Abstract
Background
Studies have shown that aging is a significant factor in worsening stroke outcomes.
While many mechanisms may aggravate brain injury in the elderly, one such potential
system may involve increased glial proliferation in the aged stroke patient that could
result in increased scar formation. We hypothesized that in aged rats a single brain-only
exposure to a low radiation dose prior to focal brain ischemia would reduce glial
proliferation and confer a long-term neuroprotective effect.
Methods
Brain-only proton irradiation (8 Gy) was performed ten days prior to middle cerebral artery occlusion (MCAO) in aged
male rats. Magnetic resonance imaging (MRI) was undertaken in naive, radiation-only
(Rad), MCAO, and MCAO+Rad groups at 2, 14 and 28 days post-stroke followed by immunohistochemistry (day 28).
Results
Ischemic lesion volume in MCAO+Rad group was decreased by 50.7% with an accelerated temporal reduction in peri-lesional
brain edema and increased water mobility within the ischemic core (39.8%) compared
to MCAO-only rats. In the peri-lesional brain region of MCAO+Rad rats there was a decreased scar formation (49%, glial fibrillary acidic protein),
brain tissue sclerosis (30%, aquaporin-4) and necrosis/apoptosis (58%, TUNEL positive
cells) compared to those in MCAO animals.
Conclusion
In aged animals a single exposure to brain-only radiation prior to focal cerebral
ischemia is neuroprotective as it prevents glial hyperproliferation, progressive brain
tissue sclerosis and reduces the apoptosis/necrosis in the peri-lesional region. Decreased
lesion volume is in agreement with accelerated reduction of brain edema in these animals.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Proportion of older people in the community as a predictor of increasing stroke incidence.Neuroepidemiology. 2001; 20: 91-95
- The response of the aged brain to stroke: too much, too soon?.Curr Neurovasc Res. 2007; 4: 216-227
- Cellular and molecular mechanisms underlying neurorehabilitation after stroke in aged subjects.Rom J Morphol Embryol. 2008; 49: 279-302
- Overexpression of human S100B exacerbates brain damage and periinfarct gliosis after permanent focal ischemia.Stroke. 2008; 39: 2114-2121
- A new in vitro model of the glial scar inhibits axon growth.Glia. 2008; 56: 1691-1709
- Cellular and molecular events underlying the dysregulated response of the aged brain to stroke: a mini-review.Gerontology. 2008; 54: 6-17
- Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery.J Cereb Blood Flow Metab. 2003; 23: 845-854
- Age and gender effects on microglia and astrocyte numbers in brains of mice.Brain Res. 2002; 956: 30-35
- GFAP mRNA increases with age in rat and human brain.Neurobiol Aging. 1993; 14: 421-429
- Aging has a complex effect on a rat model of ischemic stroke.Brain Res. 2002; 925: 148-158
- Phenotypic and functional changes in glial cells as a function of age.Neurobiol Aging. 2002; 23: 105-115
- Astrocytes are active players in cerebral innate immunity.Trends Immunol. 2007; 28: 138-145
- Astrogliosis in CNS pathologies: is there a role for microglia?.Mol Neurobiol. 2010; 41: 232-241
- Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci. 2009; 32: 638-647
- Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial.Neurology. 2001; 57: 1428-1434
- Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke.Curr Med Res Opin. 2002; 18: s18-s22
- Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke.Stroke. 2003; 34: 2543-2548
- The bright side of the glial scar in CNS repair.Nat Rev Neurosci. 2009; 10: 235-241
- Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide.J Neurol Sci. 2010; 296: 69-78
- Neurophysiological and histopathological evaluation of low-dose radiation on the cauda equina and postlaminotomy fibrosis: an experimental study in the rat.Spine (Phila Pa 1976). 2009; 34: 463-469
- Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy.Int J Radiat Biol. 2007; 83: 357-366
- The effect of immunosuppression with whole body and regional irradiation on the development of cerebral oedema in a rat model of intracerebral haemorrhage.Acta Neurochir Suppl (Wien). 1990; 51: 52-54
- The effect of immunosuppression on the development of cerebral oedema in an experimental model of intracerebral haemorrhage: whole body and regional irradiation.J Neurol Neurosurg Psychiatry. 1992; 55: 781-786
