XRT produces a variety of DNA and other cellular lesions that elicit a stress response. Altered gene profiles are one characteristic feature of this response. In the rodent CNS, increased expression of pro-inflammatory and other genes has been demonstrated within hours following XRT (28–31). These include genes of transcription factors such as nuclear factor–kappa B (NF-
B), cytokines such as tumor necrosis factor–
(TNF) and interleukin-1ß (IL-1ß), and basic fibroblast growth factor (bFGF). NF-B is important in the regulation of cytokine expression, including expression of TNF and IL1ß, both of which have been implicated in the development of demyelination (32). The expression of TNF is associated with edema observed after ischemic and hypoxic injury (33), and is also a key regulator of intercellular adhesion molecule-1 (ICAM- 1), which is associated with BBB disruption in a variety of injuries (34). Increased ICAM-1 expression has been observed in mouse brain and rat spinal cord within twenty-four hours after XRT (11, 35, 36).
In mouse brain after XRT, we observed an early dose- and time-dependent induction of ICAM-1 and heme oxygenase 1 (HO- 1). In animal models of impaired oxidative metabolism, induction of ICAM-1 paralleled the induction of HO-1 (which is a marker of oxidative stress) and subsequent neuronal death (37). Conversely, HO-1 modulates the expression of pro-inflammatory genes associated with endothelial cell activation (38). Modulating the expression of ICAM-1 and HO-1 may serve as a neuroprotective strategy against early radiation-induced BBB disruption and neuronal loss.
Similar to other CNS injury models associated with an increase in reactive oxygen species and a state of oxidative stress, the same was observed in the irradiated CNS. Amounts of malonaldehyde (MDA), an end product of lipid peroxidation, were elevated in mouse brain from six hours through seven days after XRT (17 Gy dose) to the whole cranium (unpublished data). MDA was elevated in the mouse hippocampus at one week after a dose of 10 Gy, and cells immunoreactive for MDA were observed in the dentate gyrus at twenty-four hours (39). Oxidative stress and increases in reactive oxygen species are likely to interact with radiation- induced altered gene profiles and to participate in responses to irradiation of the CNS.
Using cDNA microarrays, we have recently studied global gene expression in mouse brain during the first twenty-four hours after whole cranial XRT. XRT modulated the expression pattern of 192 genes (
2.5-fold change), with sixty-three genes of known function and 129 as expressed sequence tags (ESTs). Gene expression profiles appeared to be dose- and time-dependent. Genes that were modulated at fifteen minutes after XRT were principally those involved in protein transport and biosynthesis, apoptosis, metabolism, or DNA repair. Those genes whose expression was altered at twenty-four hours post-treatment were generally involved in signal transduction, metabolism, cell cycle, and transcription (unpublished data). Real-time PCR of selected genes of interest confirmed similar expression changes after XRT, as had been identified by microarray analysis, which allows the identification of novel genes that may play a role in CNS radiation injury and offers the potential to elucidate novel molecular targets for neuroprotection.
Answers to all your Biology Questions
