Long-Term Impact of Radiation on the Stem Cell and
Oligodendrocyte Precursors in the Brain
Georgia Panagiotakos1, George Alshamy1, Bill Chan1, Rory Abrams1, Edward Greenberg1, Amit Saxena1, Michelle Bradbury2, Mark Edgar3, Philip
Gutin1, Viviane Tabar1*
1Department of Neurosurgery, Sloan-Kettering Institute for Cancer Research, New York, New York, United States of America, 2Department of
Radiology, Sloan-Kettering Institute for Cancer Research, New York, New York, United States of America, 3Department of Pathology, Sloan-Kettering
Institute for Cancer Research, New York, New York, United States of America
Background. The cellular basis of long term radiation damage in the brain is not fully understood. Methods and Findings.
We administered a dose of 25Gy to adult rat brains while shielding the olfactory bulbs. Quantitative analyses were serially
performed on different brain regions over 15 months. Our data reveal an immediate and permanent suppression of SVZ
proliferation and neurogenesis. The olfactory bulb demonstrates a transient but remarkable SVZ-independent ability for
compensation and maintenance of the calretinin interneuron population. The oligodendrocyte compartment exhibits
a complex pattern of limited proliferation of NG2 progenitors but steady loss of the oligodendroglial antigen O4. As of nine
months post radiation, diffuse demyelination starts in all irradiated brains. Counts of capillary segments and length
demonstrate significant loss one day post radiation but swift and persistent recovery of the vasculature up to 15 months post
XRT. MRI imaging confirms loss of volume of the corpus callosum and early signs of demyelination at 12 months.
Ultrastructural analysis demonstrates progressive degradation of myelin sheaths with axonal preservation. Areas of focal
necrosis appear beyond 15 months and are preceded by widespread demyelination. Human white matter specimens obtained
post-radiation confirm early loss of oligodendrocyte progenitors and delayed onset of myelin sheath fragmentation with
preserved capillaries. Conclusions. This study demonstrates that long term radiation injury is associated with irreversible
damage to the neural stem cell compartment in the rodent SVZ and loss of oligodendrocyte precursor cells in both rodent and
human brain. Delayed onset demyelination precedes focal necrosis and is likely due to the loss of oligodendrocyte precursors
and the inability of the stem cell compartment to compensate for this loss.
Citation: Panagiotakos G, Alshamy G, Chan B, Abrams R, Greenberg E, et al (2007) Long-Term Impact of Radiation on the Stem Cell and
Oligodendrocyte Precursors in the Brain. PLoS ONE 2(7): e588. doi:10.1371/journal.pone.0000588
Radiation therapy is a powerful tool in the treatment of primary
and metastatic cancers of the brain. However, tissue tolerance of
the normal brain is very limited and radiation doses have to be
tailored to minimize the deleterious effect on the nervous system
. The late effects of radiation are of particular clinical relevance
and are manifest as cognitive impairment. There is currently no
effective treatment for radiation-induced cognitive decline[2,3].
While the pathogenesis is not fully understood, studies of brain
irradiation in humans and animals suggest the loss of myelin
sheaths with apparent preservation of axons. Vascular changes,
such as thrombosis and hyalinization are also seen, particularly at
high doses and in the subacute phase. There are controversial
views as to the relative importance of the vascular theory versus
the glial theory as a prime underlying element of pathogenesis of
late radiation effects . Histological studies of irradiated brains
essentially predate our current understanding of precursor biology
in the adult CNS. It is now recognized that there are two major
specialized zones of cell proliferation in the adult brain: the
subventricular zone (SVZ) and the dentate gyrus. These regions
contain stem cell and precursor populations that self-renew and
generate neurons and glia throughout life[8,9]. Outside these
regions the majority of the cycling cells in the adult brain (.75%)
are oligodendroglial progenitors, identified by their expression of
NG2 proteoglycan, PDGFRA or O4[10,11].
It was recently shown that irradiation leads to a dose-dependent
loss of celltypes inthe subventricular zone (SVZ) with impairment of
SVZ repopulation up to three months. Older studies have also
reported a decrease in mitotic activity non-specifically in the
‘‘subependymal plate’’ after different radiation doses with sub-
sequent delayed recovery. Additionally, there is loss of granule
cells in the hippocampus up to 3 months after brain irradiation .
