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.
Kong
L Y
LY
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Jeohn
G
G
Hudson
P M
PM
Du
L
L
Liu
B
B
Hong
J S
JS
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D013997:Time Factors
D000701:Analgesics, Opioid; D015415:Biomarkers; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; D009569:Nitric Oxide; D004399:Dynorphins; C082245:dynorphin (2-17); D007770:L-Lactate Dehydrogenase