Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium

Abstract

Many prenatal and perinatal factors are hypothesized to play a role in the cause of cerebral palsy (CP). Epidemiological data implicate maternal–fetal infection and associated increase in circulating cytokines. Murine model data suggest that excitotoxic damage can produce pathological change in brain tissue consistent with lesions observed in CP. Specifically, on day 5 after birth, mouse pups injected with ibotenate, a glutamatergic analogue, develop transcortical necrosis and white matter cysts mimicking some human perinatal lesions associated with CP. The present study builds on this murine model to assess the modulating role of several cytokines on the development of excitotoxic lesions. Pups pretreated with interleukin (IL)‐1β, IL‐6, IL‐9, or tumor necrosis factor‐α developed significantly larger ibotenate‐induced cortical and white matter damage than controls; IL‐4 did not produce such an effect. In a similar manner, IL‐9–overexpressing transgenic pups developed ibotenate‐induced brain lesions, which were significantly larger than those induced in nontransgenic control pups. Pretreatment with proinflammatory cytokines significantly increased neopallial microglial density without affecting astrocytic density; IL‐9 or IL‐4 did not produce a similar effect. To our knowledge, this is the first in vivo study to demonstrate that systemically administered proinflammatory cytokines and IL‐9 exacerbate brain lesions that are similar to those found in human infants with CP. Ann Neurol 2000; 47:54–63

Incidence of invasive Ureaplasma in VLBW infants: relationship to severe intraventricular hemorrhage

“…Furthermore, systemic inflammatory cytokines may exacerbate injury mediated by excitatory neurotransmitters such as glutamate released in response to hypoxia-ischemia. 28 In a model of ibotenate-induced excitotoxic brain injury in newborn mice, systemic pretreatment with IL-1β, IL-6 or tumor necrosis factor-α exacerbates ibotenate-induced brain lesions. 28 We have previously shown that Ureaplasma directly stimulates cord blood monocyte IL-1β release in vitro 20 and that Ureaplasma respiratory colonization in preterm infants is associated with elevated lung lavage IL-1β in vivo .…”

“…28 In a model of ibotenate-induced excitotoxic brain injury in newborn mice, systemic pretreatment with IL-1β, IL-6 or tumor necrosis factor-α exacerbates ibotenate-induced brain lesions. 28 We have previously shown that Ureaplasma directly stimulates cord blood monocyte IL-1β release in vitro 20 and that Ureaplasma respiratory colonization in preterm infants is associated with elevated lung lavage IL-1β in vivo . 15 These observations support the contention that Ureaplasma can elicit an immune response that may be detrimental to the host.…”

Histological Architecture Underlying Brain–Immune Cell–Cell Interactions and the Cerebral Response to Systemic Inflammation

“…Although the etiology may be multifocal, hypoxia–ischemia, infection/inflammation, and excitotoxicity are considered important causes of perinatal brain injury (109). Experimental studies have indicated that antecedents such as infection/inflammation, intrauterine growth restriction, or preexposure to hypoxia modulate brain vulnerability (110, 111). Very recently, one of the mechanisms underlying the causal relationship between maternal immune activation and autistic behavioral abnormalities in the offspring has been revealed (112).…”

Pathophysiology of glia in perinatal white matter injury

“…Glutamate antagonists and other agents reduced ibotenate-mediated neonatal rodent white matter necrosis (Bemelmans et al 2006; Dicou et al 2003; Dommergues et al 2000; Husson et al 2002; Marret et al 1995; Sfaello et al 2005). NMDA and AMPA/kainate receptor antagonists prevented myelin loss after perinatal hypoxia-ischemia in the term equivalent rat (Follet et al 2004; Follet et al 2000; Manning et al 2008).…”