The effects of brain irradiation on oligodendrocyte progenitors is
described in the spinal cord whereby exposure of short segments to
high dose radiation (40 Gy) results in a decrease in the number of
NG2+cells by nearly 50%  but this data was not extended
over long time periods or to the brainitself. It is unclear from current
literature if the loss of oligodendrocyte progenitors is permanent or if
delayed recovery occurs. The loss of these cells may underlie the
absence of remyelination in the late phases of radiation. Conversely
radiation may result in alterations of the microenvironment that
inhibit survival of newly born oligodendroglial progenitors and/or
their maturation into the myelin phenotype.
In this study, we quantitate the impact of whole brain
irradiation on the SVZ compartment and olfactory neurogenesis,
as well as on the oligodendrocyte progenitors and mature myelin.
Animals are followed over a period of 15 months thus allowing
Academic Editor: Schahram Akbarian, University of Massachusetts, United States
Received May 14, 2007; Accepted May 31, 2007; Published July 11, 2007
Copyright: ? 2007 Panagiotakos et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Funding: Funding provided in part by grants from the NINDS, NIH and the
Michael T. McCarthy Foundation.
Competing Interests: The authors have declared that no competing interests
* To whom correspondence should be addressed. E-mail: firstname.lastname@example.org
PLoS ONE | www.plosone.org1July 2007 | Issue 7 | e588
a detailed understanding of the kinetics of the stem cell and
progenitor subpopulations both in normal aging and post radiation.
post radiation. Such tissues are rarely available for analysis and were
obtained from surgical specimens collected over six years. Data from
rat and human tissues that had been irradiated at various periods
prior to analysis suggest a similar pattern of oligodendroglial
progenitor loss and demyelination over time post radiation. There
was no obvious vascular damage despite ultrastructural evidence of
myelin fragmentation. To our knowledge this is the first long term
study of the impact of high dose therapeutic range irradiation on
specific cell subpopulations in the subventricular zone and
oligodendrocyte progeny in the brain.
Young adult Sprague Dawley female rats (Taconic; 3 to
15 months old) were used throughout the study. A dose of 25
Gray (Gy) was administered to the cranium of 3-month-old rats
using a 250kV-orthovoltage system equipped with a 0.25mm
copper filter. A custom-designed positioning device platform based
on the standard stereotactic frame was used so that six animals
could be simultaneously irradiated. Animals were fully anesthe-
tized using a combination of Ketamine (90 mg/kg ip) and
Xylazine (4 mg/kg ip) prior to being placed in the frame. The
heads were centered in a 20 cm620 cm treatment field and x-
irradiation was limited to an adjustable 2 cm circular aperture
centered over the cranium. A lead plate shielded the rest of the
body, including the animals’ ears, hindbrain, and orbits; the
olfactory bulb was spared. The beam was directed onto the head
at a source to skin distance of 21 cm at a calculated angle of 5.7u
from vertical. An X-ray of the animals in their final position was
taken and developed in double exposure (with and without lead
shielding) to check the appropriate skull position against an X-ray
of the ‘‘ideal’’ position previously confirmed by dose calibration
tests. The full radiation dose is administered after final adjustment.
Dosimetry was performed by implanting lithium fluoride thermo-
luminescent dosimeters into various areas of the brain as well as
protected regions (ears, oropharynx, orbit and hindbrain). The
corrected dose rate was determined to be 117.5cGy/min with
a calculated dose variation at a maximum of 9% per 5 mm from
the center of the field in the dorsoventral axis. Instrument
calibration was performed regularly by the department of medical
physics. Rats were irradiated in batches of 6 animals per set;
several sets were done per week and the animals distributed
randomly into time point groups at n=4 per time point.
Bromodeoxyuridine (BrdU) Administration
For three days prior to sacrifice, irradiated and control rats were
injected daily with 300 mg/kg BrdU (97%, Aldrich) in sterile
normal saline intraperitoneally.
