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ATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson’s Disease
- Source :
- Journal of Parkinson's Disease
- Publication Year :
- 2021
- Publisher :
- IOS Press, 2021.
-
Abstract
- Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.
- Subjects :
- Research Report
Genetically modified mouse
medicine.medical_specialty
Parkinson's disease
Gastrointestinal Diseases
alpha-synuclein
Mice, Transgenic
Chromosomal translocation
ATH434
enteric neuropathy
Disease
Mice
gut dysfunction
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Internal medicine
medicine
Animals
Alpha-synuclein
Enteric neuropathy
business.industry
Parkinson Disease
medicine.disease
colonic propulsion
Bioavailability
Disease Models, Animal
Endocrinology
chemistry
Parkinson’s disease
Enteric nervous system
Neurology (clinical)
business
Subjects
Details
- ISSN :
- 1877718X and 18777171
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of Parkinson's Disease
- Accession number :
- edsair.doi.dedup.....660536ea82e093195135dcf586127959