Cyclin-dependent kinase 4 and cyclin D1 are required for excitotoxin-induced neuronal cell death in vivo.
Systemic administration of the glutamic acid analog kainic acid (KA) causes neuronal cell death in brain-vulnerable regions, such as the piriform cortex, hippocampus, and amygdala in rats. We investigated the relationship between the KA-induced neuronal apoptosis and expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1, key regulators of cell cycle progression. Expression of CDK4 and cyclin D1 was upregulated in neurons of the rat piriform cortex and amygdala 1-3 d after KA administration in vivo. CDK4 and cyclin D1 proteins were induced in the cytoplasm and nuclei of neurons, with a concomitant increase of CDK4- and cyclin D1-positive microglia in the affected areas. Continuous infusion of 100 microm CDK4 or cyclin D1 antisense oligonucleotides into the lateral ventricle using mini-osmotic pumps suppressed the excitotoxin-induced neuronal cell death in the piriform cortex and basolateral amygdaloid nucleus, whereas sense oligonucleotides exhibited no such effect. Although KA administration causes prolonged c-Fos expression in the vulnerable regions that preceded the induction of neuronal apoptosis, the CDK4 or cyclin D1 antisense oligonucleotides exhibited no suppressive effect on c-Fos levels. Our results suggest that CDK4 and cyclin D1 are essential for KA-induced neuronal apoptosis in vivo.
Ino
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Department of Neurobiology (C1), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. ino@med.m.chiba-u.ac.jp
Chiba
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D000679:Amygdala / Q000166:cytology / Q000187:drug effects; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009833:Olfactory Pathways / Q000166:cytology / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
D000943:Antigens, Differentiation; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D019938:Cyclin D1; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D007608:Kainic Acid