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 kappa-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 kappa-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.