PUBLICATION
Dapagliflozin ameliorates Lafora disease phenotype in a zebrafish model
- Authors
- Della Vecchia, S., Imbrici, P., Liantonio, A., Naef, V., Damiani, D., Licitra, R., Bernardi, S., Marchese, M., Santorelli, F.M.
- ID
- ZDB-PUB-250109-143
- Date
- 2025
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 183: 117800117800 (Journal)
- Registered Authors
- Naef, Valentina, Santorelli, Filippo Maria
- Keywords
- Dapagliflozin, Gliflozins, Lafora disease, Progressive myoclonic epilepsies, Repurposing drugs
- MeSH Terms
-
- Benzhydryl Compounds*/pharmacology
- Phenotype*
- Locomotion/drug effects
- Glucosides*/pharmacology
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Animals, Genetically Modified
- Oxidative Stress/drug effects
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Larva/drug effects
- Zebrafish*
- Behavior, Animal/drug effects
- Autophagy/drug effects
- Disease Models, Animal*
- Lafora Disease*/drug therapy
- Lafora Disease*/genetics
- Lafora Disease*/pathology
- Animals
- PubMed
- 39753095 Full text @ Biomed. Pharmacother.
Citation
Della Vecchia, S., Imbrici, P., Liantonio, A., Naef, V., Damiani, D., Licitra, R., Bernardi, S., Marchese, M., Santorelli, F.M. (2025) Dapagliflozin ameliorates Lafora disease phenotype in a zebrafish model. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 183:117800117800.
Abstract
Lafora disease (LD) is an ultra-rare and still incurable neurodegenerative condition. Although several therapeutic strategies are being explored, including gene therapy, there are currently no treatments that can alleviate the course of the disease and slow its progression. Recently, gliflozins, a series of SGLT2 transporter inhibitors approved for use in type 2 diabetes mellitus, heart failure and chronic kidney disease, have been proposed as possible repositioning drugs for the treatment of LD. With this in mind, we tested dapagliflozin (50 µM), canagliflozin (2.5 µM) and empagliflozin (200 µM) in our epm2a-/- zebrafish model, investigating their effects on pathological behaviour. In the case of dapagliflozin, we also investigated the possible mechanisms of action. Overall, the gliflozins reduced or rescued neuronal hyperexcitability and locomotor impairment. Dapagliflozin also reduced spontaneous seizure-like events in epm2a-/- larvae. At the biochemical and molecular level, dapagliflozin was found to slightly reduce glycogen content, and suppress inflammation and oxidative stress. It also ameliorates autophagic homeostasis and improves lysosomal markers. In conclusion, our preclinical study showed that dapagliflozin was able to ameliorate part of the pathological phenotype of epm2a-/- zebrafish larvae and could potentially be a suitable drug for repurposing in LD. However, since our model does not present Lafora bodies (LBs), at this early disease stage at least, it would be important to use mouse models in order to ascertain whether it is able to prevent or reduce LB formation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping