Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: An in vitro study in rat three-dimensional organotypic brain cell cultures.
Animals
Argininosuccinic Acid
/ toxicity
Argininosuccinic Aciduria
/ genetics
Brain
/ drug effects
Cells, Cultured
Creatine
/ pharmacology
Humans
Neurons
/ cytology
Neuroprotective Agents
/ pharmacology
Neurotoxicity Syndromes
/ metabolism
Organ Culture Techniques
/ methods
Rats
Tissue Scaffolds
/ chemistry
3D organotypic brain cell cultures
argininosuccinate lyase (ASL) deficiency
argininosuccinic acid
astrocytes
creatine
guanidino compounds
guanidinosuccinic acid
neurons
neurotoxicity
urea cycle disorders
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
03
11
2018
revised:
04
03
2019
accepted:
22
03
2019
pubmed:
25
3
2019
medline:
25
8
2020
entrez:
26
3
2019
Statut:
ppublish
Résumé
The urea cycle disorder (UCD) argininosuccinate lyase (ASL) deficiency, caused by a defective ASL enzyme, exhibits a wide range of phenotypes, from life-threatening neonatal hyperammonemia to asymptomatic patients, with only the biochemical marker argininosuccinic acid (ASA) elevated in body fluids. Remarkably, even without ever suffering from hyperammonemia, patients often develop severe cognitive impairment and seizures. The goal of this study was to understand the effect on the known toxic metabolite ASA and the assumed toxic metabolite guanidinosuccinic acid (GSA) on developing brain cells, and to evaluate the potential role of creatine (Cr) supplementation, as it was described protective for brain cells exposed to ammonia. We used an in vitro model, in which we exposed three-dimensional (3D) organotypic rat brain cell cultures in aggregates to different combinations of the metabolites of interest at two time points (representing two different developmental stages). After harvest and cryopreservation of the cell cultures, the samples were analyzed mainly by metabolite analysis, immunohistochemistry, and western blotting. ASA and GSA were found toxic for astrocytes and neurons. This toxicity could be reverted in vitro by Cr. As well, an antiapoptotic effect of ASA was revealed, which could contribute to the neurotoxicity in ASL deficiency. Further studies in human ASL deficiency will be required to understand the biochemical situation in the brain of affected patients, and to investigate the impact of high or low arginine doses on brain Cr availability. In addition, clinical trials to evaluate the beneficial effect of Cr supplementation in ASL deficiency would be valuable.
Substances chimiques
Neuroprotective Agents
0
Argininosuccinic Acid
2387-71-5
Creatine
MU72812GK0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1077-1087Informations de copyright
© 2019 SSIEM.
Références
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