Abstract
Perinatal infections have a negative impact on brain development. However, the underlying mechanisms leading to neurological impairment are not completely understood and reliable models of inflammation are urgently needed. Using phorbol-myristate-acetate as an activator of inflammation, we investigated the effect on the developing rodent brain. Neonatal rats and mice deficient in IL-18 or IRAK-4 were exposed to PMA. Brains were assessed for regulation of pro- and anti-inflammatory cytokines and cell death 24 hrs, 7 and 14 days after treatment. PMA induced an inflammatory response and caused widespread neurodegeneration in the brains of 3- and 7-day-old rats. In contrast, 14-day-old rats were resistant to the neurotoxic effect of PMA. Histological evaluation at the age of 14 and 21 days revealed a destruction of the cortical microstructure with decreased numerical density of neuronal cells. Mice deficient in IL-18 or IRAK-4 were protected against PMA induced brain injury. PMA treatment during a vulnerable period can alter brain development. IL-18 and IRAK-4 appear to be important for the development of PMA induced injury.
Highlights
Recent advances in the understanding of fetal physiology and neonatal intensive care medicine have resulted in markedly increased survival rates of premature infants
Brain injury with widespread loss of neurons has been noted in the cortex, hippocampus, and thalamus of postmortem specimens from patients with periventricular leukomalacia (PVL) [3]
Over the last decade the hypoxic-ischemic paradigm for neonatal brain injury has been replaced by a multifactorial hypothesis which recognizes the key role elevated levels of proinflammatory cytokines play in systemic inflammation of the brain [5]
Summary
Recent advances in the understanding of fetal physiology and neonatal intensive care medicine have resulted in markedly increased survival rates of premature infants. Severe motor and cognitive impairment still affects a considerable proportion of surviving patients, who exhibit disturbances in learning, cognition, and attention [1]. Whereas many of these disabilities have been attributed mostly to white matter injury, disrupted grey matter development appears to contribute to disabilities of preterm survivors [2]. We induced inflammation by hyperoxia in combination with lipopolysaccharide (LPS) and identified the role of inflammatory cytokines in neurodegenerative processes in the developing brain [6, 7]. An increase in degenerating cells in the thalamus of newborn rabbits prenatally exposed to endotoxins suggests impairment of grey matter [8]
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