Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome / Timothy A. FENTON in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome Type de document : texte imprimé Auteurs : Timothy A. FENTON, Auteur ; Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Jill L. SILVERMAN, Auteur Langues : Anglais (eng) Mots-clés : Animals  Lovastatin/pharmacology/administration & dosage  Angelman Syndrome/drug therapy/physiopathology/genetics  Disease Models, Animal  Mice  Gait/drug effects  Male  Cognition/drug effects  Female  Behavior, Animal/drug effects  Mice, Inbred C57BL  Ubiquitin-Protein Ligases/genetics  Motor Activity/drug effects  Angelman syndrome  Behavior  Gait  Lovastatin  Neurodevelopmental disorder  UBE3A  reviewed and approved by the UC Davis IACUC on April 20, 2023. Active protocols  are reviewed annually. Title: Novel Testing of Therapeutics for Angelman  Syndrome. Principal Investigator: Jill L. Silverman Protocol #: 23384  Institution: University of California, Davis This institution is accredited by  the Association for Assessment and Accreditation of Laboratory Animal Care,  International (AAALAC). This institution has an Animal Welfare Assurance on file  with the Office of Laboratory Animal Welfare (OLAW). The Assurance Number is  D16-00272 (A3433-01). The IACUC is constituted in accordance with U.S. Public  Health Service (PHS) Animal Welfare Policy and includes a member of the public  and a non-scientist. Consent for publication: FAST, the MIND Institute and the  NIH/NICHD IDDRC consent for the data presented herein to be publishable.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein. En ligne : https://dx.doi.org/10.1186/s11689-025-09616-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome [texte imprimé] / Timothy A. FENTON, Auteur ; Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Jill L. SILVERMAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Lovastatin/pharmacology/administration & dosage  Angelman Syndrome/drug therapy/physiopathology/genetics  Disease Models, Animal  Mice  Gait/drug effects  Male  Cognition/drug effects  Female  Behavior, Animal/drug effects  Mice, Inbred C57BL  Ubiquitin-Protein Ligases/genetics  Motor Activity/drug effects  Angelman syndrome  Behavior  Gait  Lovastatin  Neurodevelopmental disorder  UBE3A  reviewed and approved by the UC Davis IACUC on April 20, 2023. Active protocols  are reviewed annually. Title: Novel Testing of Therapeutics for Angelman  Syndrome. Principal Investigator: Jill L. Silverman Protocol #: 23384  Institution: University of California, Davis This institution is accredited by  the Association for Assessment and Accreditation of Laboratory Animal Care,  International (AAALAC). This institution has an Animal Welfare Assurance on file  with the Office of Laboratory Animal Welfare (OLAW). The Assurance Number is  D16-00272 (A3433-01). The IACUC is constituted in accordance with U.S. Public  Health Service (PHS) Animal Welfare Policy and includes a member of the public  and a non-scientist. Consent for publication: FAST, the MIND Institute and the  NIH/NICHD IDDRC consent for the data presented herein to be publishable.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein. En ligne : https://dx.doi.org/10.1186/s11689-025-09616-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Gait as a quantitative translational outcome measure in Angelman syndrome / Stela P. PETKOVA in Autism Research, 15-5 (May 2022)  

Public ISBD [article]  inAutism Research > 15-5 (May 2022) . - p.821-833 Titre : Gait as a quantitative translational outcome measure in Angelman syndrome Type de document : texte imprimé Auteurs : Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Elizabeth L. BERG, Auteur ; Timothy A. FENTON, Auteur ; Jessica DUIS, Auteur ; Jill L. SILVERMAN, Auteur Article en page(s) : p.821-833 Langues : Anglais (eng) Mots-clés : Angelman Syndrome/genetics  Animals  Autism Spectrum Disorder  Disease Models, Animal  Gait/physiology  Humans  Mice  Movement Disorders  Muscle Hypotonia  Outcome Assessment, Health Care  Angelman syndrome  animal models  autism  behavior  gait  genetics  longitudinal  motor  mouse models  neurodevelopment Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions. En ligne : http://dx.doi.org/10.1002/aur.2697 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Gait as a quantitative translational outcome measure in Angelman syndrome [texte imprimé] / Stela P. PETKOVA, Auteur ; Anna ADHIKARI, Auteur ; Elizabeth L. BERG, Auteur ; Timothy A. FENTON, Auteur ; Jessica DUIS, Auteur ; Jill L. SILVERMAN, Auteur . - p.821-833. Langues : Anglais (eng) in Autism Research > 15-5 (May 2022) . - p.821-833 Mots-clés : Angelman Syndrome/genetics  Animals  Autism Spectrum Disorder  Disease Models, Animal  Gait/physiology  Humans  Mice  Movement Disorders  Muscle Hypotonia  Outcome Assessment, Health Care  Angelman syndrome  animal models  autism  behavior  gait  genetics  longitudinal  motor  mouse models  neurodevelopment Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions. En ligne : http://dx.doi.org/10.1002/aur.2697 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

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