Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

Abstract

New therapeutic strategies are needed to protect neonates, especially premature newborns, against brain injury and associated neurobehavioral deficits. The role of pro-inflammatory cytokines, especially IL-1β, in the pathophysiological pathway leading to neonatal brain damage is increasingly recognized and represents an attractive therapeutic target. We investigated the therapeutic potential of postnatal systemic administration of the interleukin (IL)-1 receptor antagonist (IL-1Ra) in an animal model of perinatal brain injury using the insults most common to human neonates, i.e. prenatal exposure to inflammation and/or postnatal hypoxia-ischaemia (HI). We found that postnatal administration of IL-1Ra preserved motor function and exploratory behavior after either prenatal exposure to inflammatory agent lipopolysaccharide (LPS) or postnatal HI insult. The deleterious effect of combined prenatal LPS and postnatal HI on brain development was also alleviated by administration of IL-1Ra, as seen by the protected neural stem cell population, prevention of myelin loss in the internal capsule, decreased gliosis, and decreased neurobehavioral impairment. This study showed the distinct pattern of functional deficits induced by prenatal inflammation as compared to postnatal HI and the therapeutic potential of IL-1Ra administration against neonatal brain injury. Furthermore, our results highlight the potential for postnatal treatment of prenatal inflammatory stressors.

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

“…To our knowledge, our group is the first to show that NACA reduces the cerebral concentration of IL-1β after neonatal hypoxia. This could indicate that NACA has some positive effects; previous studies have shown that IL-1β is upregulated after cerebral ischemia and that anakinra, an IL1 receptor antagonist, has some neuroprotective abilities [24,25]. …”

Strategies for CNS repair following TBI

“…Animal models have shown rhIL-1ra to result in decreased loss of neurons at the cerebral cortex, region CA3 of the hippocampus and the dentate hilus following TBI as well as reduction in overall lesion size (Sanderson et al, 1999;Toulmond and Rothwell, 1995). RhIL-1ra is shown to attenuate hypoxic insults in animals in addition to preserving neuronal stem cells and white matter integrity (Girard et al, 2012). Additionally, rhIL-1ra has beneficial effects in limiting neuronal loss due to excitotoxicity (Lawrence et al, 1998).…”

A Critical Review of Models of Perinatal Infection

“…In addition to a direct neurotoxic effect of infection/inflammation, several studies have demonstrated that LPS or poly(I:C) can sensitize the brain to subsequent injury following hypoxia-ischemia [65,97]. This increased vulnerability of the neonatal brain to LPS has been attributed to IL-1β [98]. It is important to appreciate that the bacterial mimics and inflammatory agents used in these postnatal rodent models may not replicate the full repertoire of inflammatory responses observed following infection.…”