Briefly, rats were deeply anesthetized with an intraperitoneal
injection of an overdose of Pentobarbital Sodium (Nembutal
Sodium Solution; Abbot Laboratories), followed by transcardial
perfusion of 0.1% heparinized normal saline (Sigma) at 4uC and
an equal volume of 4% paraformaldehyde (PFA) in PBS also at
4uC (pH 7.4). Brains were then carefully extracted, placed in 4%
PFA for overnight fixation at 4uC and subsequently transferred to
30% sucrose at 4uC until embedding. Optimal Cutting Temper-
ature Compound (O.C.T. Compound, Tissue Tek) was used for
embedding and 25 mm or 10 mm (for histology) sections were cut
on a freezing cryostat. Sections were stored at 280uC until use for
Sections were washed briefly with PBS 0.1% BSA and blocked for
fluorescence immunohistochemistry with 10% normal goat serum
(NGS, Gibco) in PBS 0.1% BSA and 0.3% Triton X-100 for one
hour (Triton X-100 was omitted for surface antigens). Pre-
treatment steps were performed for some antibodies as follows: 2N
HCl for 30 min at 25uC for BrdU and 100% methanol for 7 min
at 220uC for MAG. Primary antibodies were incubated overnight
at 4uC and appropriate secondary antibodies (Alexa conjugates,
Molecular Probes) were applied on the following day at 25uC for
one hour. Slides were then washed in PBS, counterstained with the
nuclear marker DAPI (Molecular Probes) and mounted in 70%
glycerol. The primary antibodies used included: BrdU (1:50, BD);
chondroitin sulfate proteoglycan NG2 (1:200, Chemicon); guinea
pig Doublecortin (DCX, 1:3000, Chemicon); Calretinin (1:1000,
Swant); Rat Endothelial Cell Antigen (RECA, 1:100, Serotec); rat
Myelin Basic Protein (MBP, 1:200, Chemicon); Myelin-Associated
Glycoprotein (MAG, 1:100, Chemicon); O4 (1:100, Chemicon);
O1 (1:100, Chemicon); CNPase (1:200, Sternberger Monoclonals);
PDGFRA (1:50, Santa Cruz Biotechnology); Neurofilament M
(1:200, Chemicon); Neurofilament 70kDa (1:200, Chemicon);
Galactocerebroside (Galc, 1:200, Chemicon); von Willebrand
Factor (vWF, 1:100, BD Biosciences Pharmingen).
Stereological Analyses/Cell Counts
All stereological analyses were conducted by a trained operator
with no knowledge of animal identification. Total number of
proliferating cells (BrdU+) and proliferating oligodendrocyte
progenitor cells (BrdU/NG2+) was assessed separately in the
SVZ, cortex and corpus callosum by stereological methods using
the optical fractionator probe (Stereo Investigator Version 6,
Micro Brightfield). Fractionator probes were designed and applied
using the stereological software with the coefficient of error
(Gundersen) set at #0.04. Systematic random sampling was
applied to each of the three regions of interest as defined on serial
sections selected at discrete intervals with a random start. Data is
presented as average estimated total cell number at each time
point and for appropriately age-matched controls.
For stereological analysis of endothelial cells, serial sections of
cortex and corpus callosum stained for RECA (1:100, Serotec)
were analyzed for the following: total capillary segment number
using the optical fractionator method and total capillary length
using the virtual sphere method[17,18]. Unbiased counting frames
with inclusion/exclusion lines were used to avoid edge effects.
For the olfactory bulb, regions of interest were identified as the
anterior extension of the rostral migratory stream (distal or rostral
RMS), the granular cell layer, the glomerular layer, and the entire
olfactory bulb. We counted the total number of proliferating cells
(BrdU+) in the olfactory bulb, in addition to the number of
proliferating migrating neuroblasts in the anterior RMS (BrdU/
DCX+), the number of DCX+neuroblasts in the granular layer,
and the number of Calretinin+periglomerular interneurons. All
time-points were compared to cell counts from age-matched
controls. Statistical testing performed using ANOVA followed by
post-hoc analysis (Newman-Keuls). Data is presented as mean cell
Fluorescence Intensity Quantification
Measurements of fluorescence staining intensity were made on
digital images obtained from cryopreserved brain specimens
CNS Radiation Injury
PLoS ONE | www.plosone.org2July 2007 | Issue 7 | e588
is consistent with pathological findings of primary demyelination.
Importantly, neurofilament integrity and organization of the
axoplasm appeared normal; staining for MBP and neurofilament
proteins in late post radiation rat and human samples confirmed
a loss of myelin with apparent preservation of axons.
