New research published in the Journal of Leukocyte Biology suggests that chronic hypoxia induced an inflammatory response in the brain with concomitant demyelination, leading to behavioral deficits.
New research published in the Journal of Leukocyte Biology, shows that the development of white matter in the mouse brains is delayed when they are exposed to chronic low oxygen levels shortly after birth. If true in humans, this may help explain why infants born with cyanotic heart disease, prematurity and/or severe lung disease often exhibit developmental disabilities that effect learning during childhood, years after the low-oxygen exposure. This knowledge may inform future studies focused on the development of effective treatment strategies.
“We found that chronic hypoxia is a state of neuroinflammation in the developing brain,” said Lakshmi Raman, MD, a researcher involved in the work from the Department of Pediatrics at the University of Texas Southwestern Medical Center in Dallas, Texas. “Therefore, developing therapies to mitigate potentially detrimental inflammation may help reduce brain injury in infants exposed to chronic hypoxia and at-risk for developmental delay.”
Scientists exposed experimental groups of mice to low oxygen from days three through 28 after birth. Control mice were exposed to normal oxygen levels (21% oxygen, i.e., room air). Researches studied brain development when exposed to low oxygen through multiple methods, including quantifying myelin protein, the number of myelin-producing cells, called oligodendrocytes, total brain inflammation and the activation of brain-targeting white blood cells. The aim was to determine if perinatal chronic hypoxia produces permanent injury to the brain, including a four-week recovery period. They found that mice exposed to perinatal chronic hypoxia lost myelin in the developing brain, which resulted in motor learning deficits that persisted for weeks after the end of hypoxic exposure. The long-term myelin loss was associated with increased inflammation in the brain, as well as an increased presence of CD4 T cells in the blood that were reactive to myelin. Therefore, perinatal chronic hypoxia induced an inflammatory response in the brain with concomitant demyelination, ultimately leading to long-term behavioral deficits.
“These findings are important since the neurological effects of low neonatal oxygen levels, if extended to humans, could have clinically actionable treatment options like oxygen supplementation,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “The link between low oxygen or hypoxia and inflammation is becoming clear in a number of settings and the connection to inflammatory pathways may reveal additional anti-inflammatory treatment options for nervous system hypoxia.”
Source: Cody Mooneyhan – Federation of American Societies for Experimental Biology
Image Source: The image is in the public domain
Original Research: Abstract for “Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity” by Sterling B. Ortega, Xiagmei Kong, Ramgopal Venkataraman, Allen Michael Savedra, Steven G. Kernie, Ann M. Stowe, and Lakshmi Raman in Journal of Leukocyte Biology. Published online January 2016 doi:10.1189/jlb.5HI0914-447R
Abstract
Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity
pCH is an important risk factor for brain injury and long-term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long-term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH-mediated neuroinflammation included oligodendrocyte-directed autoimmunity, with an increase in peripheral myelin-specific CD4 T cells. Thus, both the loss of available, mature, myelin-producing glial cells and an active increase in autoreactive, myelin-specific CD4 T cell infiltration into pCH brains may contribute to early pCH-induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia-driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long-term functional disability.
“Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity” by Sterling B. Ortega, Xiagmei Kong, Ramgopal Venkataraman, Allen Michael Savedra, Steven G. Kernie, Ann M. Stowe, and Lakshmi Raman in Journal of Leukocyte Biology. Published online January 2016 doi:10.1189/jlb.5HI0914-447R
