Complestatin is a noncompetitive peptide antagonist of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors: secure blockade of ischemic neuronal death.
Complestatin, a peptide derived from Streptomyces, was found to protect cultured cortical neurons from excitotoxicity induced by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainate. This neuroprotective behavior of complestatin was attributed to a blockade of Ca2+ ion entry and accumulation, after the activation of NMDA and AMPA/kainate receptors. Complestatin reversibly interfered with NMDA- and AMPA-mediated excitatory synaptic transmission. Complestatin also protected cortical neurons from prolonged deprivation of oxygen and glucose, more effectively than combined antagonists of NMDA and AMPA/kainate receptors. Neurotoxicity, evolving within 1 to 2 days after continuous exposure to combined NMDA and AMPA/kainate antagonists, was not observed in cortical cell cultures that were exposed to complestatin. Finally, complestatin dose dependently prevented neuronal death evolving within the inner nuclear and ganglion cell layers, after transient retinal ischemia. We conclude that complestatin possesses novel pharmacological properties that effectively prevent excitotoxicity under certain pathological conditions.
Seo
S Y
SY
Department of Neuroscience and Pharmacology and Center for the Interventional Therapy of Stroke and Alzheimer's Disease, Ajou University School of Medicine, Suwon, Korea.
Yun
B S
BS
Ryoo
I J
IJ
Choi
J S
JS
Joo
C K
CK
Chang
S Y
SY
Chung
J M
JM
Oh
S
S
Gwag
B J
BJ
Yoo
I D
ID
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002733:Chlorophenols / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000502:physiology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology
D002733:Chlorophenols; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010456:Peptides, Cyclic; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C023490:complestatin; D005947:Glucose; D010100:Oxygen; D007608:Kainic Acid; D002118:Calcium