- Immunosuppression by whole-body irradiation and its effect on oedema in experimental cerebral ischaemia.Acta Neurol Scand. 1992; 86: 256-259
- Low-dose gamma-irradiation promotes survival of injured neurons in the central nervous system via homeostasis-driven proliferation of T cells.Eur J Neurosci. 2004; 19: 1191-1198
- Controlled autoimmunity in CNS maintenance and repair: naturally occurring CD4+CD25+ regulatory T-cells at the crossroads of health and disease.Neuromolecular Med. 2005; 7: 197-206
- Radiation exposure prior to ischemia decreases lesion volume, brain edema and cell death.Acta Neurochir Suppl. 2010; 106: 51-53
- Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke. 1989; 20: 84-91
- Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats.J Neurol Sci. 1997; 153: 8-11
- Comparison of two neonatal ischemic injury models using magnetic resonance imaging.Pediatr Res. 2007; 61: 9-14
- Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation.Stroke. 1995; 26: 627-634
- Temporal and regional evolution of aquaporin-4 expression and magnetic resonance imaging in a rat pup model of neonatal stroke.Pediatr Res. 2007; 62: 248-254
- The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction.Neuroscience. 1999; 89: 687-699
- Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology.J Intern Med. 2010; 267: 172-190
- Present status of magnetic resonance imaging and spectroscopy in animal stroke models.J Cereb Blood Flow Metab. 2006; 26: 591-604
- Comparison of diffusion-weighted MRI with changes in cell volume in a rat model of brain injury.NMR Biomed. 1994; 7: 96-100
- The value of diffusion-weighted imaging in assessing the ADC changes of tissues adjacent to breast carcinoma.BMC Cancer. 2009; 9: 18
- Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation.Stroke. 2000; 31: 1965-1972
- Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat.J Cereb Blood Flow Metab. 2006; 26: 38-47
- The clinical significance of diffusion-weighted MR imaging in stroke and TIA patients.Swiss Med Wkly. 2008; 138: 729-740
- Cyclooxygenase-2 mRNA expression is associated with c-fos mRNA expression and transient water ADC reduction detected with diffusion MRI during acute focal ischemia in rats.Brain Res. 2003; 961: 121-130
- Acute postischemic renormalization of the apparent diffusion coefficient of water is not associated with reversal of astrocytic swelling and neuronal shrinkage in rats.AJNR Am J Neuroradiol. 2002; 23: 180-188
- A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior.J Cereb Blood Flow Metab. 2000; 20: 563-582
- A model to predict the histopathology of human stroke using diffusion and T2-weighted magnetic resonance imaging.Stroke. 1995; 26: 1983-1989
- Ischemic stroke: effects of etiology and patient age on the time course of the core apparent diffusion coefficient.Radiology. 2001; 221: 27-34
- The temporal evolution of MRI tissue signatures after transient middle cerebral artery occlusion in rat.J Neurol Sci. 1997; 145: 15-23
- Serial analysis of the apparent diffusion coefficient time course in human stroke.Neuroradiology. 2002; 44: 294-298
- Acute and chronic changes of the apparent diffusion coefficient in neurological disorders—biophysical mechanisms and possible underlying histopathology.J Neurol Sci. 2001; 186: S15-S23
- Role of vasogenic edema and tissue cavitation in ischemic evolution on diffusion-weighted imaging: comparison with multiparameter MR and immunohistochemistry.AJNR Am J Neuroradiol. 1995; 16: 1107-1115
- In vivo measurement of the apparent diffusion coefficient in normal and malignant prostatic tissue using thin-slice echo-planar imaging.Radiol Med. 2006; 111: 1124-1133
- Inflammation and the neurovascular unit in the setting of focal cerebral ischemia.Neuroscience. 2009; 158: 972-982
- Age-dependent MRI-detected lesions at early stages of transient global ischemia in rat brain.Magma. 2004; 17: 109-116
- MRI analysis of the changes in apparent water diffusion coefficient, T(2) relaxation time, and cerebral blood flow and volume in the temporal evolution of cerebral infarction following permanent middle cerebral artery occlusion in rats.Exp Neurol. 2001; 169: 56-63
- Long-term changes of functional MRI-based brain function, behavioral status, and histopathology after transient focal cerebral ischemia in rats.Stroke. 2006; 37: 2593-2600
