Abstract
Complestatin, a peptide derived from Streptomyces, was found to protect cultured cortical neurons from excitotoxicity induced by N-methyl-d-aspartate (NMDA), α-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.
Footnotes
-
This work was supported in part by G7 grants (to I.D.Y.) from the Korean Ministry of Science and Technology, National Research Laboratory grants (to B.J.G.), and by the Korea Science and Engineering Foundation grant through Center for Cell Signaling Research Fund (to J.-M.C.).
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- DIV
- days in vitro
- LDH
- lactate dehydrogenase
- [Ca2+]I
- intracellular calcium concentration
- fura-2
- 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2′-amino-5′-methylphenoxy)-ethane-N,N,N′,N′-tetraacetic acid
- CNQX
- 6-cyano-2,3-dihydroxy-7-nitroquinoxaline
- Received April 16, 2001.
- Accepted July 9, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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Complestatin Is a Noncompetitive Peptide Antagonist of N-Methyl-d-aspartate and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/Kainate Receptors: Secure Blockade of Ischemic Neuronal Death
