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 cul tured cortical neurons from excitotoxicity induced by N-methyl-D-aspartate (NMDA), alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), o r 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 prote cted cortical neurons from prolonged deprivation of oxygen and glucose, mor e effectively than combined antagonists of NMDA and AMPA/kainate receptors. Neurotoxicity, evolving within 1 to 2 days after continuous exposure to co mbined NMDA and AMPA/kainate antagonists, was not observed in cortical cell cultures that were exposed to complestatin. Finally, complestatin dose dep endently prevented neuronal death evolving within the inner nuclear and gan glion cell layers, after transient retinal ischemia. We conclude that compl estatin possesses novel pharmacological properties that effectively prevent excitotoxicity under certain pathological conditions.