Vol. 299, Issue 1, 377-384, October 2001

Complestatin Is a Noncompetitive Peptide Antagonist of N-Methyl-D-aspartate and -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/Kainate Receptors: Secure Blockade of Ischemic Neuronal Death

So Young Seo, Bong-Sik Yun, In-Ja Ryoo, Jun-Sub Choi, Choun-Ki Joo, Su-Youne Chang, Jun-Mo Chung, Seikwan Oh, Byoung Joo Gwag and Ick Dong Yoo

Departments of Neuroscience and Pharmacology and Center for the Interventional Therapy of Stroke and Alzheimer's Disease, Ajou University School of Medicine, Suwon, Korea (S.Y.S., B.J.G.); Antibiotics Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea (B.-S.Y., I.J.R., S.O., I.D.Y.); Department of Ophthalmology, Catholic University Medical College, Seoul, Korea (J.-S.C., C.-K.J.); and Department of Biology and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea (S.-Y.C., J.-M.C.)

Complestatin, a peptide derived from Streptomyces, was found to protect cultured cortical neurons from excitotoxicity induced by N-methyl-D-aspartate (NMDA), -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.