RT Journal Article
SR Electronic
T1 Femtomolar Concentrations of Dynorphins Protect Rat Mesencephalic Dopaminergic Neurons against Inflammatory Damage
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1133
OP 1141
VO 298
IS 3
A1 Bin Liu
A1 Liya Qin
A1 San-Nan Yang
A1 Belinda C. Wilson
A1 Yuxin Liu
A1 Jau-Shyong Hong
YR 2001
UL http://jpet.aspetjournals.org/content/298/3/1133.abstract
AB The hallmark of Parkinson's disease is the death of nigral dopaminergic neurons, and inflammation in the brain has been increasingly associated with the pathogenesis of this neurological disorder. Dynorphins are among the major opioid peptides in the striato-nigral pathway and are important in regulating dopaminergic neuronal activities. However, it is not clear whether dynorphins play a role in the survival of nigral dopaminergic neurons. We have recently demonstrated that lipopolysaccharide (LPS) activates the brain immune cells microglia, in vitro and in vivo, to release neurotoxic factors to degenerate dopaminergic neurons. The purpose of this study was to explore the neuroprotective effect of dynorphins in the inflammation-mediated degeneration of dopaminergic neurons in rat midbrain neuron-glia cultures. LPS-induced neurotoxicity was significantly reduced by treatment with ultra low concentrations (10−13–10−15 M) of the κ-opioid receptor agonist dynorphin A (1–17) or the receptor binding ineffective [des-Tyr1]dynorphin A (2–17), but not by U50488, a synthetic κ-receptor agonist. The glia-mediated neuroprotective effect of dynorphins was further supported by the finding that femtomolar concentrations of dynorphins did not prevent the killing of dopaminergic neurons by 6-hydroxydopamine. However, ultra low concentrations of dynorphins inhibited LPS-induced production of superoxide. These results suggest a glia-mediated and conventional opioid receptor-unrelated mechanism of action for the neuroprotective effect of ultra low concentrations of dynorphins. Understanding the underlying mechanisms of action should further define the roles of dynorphins in the regulation of dopaminergic neurons and help devise novel strategies to combat neurodegenerative diseases. The American Society for Pharmacology and Experimental Therapeutics