Reduction by naloxone of lipopolysaccharide-induced neurotoxicity in mousecortical neuron-glia co-cultures

An inflammatory response in the CNS mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative dis eases. Using mouse cortical mixed glia cultures, we have previously demonst rated that the bacterial endotoxin lipopolysaccharide induces the activatio n of microglia and the production of proinflammatory factors. Naloxone, an opioid receptor antagonist, inhibits the lipopolysaccharide-induced activat ion of microglia and the production of proinflammatory factors. Using neuro n-glia co-cultures, we extended our study to determine if naloxone has a ne uroprotective effect against lipopolysaccharide-induced neuronal damage and analysed the underlying mechanism of action for its potential neuroprotect ive effect. Pretreatment of cultures with naloxone (1 mu M) followed by tre atment with lipopolysaccharide significantly inhibited the lipopolysacchari de-induced production of nitric oxide and the release of tumor necrosis fac tor-alpha, and significantly reduced the lipopolysaccharide-induced damage to neurons. More importantly, both naloxone and its opioid-receptor ineffec tive enantiomer (+)-naloxone were equally effective in inhibiting the lipop olysaccharide-induced generation of proinflammatory factors and the activat ion of microglia, as well as in the protection of neurons. These results indicate that the neuroprotective effect of naloxone is media ted by its inhibition of microglial activity and may be unrelated to its bi nding to the classical opioid receptors. Published by Elsevier Science Ltd.