Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease.
congenital heart disease
hypoxia
neuroprotection
tetrahydrobiopterin
Journal
Journal of the American Heart Association
ISSN: 2047-9980
Titre abrégé: J Am Heart Assoc
Pays: England
ID NLM: 101580524
Informations de publication
Date de publication:
06 08 2019
06 08 2019
Historique:
entrez:
24
7
2019
pubmed:
25
7
2019
medline:
5
1
2021
Statut:
ppublish
Résumé
Background Reduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter. Methods and Results Transgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7-12). The proliferation (n=3-6), apoptosis (n=3-6), and developmental stage (n=5-8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia-induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3-4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6-10). Hypoxia worsened sensory-motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5-9). Conclusions Suboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.
Identifiants
pubmed: 31331224
doi: 10.1161/JAHA.119.012711
pmc: PMC6761654
doi:
Substances chimiques
Biopterins
0
sapropterin
EGX657432I
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e012711Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL104173
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128546
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS045702
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090257
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA051008
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139712
Pays : United States
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