- Effect of age in rats following middle cerebral artery occlusion.Gerontology. 2003; 49: 27-32
- Subcortical lesions after transient thread occlusion in the rat: T2-weighted magnetic resonance imaging findings without corresponding sensorimotor deficits.J Magn Reson Imaging. 2005; 21: 340-346
- Longitudinal in vivo MRI of alterations in perilesional tissue after transient ischemic stroke in rats.Exp Neurol. 2008; 212: 207-212
- Dynamic changes of magnetic resonance imaging abnormalities in relation to inflammation and glial responses after photothrombotic cerebral infarction in the rat brain.Acta Neuropathol. 2001; 101: 114-122
- In vivo MRI analysis of an inflammatory injury in the developing brain.Brain Behav Immun. 2010; 24: 759-767
- Imaging immune response in vivo: cytolytic action of genetically altered T cells directed to glioblastoma multiforme.Clin Cancer Res. 2008; 14: 3832-3839
- Neuronal and glial cell populations in the piriform cortex distinguished by using an approximation of q-space imaging after status epilepticus.AJNR Am J Neuroradiol. 2004; 25: 1225-1233
- Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study.J Neurosci. 2000; 20: 8153-8159
- Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts.J Neurosci. 2003; 23: 10913-10922
- Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats. Evaluation with serial magnetic resonance imaging.Stroke. 2002; 33: 2985-2991
- In situ detection of DNA fragmentation after focal cerebral ischemia in mice.Brain Res Mol Brain Res. 1995; 28: 164-168
- Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat.J Cereb Blood Flow Metab. 1995; 15: 389-397
- Pre-embedding immunogold labeling of TUNEL stain enables evaluation of DNA strand breaks and ultrastructural alterations in individual cells of neuronal tissue.Acta Neuropathol. 2002; 104: 621-636
- Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient.Cell Death Differ. 2004; 11: 1258-1264
- Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study.Brain Res Bull. 1993; 31: 565-572
- CD8+ phagocytes in focal ischemia of the rat brain: predominant origin from hematogenous macrophages and targeting to areas of pannecrosis.Acta Neuropathol. 2001; 101: 440-448
- The radioresponse of the central nervous system: a dynamic process.Radiat Res. 2000; 153: 357-370
- Radiation-induced apoptosis of oligodendrocytes in the adult rat brain.Neurol Res. 2001; 23: 869-874
- Response of postmitotic neurons to X-irradiation: implications for the role of DNA damage in neuronal apoptosis.J Neurosci. 1998; 18: 147-155
- Oligodendrocytes in the adult rat spinal cord undergo radiation-induced apoptosis.Cancer Res. 1996; 56: 5417-5422
- Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.Radiat Res. 2009; 171: 53-65
- Radiation-induced astrogliosis and blood-brain barrier damage can be abrogated using anti-TNF treatment.Int J Radiat Oncol Biol Phys. 2009; 74: 934-941
- Regeneration beyond the glial scar.Nat Rev Neurosci. 2004; 5: 146-156
- Temporal dynamics of degenerative and regenerative events associated with cerebral ischemia in aged rats.Gerontology. 2003; 49: 356-365
- Involvement of aquaporin-4 in astroglial cell migration and glial scar formation.J Cell Sci. 2005; 118: 5691-5698
- Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy.Acta Neuropathol. 2004; 108: 493-502
- Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury.FASEB J. 2007; 21: 108-116
- Aquaporins and cell migration.Pflugers Arch. 2008; 456: 693-700
- Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study.J Neurosci. 2003; 23: 510-517
- Magnetic resonance assessment of acute and chronic stroke.Prog Cardiovasc Dis. 2000; 43: 113-134
- Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral ischemia.Neurochem Int. 2006; 49: 127-135
- Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection.Exp Transl Stroke Med. 2010; 2: 2
- Local radiotherapy induces homing of hematopoietic stem cells to the irradiated bone marrow.Cancer Res. 2007; 67: 10112-10116
- Integrated brain restoration after ischemic stroke—medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity.Altern Med Rev. 2009; 14: 14-35
Article info
Publication history
Published online: April 11, 2011
Accepted:
February 28,
2011
Received in revised form:
January 21,
2011
Received:
August 27,
2010
Identification
Copyright
© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
