ニューロンのアポトーシスと神経栄養因子の防御作用

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During development, excess neurons are produced about half of which die. The time of cell death (apoptosis) is limited to the period of formation of synapses with the target cells, and the neurons which fail to obtain sufficient amounts of trophic factor(s) released from the target cells are eliminated. This selection system is considered to be a mechanism to ensure formation of a physiologically relevant neuronal network. Mature neurons which correctly execute their functions, however, undergo apoptosis in response to exogenous toxic stimuli. Such stimuli may be responsible for neurodegenerative diseases. The mechanism underlying cell death has been analyzed using in vitro model systems. In the present communication, we used cultured rat cerebellar granule neurons, in which low potassium concentration (LK+) in the medium induces apoptosis, and this apoptosis is prevented by high concentration of potassium(HK+), BDNF. One of the lipid-modifyingk inases, phosphatidylinositol 3-kinase(PI3-K), is also activated by trophic factors includingn eurotrophins. BDNFa nd highK+ prevented low K+-induced apoptosis via PI3-K. BDNFa lso promotest he survival of basal forebrain cholinergic neurons cultured from postnatal 2-week-old (P2w) rats. The mechanism of neuronal apoptosis induced by oxidative stress using CNS neurons and PC12 cells was investigateda, nd we foundt hat generation of reactive oxygens pecies (ROS) is highlya ssociatedw ithapoptosisH. igh oxygeni nducedn euronala poptosisw, hichw as blocked by protein or RNA synthesis inhibitors. Neurotrophic factors and Bcl-2 preventedt his apoptotic cell death. Exposure to hydrogen peroxide, lipid hydroperoxide or serum deprivation triggered apoptosis associated with increased generation of ROS as determined using a ROS-specific fluorescent probe. In cultured cerebellar granule neurons from 15-day-old wild-type and p53-deficient mice, we examinet he role of p53 in regulating the life and death of CNS neurons. When exposure of γ-ray or bleomycin to neurons died in p53 dependent manner. These neuronal deaths were partially prevented by actinomycin D or cycloheximide. The pycnotic nuclei observed in these dying neurons indicated that cell death occurs via apoptosis. Although there are many evidences that p53 is involved in apoptosis in proliferating cells, it is interesting that p53 is also involved in apoptosis in postmitotic neurons as shown in this study.
社団法人日本薬理学会の論文
1998-10-01

ニューロンのアポトーシスと神経栄養因子の防御作用

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