Caspase‐1–processed interleukins in hyperoxia‐induced cell death in the developing brain

Abstract

Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. We hypothesized that two caspase-1-processed cytokines, interleukin (IL)-1␤ and IL-18, are involved in oxygen-induced neuronal cell death. Six-day-old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, and 48 hours). Neuronal cell death in the brain, as assessed by Fluoro-Jade B and silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA and protein levels of caspase 1, IL-1␤, IL-18, and IL-18 receptor ␣ (IL-18R␣). Intraperitoneal injection of recombinant human IL-18 -binding protein, a specific inhibitor of IL-18, attenuated hyperoxic brain injury. Mice deficient in IL-1 receptor-associated kinase 4 (IRAK-4), which is pivotal for both IL-1␤ and IL-18 signal transduction, were protected against oxygen-mediated neurotoxicity. These findings causally link IL-1␤ and IL-18 to hyperoxia-induced cell death in the immature brain. These cytokines might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain, which is exquisitely sensitive to a variety of iatrogenic measures including oxygen. Neurol 2005;57:50 -59 Advances in the understanding of fetal physiology have resulted in markedly increased survival rates of premature infants. Ann

Acute and long-term proteome changes induced by oxidative stress in the developing brain

“…Hyperoxia causes acute functional and morphological changes of the immature brain. [8][9][10] In addition, acute functional and morphological changes may induce further functional and morphological changes in the period of rapid brain development and thereby cause an irreversible damage in the adult brain.…”

“…21,22 Decreased levels of PEA-15 protein have been associated with astrocyte protection against TNF-induced apoptosis. 23 In addition to these differentially regulated proteins that have been linked to apoptosis and oxidative stress and are accompanied by morphological correlates, [8][9][10] a dysregulation of proteins associated with cell growth and energy metabolism suggests that these biological processes are also affected by an exposure to high oxygen levels during the brain growth spurt period (Table 1; Figure 2b). …”

“…However, in many cases, there is neither an obvious clinical explanation nor a corollary on conventional imaging studies for the neuropsychologic morbidity. Recent work has emphasized the role of intrauterine and neonatal infections, 5 pharmacologic agents 6,7 and oxygen [8][9][10] in triggering neuronal death in the developing mammalian brain.…”

“…9 This hyperoxiainduced apoptosis is associated with oxidative stress, upregulation of inflammatory cytokines, decreased expression of neurotrophins and decreased activation of neurotrophin-regulated pathways. 9,10 The timing of greatest vulnerability coincides with the peak of the brain growth spurt, which starts at about midpregnancy in humans and extends well into the third postnatal year. In mice and rats, this developmental period occurs within the first three postnatal weeks; 13 cross-species extrapolation with regard to the timing of the main brain growth spurt period thereby renders 6-dayold mice a model for preterm human infants.…”

Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter

“…Hyperoxia increased apoptotic cell death in cells of 7-d-old Wistar rats and C57BL/6 mice in brain regions such as the caudate nucleus, layers II and IV of the frontal, parietal, cingulate, and retrosplenial cortices, as well as white matter tracts and the periventricular region. This cell death was associated with oxidative stress, decreased expression of neurotrophins, decreased activation of neurotrophin-regulated pathways, and increased levels of proinflammatory cytokines (Felderhoff-Mueser et al, 2004;Felderhoff-Mueser et al, 2005). In these studies, neuroanatomical localization of cell death was characterized, but cell type was not specified.…”