Prevention of apoptotic but not necrotic cell death following neuronal injury by neurotrophins signaling through the tyrosine kinase receptor

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Object. Neurotrophins prevent the death of neurons during embryonal development and have potential as therapeutic agents. During development, neuronal death occurs only by apoptosis and not by necrosis. Following injury, however, neurons can die by both processes. Data from prior studies have not clearly indicated whether neurotrophins can decrease apoptosis compared with necrosis. The goal of this study was to determine the effect of neurotrophin treatment on each of these processes following injury and to characterize the receptor(s) required.

Methods. The authors used an in vitro model of injury with the aid of primary cortical neurons obtained from rat embryos. After 9 days in culture and the elimination of glia, homogeneous and mature neurons were available for experimentation. Noxious stimuli were applied, including radiation, hypoxia, and ischemia. Subsequent cell death by apoptosis or necrosis was noted based on morphological and enzymatic assessments (such as lactate dehydrogenase [LDH] release) and assays for DNA fragmentation. The effect of treatment with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 was determined. Finally, Western blot analyses were performed to note the neurotrophin receptor status in the neurons (tyrosine kinase receptors [Trks] and p75).

The authors studied different stimuli-induced cell death by using different processes. With the application of radiation, cells died primarily by apoptosis, as evidenced by cell shrinkage, the presence of apoptotic bodies, and specific DNA fragmentation. This was a delayed process (> 6 hours) that could be reduced by gene transcription or protein synthesis inhibitors. With ischemia, cells died immediately by necrosis, showing cell enlargement and rupture. Ischemic cell death was not affected by the inhibition of macromolecular synthesis. Hypoxia produced a mixture of the two cell death processes.

Both BDNF and neurotrophin-3 demonstrated protection against apoptotic cell death only. Statistically significant decreases of both LDH release and apoptosis-specific DNA fragmentation were noted following radiation and hypoxia, but not for ischemia. Nerve growth factor, unlike the other neurotrophins, did not affect apoptosis because a functional receptor, Trk A, was not expressed by the cortical neurons. There was expression of both Trk B and Trk C, which bind BDNF and neurotrophin-3.

Conclusions. These findings have significant clinical implications. Neurotrophins may only be effective in disorders in which apoptosis, and not necrosis, is the major process. Furthermore, the Trk signaling cascade must be activated for this response to occur. Because the expression of these receptors diminishes in adulthood, neurotrophin application may be most appropriate in the pediatric population.

Article Information

Address reprint requests to: Dong H. Kim, Department of Neurosurgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115. email:dkim7@partners.org.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photomicrographs of cortical cells after culture. Left: Three-day cultures stained with glial fibrillary acidic protein reveal the presence of large astrocytes and multiple small and immature cortical neurons without extensive axons or dendrites. Right: Nine-day cultures after treatment with cytosine arabinoside. These cells are stained with a neuron-specific enolase. No glia are present and the neurons are mature, with extensive networks of axons and dendrites. These cells are ready for experimentation. Original magnification × 10.

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    Photomicrographs of changes in nuclear morphology visualized by hoechst 33258. A: Control cultures demonstrate even nuclear staining (arrow). B: After the application of 32 Gy radiation (all staining was performed 24 hours postinjury), nuclear morphological changes demonstrate chromatin condensation (long arrow) and apoptotic bodies (short arrow). C: After 1 hour of ischemia, no apoptotic bodies are visible. D: After 6 hours of hypoxia, some neurons reveal apoptotic bodies (arrow)—but at a lower incidence than with radiation. Original magnification × 20.

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    Bar graph demonstrating the effect of actinomycin D (Act. D) and cycloheximide (CHX) on LDH release following the application of 32 Gy radiation, 6 hours of hypoxia, or 1 hour of ischemia. Administration of cycloheximide or actinomycin D 1 hour prior to injury decreased LDH release following irradiation and hypoxia, but not following ischemia. Data are expressed as the means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001.

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    Bar graph demonstrating LDH release following the application of 32 Gy radiation and treatment with NGF, BDNF, and neurotrophin-3 (NT3). Note that NGF has no effect on LDH release, whereas BDNF and neurotrophin-3 confer significant, dose-dependent protection from radiation injury.