In summary this study demonstrates permanent suppression of
the SVZ stem cell compartment following radiation as well as an
early and sustained loss of oligodendrocyte precursor cells with
subsequent delayed demyelination. The detailed analysis of
various cell populations over time reveals potential therapeutic
windows that could target the recovery phases of neural precursors
post injury prior to the occurrence of structural damage to the
myelin sheaths. The rat model is validated by similar findings in
human tissue. Based on this model, therapeutic strategies may be
directed at reducing initial precursor cell loss or possibly at
replacing the lost precursor cells via transplantation of primary or
stem cell derived oligodendrocyte precursors as a means of
preventing late radiation-induced demyelination.
the SVZ at various times post radiation (A). Quantitative
measurements shown in (B) demonstrate significant suppression
on day 1 that is maintained well below normal controls with
a minor recovery peak at 9 months post radiation, also illustrated
in (A). BrdU/NG2 kinetics in the corpus callosum (CC) and cortex
(Cx) are noted for a more sustained recovery of cell numbers to
approach those of normal age-matched controls, particularly
beyond 9 months post XRT. (*** p,0.001; ** p,0.01; * p,0.05;
ANOVA). Bars=SEM. Scale bar in (A) corresponds to 50 mm in
all panels except 12 months where it corresponds to 100 mm.
Found at: doi:10.1371/journal.pone.0000588.s001 (3.14 MB TIF)
Immunohistochemistry of coronal sections through
noted at 2 months post XRT with further decrease and no
recovery at 15 months post radiation. MAG, a marker associated
with more mature oligodendrocytes, is depleted only at late time
points. Human white matter samples in (B) were acquired from
non-irradiated (normal brain) and irradiated specimens up to
7 months post XRT (labeled ‘‘early’’) and between 9 months and
7 years (labeled ‘‘late’’). Immunohistochemistry for markers of
intermediate/late oligodendrocyte progenitors O1, Galc and
MAG show a similar pattern of delayed loss of expression with
profound loss and no evidence of recovery in the late phases. Scale
bar corresponds to 100 mm in all panels.
Found at: doi:10.1371/journal.pone.0000588.s002 (6.67 MB TIF)
Rat samples in (A) demonstrate progressive loss of O1
tissues at 14 months post XRT in both specimens. Immunohistol-
ogy for MBP demonstrates loss of myelin (red) without obvious loss
of neurofilament (green). Antibodies against NF-70 were used for
Panels of human (A) and rat (B) control and irradiated
human tissues and NF-M for rat tissues. Scale bar corresponds to
100 mm in all panels. Representative sections at the level of the
hippocampal commissure and dorsal fornix in the rat are shown in
the normal age-matched and irradiated rat brain in (A) and (B)
respectively. There is severe focal necrosis with myelin (red) and
cell loss (DAPI, blue nuclei). Two of the human specimens were
acquired in the context of symptomatic radiation necrosis.
Histological assessment (H&E) demonstrates pale-staining foci of
necrosis without surrounding hypercellularity (C) and amorphous
necrotic debris with scattered macrophages in (D). Scale bars
correspond to 100 mm in (A), (B) and (C) and to 50 mm in (D).
Found at: doi:10.1371/journal.pone.0000588.s003 (6.13 MB TIF)
and in select patients presenting with clinical symptoms post
radiation. Representative sections at the level of the hippocampal
commissure and dorsal fornix in the rat are shown in the normal
age-matched and irradiated rat brain in (A) and (B) respectively.
There is severe focal necrosis with myelin (red) and cell loss (DAPI,
blue nuclei). Two of the human specimens were acquired in the
context of symptomatic radiation necrosis. Histological assessment
(H&E) demonstrates pale-staining foci of necrosis without
surrounding hypercellularity (C) and amorphous necrotic debris
with scattered macrophages in (D). Scale bars correspond to
100 mm in (A), (B) and (C) and to 50 mm in (D).
Found at: doi:10.1371/journal.pone.0000588.s004 (5.01 MB TIF)
Necrosis is seen in some rat tissues beyond 15 months
We would like to thank Lorenz Studer for critical comments on the
manuscript, Thomas Losasso, PhD from the department of Medical
Physics at Sloan-Kettering for his assistance in dosimetry and design of the
radiation set-up, Robert Febo for assistance in instrument calibration and
other technical aspects of the radiation experiments, Sonja Clairmont for
technical assistance and Nina Lampen and Leona Cohen-Gould for tissue
processing and imaging for electron microscopy.
