Vascular Damage after Fractionated Whole-Brain Irradiation in Rats

Abstract Brown, W. R., Thore, C. R., Moody, D. M., Robbins, M. E. and Wheeler, K. T. Vascular Damage after Fractionated Whole-Brain Irradiation in Rats. Radiat. Res. 164, 662–668 (2005). Whole-brain irradiation of animals and humans has been reported to lead to late delayed structural (vascular damage, demyelination, white matter necrosis) and functional (cognitive impairment) alterations. However, most of the experimental data on late delayed radiation-induced brain injury have been generated with large single doses or short fractionation schemes that may provide a less accurate indication of the events that occur after clinical whole-brain radiotherapy. The pilot study reported here investigates cerebral vascular pathology in male Fischer 344 rats after whole-brain irradiation with a fractionated total dose of 137Cs γ rays that is expected to be biologically similar to that given to brain tumor patients. The brains of young adult rats (4 months old) were irradiated with a total dose of 40 Gy, given as eight 5-Gy fractions twice per week for 4 weeks. Brain capillary and arteriole pathology was studied using an alkaline phosphatase enzyme histochemistry method; vessel density and length were quantified using a stereology method with computerized image processing and analysis. Vessel density and length were unchanged 24 h after the last dose, but at 10 weeks postirradiation, both were substantially decreased. After 20 weeks, the rate of decline in the vessel density and length in irradiated rats was similar to that in unirradiated age-matched controls. No gross gliosis or demyelination was observed 12 months postirradiation using conventional histopathology techniques. We suggest that the early (10-week) and persistent vascular damage that occurs after a prolonged whole-brain irradiation fractionation scheme may play an important role in the development of late delayed radiation-induced brain injury.

[1]  Carl D Langefeld,et al.  Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis. , 2004, Radiology.

[2]  J. Hopewell,et al.  Experimental evidence to support the hypothesis that damage to vascular endothelium plays the primary role in the development of late radiation-induced CNS injury. , 2004, The British journal of radiology.

[3]  C. Wong,et al.  Early Radiation-Induced Endothelial Cell Loss and Blood–Spinal Cord Barrier Breakdown in the Rat Spinal Cord , 2004, Radiation research.

[4]  K. Hole,et al.  Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[5]  L. Vidal,et al.  Stereological changes in the capillary network of the aging dorsal lateral geniculate nucleus. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[6]  L. Kubínová,et al.  Quantification of Rat Retinal Growth and Vascular Population Changes after Single and Split Doses of Proton Irradiation: Translational Study Using Stereology Methods , 2003, Radiation research.

[7]  T. Merchant,et al.  Differences in ICAM‐1 and TNF‐α expression between large single fraction and fractionated irradiation in mouse brain , 2003, International journal of radiation biology.

[8]  Albert B. Shackman.  Raymond Edward Parks, MD , 2002 .

[9]  V. Challa,et al.  Temporal Expression Pattern of Cerebrovascular Endothelial Cell Alkaline Phosphatase During Human Gestation , 2002, Journal of neuropathology and experimental neurology.

[10]  M. Sontag,et al.  Late Effects of Ionizing Radiation on the Microvascular Networks in Normal Tissue , 2000, Radiation research.

[11]  J. Fike,et al.  The Radioresponse of the Central Nervous System: A Dynamic Process , 2000, Radiation research.

[12]  Z. Fuks,et al.  Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. , 2000, Cancer research.

[13]  P. Wen,et al.  Management of brain metastases. , 1999, Oncology.

[14]  G. Rosner,et al.  Serial in vivo observations of cerebral vasculature after treatment with a large single fraction of radiation. , 1998, Radiation research.

[15]  T E Schultheiss,et al.  Radiation response of the central nervous system. , 1995, International journal of radiation oncology, biology, physics.

[16]  D. Roman,et al.  Neuropsychological effects of cranial radiation: current knowledge and future directions. , 1995, International journal of radiation oncology, biology, physics.