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    Bar graphs demonstrating LDH release following radiation and neurotrophin treatment. A: One hour before irradiation (32 Gy), BDNF, NGF, or neurotrophin-3 (100 ng/ml) was added. The percentage of released LDH was measured at 24 hours. A significant treatment effect was noted with BDNF and neurotrophin-3, but not with NGF. B: Measuring fragmented DNA by ELISA following the same injury and treatment. An identical response occurred with BDNF and neurotrophin-3. Error bars represent the SD. ***p < 0.001. OD = optical density.

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    Bar graphs demonstrating LDH release following hypoxia and neurotrophin treatment. A: A dose (100 ng/ml) of BDNF, NGF, or neurotrophin-3 was added 1 hour before hypoxia (6 hours), and the percentage of released LDH was measured at 24 hours. A significant treatment effect was noted with BDNF and neurotrophin-3, but not with NGF. B: Measuring fragmented DNA by ELISA following the same injury and treatment. An identical response occurred with BDNF and neurotrophin-3. Error bars represent the SD. *p < 0.05, **p < 0.01, and ***p < 0.001.

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    Bar graphs demonstrating LDH release following ischemia and neurotrophin treatment. A: A dose (100 ng/ml) of BDNF, NGF, or neurotrophin-3 was added 1 hour before ischemia (1 hour), and the percentage of released LDH was measured at 24 hours. No treatment effect was noted with BDNF, neurotrophin-3, or NGF treatments. B: Measuring fragmented DNA by ELISA following the same injury and treatment. Very little change in absorbance occurred before or after injury, indicating a paucity of apoptotic death. This analysis also revealed no treatment effect. Error bars represent the SD.

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    Western blots demonstrating the expression of the Trk in primary cortical neurons. Cells were harvested on Days 0 through 10 following culture, the protein was extracted, and Trk expression was detected on Western blotting by using antibody 203, an anti—pan-Trk antibody. Expression of the Trk is noted after 6 days in culture; the maximum expression occurred after 8 to 10 days in culture. The lane immediately following Day 10 represents a negative control (Ctrl); the last lane on the right represents a positive control.

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    Western blots demonstrating the expression of the p75 receptor in primary cortical neurons. Cells were harvested on Days 0 through 10 following culture, the protein was extracted, and p75 expression was detected on Western blotting by using antibody 9992. No expression of the p75 receptor was noted (the bands represent nonspecific background).

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    Western blots demonstrating the appearance of phosphorylated tyrosine following incubation with the neurotrophins. Nine-day cortical neuron cultures were treated with BDNF, NGF, neurotrophin-3, or a combination of K252a and BDNF or K252a and neurotrophin-3 (K252a is an alkaloid that inhibits neurotrophin activation of the Trk). Cells were harvested 24 hours later and the presence of phosphorylated tyrosine was detected on Western blot analysis by using antibodies 4G10 (left lane) and PY20 (right lane). Only the cells treated with BDNF and neurotrophin-3 demonstrated a positive response, indicating the presence of Trk B and Trk C, but not Trk A.

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    Bar graph exhibiting the effect of K252a on NGF, BDNF, and neurotrophin-3 treatment following irradiation. The K252a (100 nM) was added 30 minutes before NGF, BDNF, or neurotrophin-3 and kept in the medium during irradiation (32 Gy). After 24 hours of repeated incubation, the percentage of released LDH was measured. The K252a completely blocked the protective effect of both BDNF and neurotrophin-3. Error bars represent the SD. ***p , 0.001.

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    Bar graph demonstrating the effect of K252a on BDNF treatment following irradiation as measured on DNA fragmentation ELISA. The K252a (100 nM) was added 30 minutes before BDNF and kept in the medium during irradiation (32 Gy). After 24 hours of repeated incubation, ELISA was performed and absorbance was measured. The K252a completely blocked the effect of BDNF. Error bars represent the SD. **p , 0.01, and ***p , 0.001.

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    Yuan JYanker BA: Apoptosis in the nervous system. Nature 407:8028092000Yuan J Yanker BA: Apoptosis in the nervous system. Nature 407:802–809 2000

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