Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain.

BACKGROUND: Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy. METHODS: To create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1-5 and myelination was assessed. RESULTS: Here, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation. CONCLUSIONS: In this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.

Macromolecule biosynthesis: a key function of sleep.

The function(s) of sleep remains a major unanswered question in biology. We assessed changes in gene expression in the mouse cerebral cortex and hypothalamus following different durations of sleep and periods of sleep deprivation. There were significant differences in gene expression between behavioral states; we identified 3,988 genes in the cerebral cortex and 823 genes in the hypothalamus with altered expression patterns between sleep and sleep deprivation. Changes in the steady-state level of transcripts for various genes are remarkably common during sleep, as 2,090 genes in the cerebral cortex and 409 genes in the hypothalamus were defined as sleep specific and changed (increased or decreased) their expression during sleep. The largest categories of overrepresented genes increasing expression with sleep were those involved in biosynthesis and transport. In both the cerebral cortex and hypothalamus, during sleep there was upregulation of multiple genes encoding various enzymes involved in cholesterol synthesis, as well as proteins for lipid transport. There was also upregulation during sleep of genes involved in synthesis of proteins, heme, and maintenance of vesicle pools, as well as antioxidant enzymes and genes encoding proteins of energy-regulating pathways. We postulate that during sleep there is a rebuilding of multiple key cellular components in preparation for subsequent wakefulness.

Age-related changes in adenosine metabolic enzymes in sleep/wake regulatory areas of the brain.

The impact of age on the enzymatic activities of adenosine metabolic enzymes, i.e., adenosine deaminase, adenosine kinase, cytosolic- and ecto-5'-nucleotidase have been assessed in the brain sleep/wake regulatory areas of young, intermediate and old rats (2, 12 and 24 months, respectively). There were significant spatial differences in the distribution of enzymes of adenosine metabolism in the brain. Age did not impact on the enzymatic activity of adenosine deaminase. Adenosine kinase activity increased significantly in the cerebral cortex of old animals. However, there were no differences in the activity of adenosine kinase between young and intermediate aged rats. The largest age-related changes were in the activity of cytosolic- and ecto-5'-nucleotidase and there was a significant age-related increase in the activity of these enzymes in the sleep/wake regulatory areas. In addition, the activity of cytosolic- and ecto-5'-nucleotidase increased in the cerebral cortex of old and intermediate age rats when compared to young animals. An increase in the enzymatic activities in the cerebral cortex of adenosine kinase and 5'-nucleotideases was accompanied by an increase in the level of their mRNA. An increase in the activity of 5'-nucleotideases with age likely leads to an increase in adenosine levels in the brain.