[17]  D. Nelson,et al.  Disruption of the blood-brain barrier as the primary effect of CNS irradiation. , 1994, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[18]  E. Neuwelt,et al.  Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  L. Eidus,et al.  Endothelial cell population dynamics in rat brain after local irradiation. , 1991, British Journal of Radiology.

[20]  N. Vick,et al.  Effects of treatment on long‐term survivors with malignant astrocytomas , 1990, Annals of neurology.

[21]  T. Beach,et al.  An animal model of prophylactic cranial irradiation: histologic effects at acute, early and delayed stages. , 1990, International journal of radiation oncology, biology, physics.

[22]  P. Gutin,et al.  Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas. , 1989, International journal of radiation oncology, biology, physics.

[23]  T. K. Yeung,et al.  Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. , 1988, The British journal of radiology.

[24]  S. Lauk.  Endothelial alkaline phosphatase activity loss as an early stage in the development of radiation-induced heart disease in rats. , 1987, Radiation research.

[25]  K. Fischer-Dzoga,et al.  Radiosensitivity of vascular tissue. I. Differential radiosensitivity of capillaries: a quantitative in vivo study. , 1984, Radiation research.

[26]  L. F. Fajardo,et al.  Response of swine skin microvasculature to acute single exposures of X rays: quantification of endothelial changes. , 1984, Radiation research.

[27]  M. A. Bell,et al.  Staining for microvascular alkaline phosphatase in thick celloidin sections of nervous tissue: morphometric and pathological applications. , 1984, Microvascular research.

[28]  K. Wheeler,et al.  Structural alterations of the DNA in cerebellar neurons after whole-brain irradiation. , 1981, Radiation research.

[29]  V. Smith,et al.  Therapeutic irradiation and brain injury. , 1980, International journal of radiation oncology, biology, physics.

[30]  D. Hirst,et al.  The response of mesenteric blood vessels to irradiation. , 1979, Radiation research.

[31]  L. F. Fajardo,et al.  Capillary injury preceding radiation-induced myocardial fibrosis. , 1971, Radiology.

[32]  J. Brady,et al.  Long-term effects of radiation on the vascularity of rat bone--quantitative measurements with a new technique. , 1971, Radiation research.

[33]  H. Curtis,et al.  Chromosome aberrations in liver cells of guinea pigs. , 1971, Journal of gerontology.

[34]  T. Makinodan,et al.  Age-Associated Changes in the DNA of Mouse Tissue , 1971, Science.

[35]  A. Jemal,et al.  Cancer Statistics, 2005 , 2005, CA: a cancer journal for clinicians.

[36]  V. Challa,et al.  Increase of white matter string vessels in Alzheimer's disease. , 2004, Journal of Alzheimer's disease : JAD.

[37]  M. Sontag,et al.  Early effects of ionizing radiation on the microvascular networks in normal tissue. , 1999, Radiation research.

[38]  Jack F. Fowler,et al.  Brief summary of radiobiological principles in fractionated radiotherapy , 1992 .

[39]  A. Kogel.  The Nervous System: Radiobiology and Experimental Pathology , 1991 .

[40]  J. Hopewell,et al.  Development of blood vessel-related radiation damage in the fimbria of the central nervous system. , 1990, International journal of radiation oncology, biology, physics.

[41]  D Campling,et al.  Effects of Radiation on the Microvasculature , 1989 .

[42]  T. K. Yeung,et al.  Effects of radiation on the microvasculature. Implications for normal-tissue damage. , 1989, Frontiers of radiation therapy and oncology.

[43]  R. Kallman,et al.  Quantitative estimation of histological changes in subcutaneous vasculature of the mouse after x-irradiation. , 1977, International journal of radiation oncology, biology, physics.

[44]  H. Reinhold,et al.  Radiosensitivity of capillary endothelium. , 1973, The British journal of radiology.