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)-1beta, IL-6, IL-9, or tumor necrosis factor-alpha 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.

Inflammation‐induced sensitization of the brain in term infants

“…20,61 Similarly, delivery of LPS to pregnant rats on the last 2 days of gestation exacerbated ibotenate-induced brain damage in postnatal day 4 pups, with the highest dose of LPS doubling the lesion size. 17 Several studies have evaluated the time window during which sensitization of the brain will persist following exposure to inflammatory factors in the perinatal period.…”

“…20,61 Similarly, delivery of LPS to pregnant rats on the last 2 days of gestation exacerbated ibotenate-induced brain damage in postnatal day 4 pups, with the highest dose of LPS doubling the lesion size.…”

“…Substantial numbers of preclinical studies have demonstrated the sensitizing effects of gestational or neonatal systemic inflammation, gestational chronic mild maternal stress, and gestational hypoxia on perinatal excitotoxic or hypoxic-ischaemic lesions. [16][17][18][19][20][21] Genetic factors have also been shown to influence the developing brain's response to sensitizing factors. 22,23 Robust epidemiological studies, performed in preterm and term-born neonates, support a role for inflammation as a sensitizer.…”

Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

“…Supporting this hypothesis, exposure of the human fetal brain to chorioamnionitis-driven inflammation makes the developing brain exquisitely vulnerable to perinatal hypoxic-ischemic insults (Dommergues et al, 2000;Eklind et al, 2001). This two-hit mechanism seems to be key in the pathophysiology of cerebral palsy (CP) and other neurological impairments linked to term and preterm (23-32 weeks of gestation) birth (Dammann et al, 2002).…”

“…To test it, we used a well characterized mouse model of neonatal excitotoxic brain lesions (Marret et al, 1995;Gressens et al, 1997;Dommergues et al, 2000;Tahraoui et al, 2001;Husson et al, 2002), which mimic lesions observed in preterm and term human infants who will later develop CP. In this model, intracerebral administration of glutamate analogs acting on NMDA or non-NMDA receptors replicates the excess release of glutamate induced, among others, by hypoxic-ischemic insult (Volpe, 2001).…”