Conceived and designed the experiments: VT PG. Performed the
experiments: GP GA BC RA EG AS MB. Analyzed the data: VT GP
GA BC RA ME. Wrote the paper: VT GP. Other: Performed most of the
tissue preparation and the majority of the experiments and data analysis,
contributed significantly to the manuscript preparation and contributed to
the supervision of all aspects of the study: GP. Performed the majority of
the human tissue immunohistochemical analyses, assisted with animal
irradiation and care: GA. Performed the majority of the radiation
experiments, and the majority of the stereological analyses: BC.
Contributed to the immunohistochemistry and tissue preparation and
performed the capillary analysis including stereology: RA. Assisted with the
radiation experiments and immunohistochemistry: EG. Assisted with the
design of the radiation apparatus and the early radiation experiments: AS.
Performed the MRI imaging and analyses: MB. Performed the histology
and ultrastructural analyses: ME.
1. Fike JR, Cann CE, Turowski K, Higgins RJ, Chan AS, et al. (1988) Radiation
dose response of normal brain. Int J Radiat Oncol Biol Phys 14: 63–70.
2. DeAngelis LM, Gutin PH, Leibel SA, Posner JB (2002) Intracranial Tumors.
Diagnosis and Treatment. Martin Dunitz Ltd.
3. Roman DD, Sperduto PW (1995) Neuropsychological effects of cranial
radiation: current knowledge and future directions. Int J Radiat Oncol Biol
Phys 31: 983–998.
4. Oi S, Kokunai T, Ijichi A, Matsumoto S, Raimondi AJ (1990) Radiation-
induced brain damage in children–histological analysis of sequential tissue
changes in 34 autopsy cases. Neurol Med Chir (Tokyo) 30: 36–42.
5. Sano K, Morii K, Sato M, Mori H, Tanaka R (2000) Radiation-induced diffuse
brain injury in the neonatal rat model–radiation-induced apoptosis of
oligodendrocytes. Neurol Med Chir (Tokyo) 40: 495–499.
6. Duffner PK, Cohen ME, Thomas PR, Lanza RP (1985) The long-term effects of
cranial irradiation on the central nervous system. Cancer 56: 1841–1846.
7. Hopewell JW, van der Kogel AJ (1999) Pathophysiological mechanisms leading
to the development of late radiation-induced damage to the central nervous
system. Front Radiat Ther Oncol 33: 265–275.
8. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, et al.
(1998) Neurogenesis in the adult human hippocampus. Nature Med 4:
9. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999)
Subventricular zone astrocytes are neural stem cells in the adult mammalian
brain. Cell 97: 703–716.
10. Gensert JM, Goldman JE (2001) Heterogeneity of cycling glial progenitors in the
adult mammalian cortex and white matter. J Neurobiol 48: 75–86.
CNS Radiation Injury
PLoS ONE | www.plosone.org12 July 2007 | Issue 7 | e588
11. Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell
in health and disease. Trends Neurosci 24: 39–47.
12. Tada E, Yang C, Gobbel GT, Lamborn KR, Fike JR (1999) Long-term
impairment of subependymal repopulation following damage by ionizing
irradiation. Exp Neurol 160: 66–77.
13. Cavanagh JB, Hopewell JW (1972) Mitotic activity in the subependymal plate of
rats and the long-term consequences of X-irradition. J Neurol Sci 15: 471–482.
14. Tada E, Parent JM, Lowenstein DH, Fike JR (2000) X-irradiation causes
a prolonged reduction in cell proliferation in the dentate gyrus of adult rats.
Neuroscience 99: 33–41.
15. Keirstead HS, Levine JM, Blakemore WF (1998) Response of the oligodendro-
cyte progenitor cell population (defined by NG2 labelling) to demyelination of
the adult spinal cord. Glia 22: 161–170.
16. Blakemore WF, Gilson JM, Crang AJ (2000) Transplanted glial cells migrate
over a greater distance and remyelinate demyelinated lesions more rapidly than
endogenous remyelinating cells. J Neurosci Res 61: 288–294.
17. Mouton PR, Gokhale AM, Ward NL, West MJ (2002) Stereological length
estimation using spherical probes. J Microsc 206: 54–64.
18. Lee GD, Aruna JH, Barrett PM, Lei DL, Ingram DK, et al. (2005) Stereological
analysis of microvascular parameters in a double transgenic model of
Alzheimer’s disease. Brain Res Bull 65: 317–322.
19. van der Kogel AJ (2001) Central Nervous System Radiation injury in Small
Animal Models. In: Gutin PH, Leibel S, Sheline GE, eds. Radiation Injury to
the Nervous System. New York: Raven Press. pp 91–111.
