A dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein.
Neuronal apoptosis inhibitory protein (NAIP/BIRC1), the inhibitor of apoptosis protein (IAP) family member, suppresses neuronal cell death induced by a variety of insults, including cell death from ischemia and stroke. The goal of the present study was to develop an efficient method for identification of compounds with the ability to upregulate endogenous NAIP and to determine the effects on these compounds on the cellular response to ischemia. A novel NAIP-enzyme-linked immunosorbent assay (ELISA)-based in vitro drug-screening system is established. Use of this system identified an antagonist of dopamine D4 receptor, termed L-745,870, with a potent NAIP upregulatory effect. L-745,870-mediated NAIP upregulation in neuronal and nonneuronal cultured cells resulted in decreased vulnerability to oxidative stress-induced apoptosis. Reducing NAIP expression via RNA interference techniques resulted in prevention of L-745,870-mediated protection from oxidative stress. Further, systemic administration of L-745,870 attenuated ischemia-induced damage of the hippocampal CA1 neurons and upregulated NAIP expression in the rescued hippocampal CA1 neurons in a gerbil model. These data suggest that the NAIP upregulating compound, L-745,870, has therapeutic potential in acute ischemic disorders and that our NAIP-ELISA-based drug screening may facilitate the discovery of novel neuroprotective compounds.
Okada
Yoshinori
Y
Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.
Sakai
Harumi
H
Kohiki
Eri
E
Suga
Etsuko
E
Yanagisawa
Yoshiko
Y
Tanaka
Kazunori
K
Hadano
Shinji
S
Osuga
Hitoshi
H
Ikeda
Joh-E
JE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D065127:Dopamine D2 Receptor Antagonists; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051616:Neuronal Apoptosis-Inhibitory Protein; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4; D015854:Up-Regulation / Q000187:drug effects*; D024483:Vitamin K 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; C493599:DRD4 protein, human; D065127:Dopamine D2 Receptor Antagonists; C496800:NAIP protein, human; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D011725:Pyridines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D024483:Vitamin K 3