Nitric oxide plays a key role in myelination in the developing brain.
Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates, but there is little information available about its effect on the developing brain. We explored the effects of both iNO and endogenous NO on developing white matter in rodents. Rat or mouse pups and their mothers were placed in a chamber containing 5 to 20 ppm of NO for 7 days after birth. Neonatal exposure to iNO was associated with a transient increase in central nervous system myelination in rats and C57BL/6 mice without any deleterious effects at low doses (5 ppm) or behavioral consequences in adulthood. Exposure to iNO was associated with a proliferative effect on immature oligodendrocytes and a subsequent promaturational effect. The role of endogenous NO in myelination was investigated in animals treated with the nitric oxides synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) in the neonatal period; this led to protracted myelination defects and subsequent behavioral deficits in adulthood. These effects were reversed by rescuing L-NAME-treated animals with iNO. Thus, we demonstrate considerable effect of both exogenous and endogenous NO on myelination in rodents. These data point to potential new avenues for neuroprotection in human perinatal brain damage.
Olivier
Paul
P
INSERM, AVENIR R05230HS, Paris, France.
Loron
Gauthier
G
Fontaine
Romain H
RH
Pansiot
Julien
J
Dalous
Jérémie
J
Thi
Hoa Pham
HP
Charriaut-Marlangue
Christiane
C
Thomas
Jean-Léon
JL
Mercier
Jean-Christophe
JC
Gressens
Pierre
P
Baud
Olivier
O
D000280:Administration, Inhalation; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D001526:Behavioral Symptoms / Q000139:chemically induced / Q000201:enzymology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D009483:Neuropsychological Tests; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000494:pharmacology; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects; D018709:Statistics, Nonparametric; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D019394:Ki-67 Antigen; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D019331:NG-Nitroarginine Methyl Ester; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019081:O Antigens; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4