Low Dose Cranial Irradiation-Induced Cerebrovascular Damage Is Reversible in Mice

Abstract

BackgroundHigh-dose radiation-induced blood-brain barrier breakdown contributes to acute radiation toxicity syndrome and delayed brain injury, but there are few data on the effects of low dose cranial irradiation. Our goal was to measure blood-brain barrier changes after low (0.1 Gy), moderate (2 Gy) and high (10 Gy) dose irradiation under in vivo and in vitro conditions.MethodologyCranial irradiation was performed on 10-day-old and 10-week-old mice. Blood-brain barrier permeability for Evans blue, body weight and number of peripheral mononuclear and circulating endothelial progenitor cells were evaluated 1, 4 and 26 weeks postirradiation. Barrier properties of primary mouse brain endothelial cells co-cultured with glial cells were determined by measurement of resistance and permeability for marker molecules and staining for interendothelial junctions. Endothelial senescence was determined by senescence associated β-galactosidase staining.Principle FindingsExtravasation of Evans blue increased in cerebrum and cerebellum in adult mice 1 week and in infant mice 4 weeks postirradiation at all treatment doses. Head irradiation with 10 Gy decreased body weight. The number of circulating endothelial progenitor cells in blood was decreased 1 day after irradiation with 0.1 and 2 Gy. Increase in the permeability of cultured brain endothelial monolayers for fluorescein and albumin was time- and radiation dose dependent and accompanied by changes in junctional immunostaining for claudin-5, ZO-1 and β-catenin. The number of cultured brain endothelial and glial cells decreased from third day of postirradiation and senescence in endothelial cells increased at 2 and 10 Gy.ConclusionNot only high but low and moderate doses of cranial irradiation increase permeability of cerebral vessels in mice, but this effect is reversible by 6 months. In-vitro experiments suggest that irradiation changes junctional morphology, decreases cell number and causes senescence in brain endothelial cells.

Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum

“…In the juvenile rat brain, we found that BBB disruption after irradiation varies among brain regions and that the cerebellum is the most sensitive region to irradiation in this respect. This finding is in line with another study demonstrating BBB disruption 1 week and 4 weeks post irradiation in the cerebellum of both juvenile and adult mouse brains7. However, BBB integrity in the cerebrum was only disrupted after 1 week and in the adult brain and after 4 weeks in the juvenile brain indicating that the cerebellar BBB is more sensitive to cranial irradiation.…”

“…Radiation-induced endothelial cell death is of crucial importance for the development of brain injury3536 since this may lead to structural changes in blood vessels, decreased blood vessel density and length, and increased vessel permeability737. In the current study we observed that cranial irradiation to the juvenile rat resulted in a lack of growth of the cerebellum, both in the gray and white matter.…”

“…Radiotherapy is one of the most effective treatments for brain tumors, but it is also a well-known risk factor for central nervous system injury3. Ionizing radiation induces oxidative stress, inflammation, stem/progenitor cell death, and microvascular injury4567, all of which can lead to progressive cognitive decline and other behavioral abnormalities at long-term follow up8910. These delayed and long-lasting adverse side effects of radiotherapy have serious impacts on the patient’s quality of life, and are recognized as important measurements of therapeutic outcomes of childhood brain tumors.…”

“…Irradiation of the cerebellum has multiple effects on its development, including reduction of its overall size, foliar/lobular malformations, and long-lasting blood-brain barrier (BBB) damage in the cerebrum and cerebellum of young mice7. A better understanding of irradiation-induced cerebellar pathology is needed to develop novel strategies to prevent the long-lasting side effects of radiotherapy.…”

Understanding and exploiting nanoparticles' intimacy with the blood vessel and blood

“…58,59 P-glycoproteins which remove foreign substances from the brain back to the blood circulation are expressed exclusively by the ECs of the blood brain barrier (BBB). The albumin permeability across the BBB was found to be 25-fold lower than that of the pulmonary microvascular beds (0.043 Â 10 À6 cm s À1 ), 82 aptly illustrates the restrictive nature of this understandably restrictive bed to protect a privileged organ, the brain. 40,61 In addition to the exclusive expression of these specific biomarkers, the endothelium bed heterogeneity is defined by differential or uneven expression pattern of the commonly shared ECs biomarkers.…”