Correlation between delayed neuronal cell death and selective decrease in phosphatidylinositol 4-kinase expression in the CA1 subfield of the hippocampus after transient forebrain ischemia.
Transient forebrain ischemia induces a delayed neuronal death in the CA1 area of the hippocampus. However, the mechanism leading to this phenomenon has yet to be established. The authors used an mRNA differential-display method to isolate genes for which mRNA levels change only in the hippocampus during ischemia/reperfusion. They succeeded in identifying the product of one down-regulated gene as phosphatidylinositol 4-kinase (PI 4-K). Compared with control levels, PI 4-K mRNA expression in the hippocampus, but not the cerebral cortex, was significantly decreased by 30% and about 80% 1 and 7 days after ischemia/reperfusion, respectively. Interestingly, PI 4-K and PI bisphosphate levels were selectively decreased in the CA1 region, but not other regions, whereas TUNEL-positive cells could be detected 3 days after ischemia. Consistent with these results, PI 4-K expression was suppressed by hypoxia in SK-N-MC neuroblastoma cells before loss of cell viability. Overexpression of wild-type PI 4-K, but not the kinase-negative mutant of PI 4-K (K1789A), recovered the loss of viability induced by hypoxia. These findings strongly suggest that a prior decrease in PI 4-K and PI bisphosphate levels caused by brain ischemia/hypoxia is partly involved in delayed neuronal cell death.
Furuta
Yudai
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Uehara
Takashi
T
Nomura
Yasuyuki
Y
D019870:1-Phosphatidylinositol 4-Kinase / Q000096:biosynthesis*; D000818:Animals; D015152:Blotting, Northern; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000502:physiology*; D002540:Cerebral Cortex / Q000502:physiology; D018076:DNA, Complementary / Q000032:analysis; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000502:physiology*; D016548:Prosencephalon / Q000098:blood supply*; D051381:Rats; D017208:Rats, Wistar
D018076:DNA, Complementary; D019870:1-Phosphatidylinositol 4-Kinase