Interleukin-1β-induced brain injury in the neonatal rat can be ameliorated by α-phenyl-n-tert-butyl-nitrone

Abstract

To examine the possible role of inflammatory cytokines in mediating perinatal brain injury, we investigated effects of intracerebral injection of interleukin-1beta (IL-1β) on brain injury in the neonatal rat and the mechanisms involved. Intracerebral administration of IL-1β (1 μg/kg) resulted in acute brain injury, as indicated by enlargement of ventricles bilaterally, apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. IL-1β also induced axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of β-amyloid precursor protein, short beaded axons and dendrites, and loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas. Administration of α-phenyl-n-tertbutyl-nitrone (PBN, 100 mg/kg i.p.) immediately after the IL-1β injection protected the brain from IL-1β-induced injury. Protection of PBN was linked with the attenuated oxidative stress induced by IL-1β, as indicated by decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde or nitrotyrosine positive cells following IL-1β exposure. PBN also attenuated IL-1β-stimulated inflammatory responses as indicated by the reduced activation of microglia. The finding that IL-1β induced perinatal brain injury was very similar to that induced by lipopolysaccharide (LPS), as we previously reported and that PBN was capable to attenuate the injury induced by either LPS or IL-1β suggests that IL-1β may play a critical role in mediating brain injury associated with perinatal infection/inflammation.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling

“…As the receptor for IL-1b is ubiquitously expressed among all brain cell types (Allan et al, 2005), a chronic exposure of gray matter tissue to IL-1b in MS patients as suggested by our differential gene expression analysis may be a crucial factor driving MS pathogenesis. In rats, intracerebral administration of IL-1b led to oligodendrocytes apoptosis (Fan et al, 2009), and subarachnoid injection of proinflammatory cytokines such as TNF and IFNc lead to subpial demyelination (Gardner et al, 2013). Chronic IL-1b release, as suggested by the global upregulation of IL1B in MS NAGM, may be further pathologically relevant as it was reported to lead to neuronal death mediated by astrocytes (Thornton et al, 2006).…”

Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?

“…Neonatal administration of inflammatory cytokines such as Il-1β reduces the number of developing oligodendrocytes (Cai et al, 2004; Fan et al, 2009). Maternal and early postnatal immune challenges impair myelination (Fan et al, 2005; Makinodan et al, 2008; Paintlia et al, 2008) and long-range synchronization (Dickerson et al, 2010).…”

The Yin and Yang of Microglia

“…Microglial activation has often been the first – or at least a significant – cellular event detected in and around a lesion in several animal models of developing brain injuries such as those induced by mechanical trauma, infection/inflammation, excitotoxic insults and hypoxia-ischemia [59,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]. Moreover, microglial activation has been demonstrated in postmortem brain specimens of premature infants with periventricular leukomalacia [87,88,89].…”