[article]
| 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 |
in Journal of Neurodevelopmental Disorders > 17 (2025)
[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 |
|  |
Acute administration of lovastatin had no pronounced effect on motor abilities, motor coordination, gait nor simple cognition in a mouse model of Angelman syndrome in Journal of Neurodevelopmental Disorders, 17 (2025)
