Reduction of Lipopolysaccharide-Induced Neurotoxicity in Mouse Mixed Cortical Neuron/Glia Cultures by Ultralow Concentrations of Dynorphins

Previously we reported that ultralow concentrations of dynorphins (10 –16 to 10 –12 M) inhibited lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and proinflammatory cytokines in mouse glia without the participation of κ-opioid receptors. In the current study using mouse cortical neuron-glia cocultures, we examined the possibility that inhibition of glia inflammatory response by dynorphins might be neuroprotective for neurons. LPS, in a concentration-dependent manner, markedly increased the release of lactate dehydrogenase (LDH), an indicator of cellular injury. Ultralow concentrations (10 –14 to 10 –12 M) of dynorphin (dyn) A-(1–8) significantly prevented the LPS-induced release of LDH, loss of neurons, and changes in cell morphology, in addition to inhibition of LPS-induced nitrite production. Meanwhile, ultralow concentrations (10 –15 to 10 –13 M) of des-[Tyr 1 ]-dyn A-(2–17), a nonopioid peptide which does not bind to κ-opioid receptors, exhibited the same inhibitory effect as dyn A-(1–17). These results suggest that dynorphins at ultralow concentrations are capable of reducing LPS-induced neuronal injury and these neuroprotective effects of dynorphins are not mediated by classical opioid receptors.