Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition

Fukuda, Hirotsugu; Fukuda, Aya; Zhu, Changlian; Korhonen, Laura; Swanpalmer, John; Hertzman, S.; Leist, Marcel; Lannering, Birgitta; Lindholm, Dan; Björk‐Eriksson, Thomas; Márky, Ildikó; Blomgren, Klas

doi:10.1038/sj.cdd.4401472

Cited by 108 publications

(167 citation statements)

References 48 publications

(57 reference statements)

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“…This decrease in cell proliferation was observed throughout the entire hippocampal formation, confirming the deleterious effect of irradiation at this dose on progenitor proliferation in the developing brain ( Fig. S2 B and C) (14,34).…”

Section: Irradiation Dramatically Reduces Precursor Cell Proliferatiosupporting

confidence: 73%

“…In addition, the lifelong birth of new granule neurons in the dentate gyrus (DG) of rodents and humans (8,9) is assumed to be important for maintaining memory function. Even at low doses, irradiation reduces the number of proliferating cells in the DG of rodents by increased apoptotic cell death, indicating particular vulnerability of progenitor cells to ionizing radiation (10)(11)(12)(13)(14). In humans, radiotherapy severely decreases the numbers of immature neurons in the hippocampus (15).…”

mentioning

confidence: 99%

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Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain

Naylor

Bull²,

Nilsson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

184

168

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Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors.exercise ͉ juvenile ͉ open field ͉ radiotherapy ͉ stem cell

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Section: Irradiation Dramatically Reduces Precursor Cell Proliferatiosupporting

confidence: 73%

mentioning

confidence: 99%

Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain

Naylor

Bull²,

Nilsson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

184

168

View full text Add to dashboard Cite

show abstract

“…The smaller volume observed after irradiation is therefore most likely explained by arrested growth, resulting in reduced volumes in irradiated brains compared with control brains. 26 Cell death may also contribute to the smaller volumes through an acute loss of cells, 24,30 and the corresponding volume. This is most evident in areas where postnatal neurogenesis occurs.…”

Section: Discussionmentioning

confidence: 99%

“…Persistent Volume Changes in the Hippocampal Granule Cell Layer and Molecular Layer up to 1 year After Irradiation Alterations in brain growth after irradiation to the developing brain have been demonstrated earlier [23][24][25] and might have negative effects on hippocampal structure and function. We therefore assessed if irradiation affected the total volumes of the GCL, hilus, or ML.…”

Section: Irradiation Altered Microvessel Structure and Complexity In mentioning

confidence: 99%

Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

Boström

Kalm

Karlsson

et al. 2013

J Cereb Blood Flow Metab

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We investigated the effects of ionizing radiation on microvessel structure and complexity in the hippocampus. We also assessed neurogenesis and the neurovascular niche. Postnatal day 14 male C57BL/6 mice received a single dose of 8 Gy to the whole brain and were killed 6 hours, 1 week, 7 weeks, or 1 year later. Irradiation decreased the total number of microvessels and branching points from 1 week onwards and decreased the total microvessel area 1 and 7 weeks after irradiation. After an initial increase in vascular parameter densities, concomitant with reduced growth of the hippocampus, the densities normalized with time, presumably adapting to the needs of the surrounding nonvascular tissue. Irradiation decreased the number of neural stem and progenitor cells in the hippocampus. The relative loss increased with time, resulting in almost completely ablated neurogenesis (DCX þ cells) 1 year after irradiation (77% decreased 1 week, 86% decreased 7 weeks, and 98% decreased 1 year after irradiation compared with controls). After irradiation, the distance between undifferentiated stem cells and microvessels was unaffected, and very few dying endothelial cells were detected. Taken together, these results indicate that the vasculature adjusts to the surrounding neural and glial tissue after irradiation, not vice-versa.

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“…AIF is a mitochondrial protein that induces caspase-independent neuronal apoptosis after translocation to the nucleus (Cheung et al, 2006). AIF has been reported to be essential for normal PCD during early embryogenesis (Joza et al, 2001), for PCD of embryonic cortical neurons (Cheung et al, 2006), and is also involved in cell death in the postnatal and adult brain after irradiation (Fukuda et al, 2004) and hypoxia-ischemia (Wang et al, 2004;Culmsee et al, 2005;Zhu et al, 2006;Blomgren et al, 2007;Cao et al, 2007). We examined PCD in several populations of developing neurons in Hq mutant mice that have an ϳ80% reduction in the expression of AIF (Klein et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Developing Postmitotic Mammalian NeuronsIn VivoLacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

Oppenheim¹,

Blomgren²,

Ethell³

et al. 2008

J. Neurosci.

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Previous studies have shown that caspases and Apaf-1 are required for the normal programmed cell death (PCD) in vivo of immature postmitotic neurons and mitotically active neuronal precursor cells. In contrast, caspase activity is not necessary for the normal PCD of more mature postmitotic neurons that are establishing synaptic connections. Although normally these cells use caspases for PCD, in the absence of caspase activity these neurons undergo a distinct nonapoptotic type of degeneration. We examined the survival of these more mature postmitotic neuronal populations in mice in which Apaf-1 has been genetically deleted and find that they exhibit quantitatively normal PCD of developing postmitotic neurons. We next characterized the morphological mode of PCD in these mice and show that the neurons degenerate by a caspase-independent, nonapoptotic pathway that involves autophagy. However, autophagy does not appear to be involved in the normal PCD of postmitotic neurons in which caspases and Apaf-1 are present and functional because quantitatively normal neuronal PCD occurred in the absence of a key gene required for autophagy (ATG7). Finally, we examined the possible role of another caspase-independent type of neuronal PCD involving the apoptosis-inducing factor (AIF). Mice deficient in AIF also exhibit quantitatively normal PCD of postmitotic neurons after caspase inhibition. Together, these data indicate that, when key components of the type 1 apoptotic pathway (i.e., caspases and Apaf-1) are perturbed in vivo, developing postmitotic neurons nonetheless undergo quantitatively normal PCD by a caspase-independent pathway involving autophagy and not requiring AIF.

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Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition

Cited by 108 publications

References 48 publications

Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain

Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain

Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

Developing Postmitotic Mammalian NeuronsIn VivoLacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

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