Radiation-Induced Blood-Brain Barrier Changes: Pathophysiological Mechanisms and Clinical Implications
The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fraction
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Radiation-Induced Blood-Brain Barrier Changes: Pathophysiological Mechanisms and Clinical Implications D. d'Avella\ R. Cicciarello2, F. F. Angileri 1, S. Lncerna 1, D. La Torre\ and F. Tomasello Neurosurgical Clinic and Institute of Oncology of the University of Messina Medical School, Messina, Italy
Summary The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 ± cGy/d, 5 d/wk; total dose, 4,000cGy). BBB changes were assessed by means of the quantitative 14C-o.-aminoisobutyric acid (AlB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AlB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, welldefined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.
Keywords: Blood-brain barrier; radiation.
Introduction Radiotherapy plays an important role in supplementing surgical and medical therapy for malignant cerebral tumors. WBR can produce acute and chronic effects in the central nervous system (CNS) which range from transient functional changes to overt encephalopathy with widespread morphological changes and, occasionally, late parenchymal necrosis [6]. All these effects have well-known clinical importance, particularly in young patients in whom longterm intellectual and neuropsychological impairment have been reported after therapeutic irradiation [8].
Though widely investigated, the pathogenesis of WBR adverse reactions remains a subject of continuing controversy. Brain dysfunction has been ascribed either to alterations in the cerebral microvasculature leading to BBB dysfunction and brain edema and/ or ischemia, to demyelinization phenomena, or to metabolic alterations [3,7,9]. Previous work from our laboratory has documented the feasibility of using a rodent model employing fractionated WBR to study radiation-induced structural and functional changes in the CNS and their temporal progression [2-5]. The present study further examined potentially adverse effects of WBR in this model and was des
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