Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: Key role of TNFα pathway and protection by etanercept

Systemic inflammation sensitizes the perinatal brain to an ischemic/excitotoxic insult but the mechanisms are poorly understood. We hypothesized that the mechanisms involve an imbalance between pro- and anti-inflammatory factors. A well characterized mouse model where a systemic injection of IL-1 beta during the first five postnatal days (inflammatory insult) is combined with an intracerebral injection of the glutamatergic analogue ibotenate (excitotoxic insult) at postnatal day 5 was used. Following the inflammatory insult alone, there was a transient induction of IL-1 beta and TNF alpha, compared with controls measured by quantitative PCR, ELISA, and Western blot. Following the combined inflammatory and excitotoxic insult, there was an induction of IL-1 beta, TNF alpha, and IL-6 but not of IL-10 and TNFR1, indicating an altered pro-/anti-inflammatory balance after IL-1 beta sensitized lesion. We then tested the hypothesis that the TNF alpha pathway plays a key role in the sensitization and insult using TNF alpha blockade (etanercept) and TNF alpha(-/-) mice. Etanercept given before the insult did not affect brain damage, but genetic deletion of TNF alpha or TNF alpha blockade by etanercept given after the combined inflammatory and excitotoxic insult reduced brain damage by 50%. We suggest this protective effect was centrally mediated, since systemic TNF alpha administration in the presence of an intact blood-brain barrier did not aggravate the damage and etanercept almost abolished cerebral TNF alpha production. In summary, sensitization was, at least partly, mediated by an imbalance between pro- and anti-inflammatory cytokines. Cerebral TNF alpha played a key role in mediating brain damage after the combined inflammatory and excitatory insult. (C) 2009 Elsevier Inc. All rights reserved.