Complestatin antagonizes the AMPA/kainate-induced neurotoxicity in cultured chick telencephalic neurons.
Excitatory amino acids are known to induce considerable neurotoxicity in central nervous system. In the present study, the neurotoxicity was induced by application of kainate or AMPA in chick telencephalic neuron, and neuroprotective activity was tested with complestatin that was isolated from streptomyces species. In cultured telencephalic neurons exposed to 500 microM kainate for 2 days, the AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 5 microM) completely blocked kainate-induced neurotoxicity. Also, complestatin (0.5 microM) completely blocked kainate-induced neuronal injury at a concentration lower than that required for prototype AMPA/kainate receptor antagonist DNQX. In addition, complestatin blocked AMPA-induced neurotoxicity when the neurons were pretreated with cyclothiazide, a desensitization blocker of AMPA receptor. Surprisingly, when the onset of the treatment was delayed for 6 hours, complestatin led to a reduction in kainate-induced neuronal injury. While inhibition of protein kinase C (PKC) by staurosporin induced neurotoxicity, that was blocked by complestatin. Activation of PKC by phorbol dibutyrate partially inhibited the kainate-induced neurotoxicity. These results suggest that complestatin may be used as an anti-excitotoxic agent and involved in the PKC activation contributing to inhibition of neurotoxicity.
Yoo
Ick Dong
ID
Antibiotics Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon.
Yun
Bongsik
B
Ryoo
In Ja
IJ
Lee
Soo Young
SY
Shin
Myeong Heon
MH
Oh
Seikwan
S
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D002733:Chlorophenols / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000494:pharmacology; D013687:Telencephalon / Q000502:physiology*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D002733:Chlorophenols; D018691:Excitatory Amino Acid Antagonists; D007608:Kainic Acid; D009842:Oligopeptides; D010456:Peptides, Cyclic; D015240:Phorbol 12,13-Dibutyrate; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D019311:Staurosporine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C056723:FG 9041; C023490:complestatin