Abstract
More than half of the initially-formed neurons are deleted in certain brain regions during normal development. This process, whereby cells are discretely removed without interfering with the further development of remaining cells, is called programmed cell death (PCD). The term apoptosis is used to describe certain morphological manifestations of PCD. Many of the effectors of this developmental cell death program are highly expressed in the developing brain, making it more susceptible to accidental activation of the death machinery, e.g. following hypoxia-ischemia or irradiation. Recent evidence suggests, however, that activation and regulation of cell death mechanisms under pathological conditions do not exactly mirror physiological, developmentally regulated PCD. It may be argued that the conditions after e.g. ischemia are not even compatible with the execution of PCD as we know it. Under pathological conditions cells are exposed to various stressors, including energy failure, oxidative stress and unbalanced ion fluxes. This results in parallel triggering and potential overshooting of several different cell death pathways, which then interact with one another and result in complex patterns of biochemical manifestations and cellular morphological features. These types of cell death are here called “pathological apoptosis,” where classical hallmarks of PCD, like pyknosis, nuclear condensation and caspase-3 activation, are combined with non-PCD features of cell death. Here we review our current knowledge of the mechanisms involved, with special focus on the potential for therapeutic intervention tailored to the needs of the developing brain.
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Abbreviations
- AIF:
-
apoptosis-inducing factor
- AMPA:
-
alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid
- APAF-1:
-
apoptosis protease-activating factor-1
- BDNF:
-
brain-derived neurotrophic factor
- CREB:
-
cAMP-response element-binding protein
- DG:
-
dentate gyrus
- EE:
-
early elimination
- ERK:
-
extracellular signal-regulated protein kinase
- HI:
-
hypoxia-ischemia
- IL:
-
interleukin
- JNK:
-
jun N-terminal kinase
- MAP kinase:
-
mitogen-associated protein kinase
- mtPT:
-
mitochondrial permeability transition
- NOS:
-
nitrogen oxide synthase
- NGF:
-
nerve growth factor
- NMDAR:
-
N-methyl-D-aspartate receptor
- P7:
-
postnatal day 7
- PCD:
-
programmed cell death
- ROS:
-
reactive oxygen species
- SGZ:
-
subgranular zone (of the dentate gyrus)
- SOD2:
-
superoxide dismutase 2
- SVZ:
-
subventricular zone (of the lateral ventricular wall)
- TRX 2:
-
thioredoxin 2
- XIAP:
-
X-linked inhibitor of apoptosis protein
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Blomgren, K., Leist, M. & Groc, L. Pathological apoptosis in the developing brain. Apoptosis 12, 993–1010 (2007). https://doi.org/10.1007/s10495-007-0754-4
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DOI: https://doi.org/10.1007/s10495-007-0754-4