The central nervous system (CNS) is a major dose-limiting organ in clinical …

• Abstract
• Introduction
• Specific cell types in the central nervous system and their function
• Clinical radiation therapy
• Histopathologic changes
• Early gene induction
• Apoptosis
• Inhibition of neurogenesis
• Hypoxia, barrier disruption, and necrosis of the white matter
• ICAM-1
• Cell replacement
• Reducing apoptotic cell death
• Reducing secondary cell death
• Conclusion
• References
• Figure

Biology Articles » Biophysics » Medical Biophysics » Mechanisms of radiation injury to the central nervous system: implications for neuroprotection » ICAM-1

ICAM-1

- Mechanisms of radiation injury to the central nervous system: implications for neuroprotection

The other class of proteins that are implicated in VEGF-mediated permeability increase is the adhesion molecules. Increased ICAM- 1 expression is associated with a diversity of CNS injury models where BBB disruption is present (79–81). Radiation-induced upregulation of adhesion molecules in the vasculature has been well documented for other organs (82). VEGF increases the expression of ICAM-1 in the CNS and in cultured brain microvascular endothelial cells (65, 83, 84).

ICAM-1 expression increases in white matter, but not in gray matter of rat spinal cord following a myelopathic dose of 22 Gy. The majority of glial cells expressing ICAM-1 appeared to be astrocytes. After 22 Gy, total ICAM-1 protein increased (at twentyfour hours post-irradiation), and was again elevated at seventeen to twenty weeks post-treatment. The time course, dose response, and spatial distribution of increased ICAM-1 expression paralleled the observations of BSCB disruption and albumin leakage (11). ICAM-1–mediated leukocyte binding, cytoskeletal rearrangements, and signaling to tight junctions may all contribute to barrier disruption (85, 86). Given the central role of ICAM-1 in the inflammatory status of endothelial cells, these findings are again consistent with the role of "inflammation" in propagating the CNS damage after XRT.

TARGETING DAMAGE PATHWAY FOR NEUROPROTECTION
The data described suggest a model in which cell death and microenvironmental changes impacting cell fate and cell interactions contribute to tissue injury. We hypothesize that clonogenic cell death of endothelial cells following XRT initiates the initial breakdown of the BBB. This leads to vasogenic edema, ischemia, and hypoxia. Hypoxia induces HIF1-mediated increases in VEGF expression that, in turn, leads to a secondary damage cascade with further increase in vascular permeability, hypoxia, VEGF and ICAM-1 expression, and subsequent demyelination, and tissue necrosis. These finding have implications for neuroprotective strategies (Figure 1).