are short non-coding RNAs that regulate gene expression by targeting complementary sequences in mRNA transcripts, primarily in the 3' untranslated region. They play a role in modulating neural excitability and different processes in the nervous system. Additionally, the expression of microRNAs is regulated by neuronal activity, forming feedback loops.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Clinical Neurology
Gareth Morris, Massimo Avoli, Christophe Bernard, Kate Connor, Marco de Curtis, Chris G. Dulla, John G. R. Jefferys, Caterina Psarropoulou, Kevin J. Staley, Mark O. Cunningham
Summary: In vitro preparations offer valuable tools for studying and modeling seizures and epilepsy, as well as screening anti-seizure compounds. However, these models are simplifications of reality and have limitations. Therefore, a combination of in vitro models, in vivo studies, chronic epilepsy animal models, and human cell/tissue-derived preparations is recommended to maximize their potential value.
Article
Multidisciplinary Sciences
Mona Heiland, Niamh M. C. Connolly, Omar Mamad, Ngoc T. Nguyen, Jaideep C. Kesavan, Elena Langa, Kevin Fanning, Albert Sanfeliu, Yan Yan, Junyi Su, Morten T. Veno, Lara S. Costard, Valentin Neubert, Tobias Engel, Thomas D. M. Hill, Thomas M. Freiman, Arun Mahesh, Vijay K. Tiwari, Felix Rosenow, Sebastian Bauer, Jorgen Kjems, Gareth Morris, David C. Henshall
Summary: This study suggests that modulation of miR-335-5p may be a potential strategy to regulate voltage-gated sodium channels (VGSCs) and affect neuronal excitability and seizures. Changes in miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yichen Qiu, Nathanael O'Neill, Benito Maffei, Clara Zourray, Amanda Almacellas-Barbanoj, Jenna C. Carpenter, Steffan P. Jones, Marco Leite, Thomas J. Turner, Francisco C. Moreira, Albert Snowball, Tawfeeq Shekh-Ahmad, Vincent Magloire, Serena Barral, Manju A. Kurian, Matthew C. Walker, Stephanie Schorge, Dimitri M. Kullmann, Gabriele Lignani
Summary: The article presents a gene therapy strategy to down-regulate the excitability of overactive neurons in epilepsy models, leading to a persistent antiepileptic effect without interfering with normal behaviors.
