Nitric Oxide Plays a Key Role in Myelination in the Developing Brain

Abstract

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.

Two-Year Outcomes of a Randomized Controlled Trial of Inhaled Nitric Oxide in Premature Infants

“…The investigators speculated that the beneficial effect of iNO was mediated through enhancement of somatic growth or by directly affecting the brain through mechanisms involving the cerebral vasculature or neuronal maturation. 27,28 Of note, the current study used the Bayley-III as a component of neurodevelopment assessment. Investigators have suggested that this latest iteration of the Bayley scales underestimates the proportions of children with developmental delay at 2 years of age when compared with the Bayley Scales of Infant Development, second edition, particularly in low-scoring children.…”

Inhaled Nitric Oxide Reduces Brain Damage by Collateral Recruitment in a Neonatal Stroke Model

“…5,6 Endogenous NO is widely recognized as an important messenger and effector molecule for vascular tone and tolerance to damage as well as a mediator in a variety of acute and chronic inflammatory systems. 7 NO is also involved in several critical processes in the developing brain; indeed, exposure to inhaled NO (iNO) during the first week of postnatal life has recently been shown to play a key role in myelination in the developing brain 8 and to significantly reduce the size of excitotoxic lesions in neonatal rat pups. 9 We recently demonstrated, by using 2-dimensional color-coded pulsed ultrasound imaging, that collateral recruitment or failure during ischemia, as revealed by changes in blood flow velocities in the basilar trunk (BT), determined the extent of the ischemic lesion in P7 rats 10 and was…”

“…5,6 Endogenous NO is widely recognized as an important messenger and effector molecule for vascular tone and tolerance to damage as well as a mediator in a variety of acute and chronic inflammatory systems. 7 NO is also involved in several critical processes in the developing brain; indeed, exposure to inhaled NO (iNO) during the first week of postnatal life has recently been shown to play a key role in myelination in the developing brain 8 and to significantly reduce the size of excitotoxic lesions in neonatal rat pups.…”

The effect of pramiracetam in the myelination of the hippocampus in the BALB/c mouse (Mus musculus)

“…While the exact mode of action of pramiracetam is still not fully understood, the effects of increasing NO activity may not be sufficient to cause demyelination. Furthermore, since NO at normal levels may promote myelination, [16] it may be inferred that pramiracetam, given the clinical trials that was performed, may actually be protective rather than damaging to neurons.…”

“…[9] NO has been implicated to have a role in the myelination of the developing [2] brains as well as being associated with an increase in central nervous system myelination in rats. [16,17] However, NO has been shown to be capable of being toxic to oligodendrocytes and can induce the degeneration of axons that may lead to the process of demyelination. [17,18] Since neurons are irreplaceable and given the potential of pramiracetam to affect NO levels and the relation of NO to demyelination, it would be a relevant area of inquiry to explore these relationships further.…”