20. Schmitz C, Born M, Dolezel P, Rutten BP, de Saint-Georges L, et al. (2005)
Prenatal protracted irradiation at very low dose rate induces severe neuronal loss
in rat hippocampus and cerebellum. Neuroscience 130: 935–948.
21. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Regeneration of
a germinal layer in the adult mammalian brain. Proc Natl Acad Sci USA 96:
22. Gritti A, Bonfanti L, Doetsch F, Caille I, Alvarez-Buylla A, et al. (2002)
Multipotent neural stem cells reside into the rostral extension and olfactory bulb
of adult rodents. J Neurosci 22: 437–445.
23. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult
hippocampal neurogenesis. Science 302: 1760–1765.
24. Little JB (2003) Genomic instability and bystander effects: a historical
perspective. Oncogene 22: 6978–6987.
25. Aguirre A, Gallo V (2004) Postnatal neurogenesis and gliogenesis in the olfactory
bulb from NG2-expressing progenitors of the subventricular zone. J Neurosci 24:
26. Polito A, Reynolds R (2005) NG2-expressing cells as oligodendrocyte
progenitors in the normal and demyelinated adult central nervous system.
J Anat 207: 707–716.
27. Gensert JM, Goldman JE (1997) Endogenous progenitors remyelinate
demyelinated axons in the adult CNS. Neuron 19: 197–203.
28. McTigue DM, Wei P, Stokes BT (2001) Proliferation of NG2-positive cells and
altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci 21:
29. Pfeiffer SE, Warrington AE, Bansal R (1993) The oligodendrocyte and its many
cellular processes. Trends Cell Biol 3: 191–197.
30. Bansal R, Pfeiffer SE (1997) Regulation of oligodendrocyte differentiation by
fibroblast growth factors. Adv Exp Med Biol 429: 69–77.
31. Chari DM, Blakemore WF (2002) Efficient recolonisation of progenitor-depleted
areas of the CNS by adult oligodendrocyte progenitor cells. Glia 37: 307–313.
32. Bu J, Banki A, Wu Q, Nishiyama A (2004) Increased NG2(+) glial cell
proliferation and oligodendrocyte generation in the hypomyelinating mutant
shiverer. Glia 48: 51–63.
33. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, et al.
(2006) Origin of oligodendrocytes in the subventricular zone of the adult brain.
J Neurosci 26: 7907–7918.
34. Levison SW, Goldman JE (1993) Both oligodendrocytes and astrocytes develop
from progenitors in the subventricular zone of postnatal rat forebrain. Neuron
35. Bentzen SM (2006) Preventing or reducing late side effects of radiation therapy:
radiobiology meets molecular pathology. Nat Rev Cancer 6: 702–713.
36. Hodges H, Katzung N, Sowinski P, Hopewell JW, Wilkinson JH, et al. (1998)
Late behavioural and neuropathological effects of local brain irradiation in the
rat. Behav Brain Res 91: 99–114.
37. Belka C, Budach W, Kortmann R, Bamberg M (2001) Radiation induced CNS
toxicity-molecular and cellular mechanisms. British Journal of Cancer 85:
38. Suzuki K, Ojima M, Kodama S, Watanabe M (2003) Radiation-induced DNA
damage and delayed induced genomic instability. Oncogene 22: 6988–6993.
39. Reinhold HS, Calvo W, Hopewell JW, van der Berg AP (1990) Development of
blood vessel-related radiation damage in the fimbria of the central nervous
system. Int J Radiat Oncol Biol Phys 18: 37–42.
40. Ljubimova NV, Levitman MK, Plotnikova ED, Eidus LK (1991) Endothelial cell
population dynamics in rat brain after local irradiation. Br J Radiol 64: 934–940.
41. Lyubimova N, Hopewell JW (2004) Experimental evidence to support the
hypothesis that damage to vascular endothelium plays the primary role in the
development of late radiation-induced CNS injury. Br J Radiol 77: 488–492.
42. Otsuka S, Coderre JA, Micca PL, Morris GM, Hopewell JW, et al. (2006)
Depletion of neural precursor cells after local brain irradiation is due to radiation
dose to the parenchyma, not the vasculature. Radiat Res 165: 582–591.
CNS Radiation Injury
PLoS ONE | www.plosone.org13 July 2007 | Issue 7 | e588