Radiation research
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Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later. Compared to sham-irradiated rats, the irradiated rats demonstrated impaired MWM performance. ⋯ Further analysis of CA1 revealed that the relative levels of the GluR1 and GluR2 subunits of the AMPA receptor and synaptophysin were not altered by whole-brain irradiation. In summary, a clinically relevant regimen of fractionated whole-brain irradiation led to significant impairments in spatial learning and reference memory and alterations in the relative levels of subunits of the NMDA, but not the AMPA, receptors in hippocampal CA1. These findings suggest for the first time that radiation-induced cognitive impairments may be associated with alterations in glutamate receptor composition.
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Selective irradiation of the vasculature of the rat spinal cord was used in this study, which was designed specifically to address the question as to whether it is the endothelial cell or the glial progenitor cell that is the target responsible for late white matter necrosis in the CNS. Selective irradiation of the vascular endothelium was achieved by the intraperitoneal (ip) administration of a boron compound known as BSH (Na(2)B(12)H(11)SH), followed by local irradiation with thermal neutrons. The blood-brain barrier is known to exclude BSH from the CNS parenchyma. ⋯ The response to irradiation with an equivalent dose of X rays (ED(90): 23 Gy) was intermediate between these extremes as it was to thermal neutrons in the presence of BPA at a slightly lower dose equivalent to the approximate ED(60) for radiation myelopathy. The conclusions from these studies, performed at dose levels approximately iso-effective for radiation-induced myelopathy as a consequence of white matter necrosis, were that the large differences observed in glial progenitor survival were directly related to the dose distribution in the parenchyma. These observations clearly indicate the relative importance of the dose to the vascular endothelium as the primary event leading to white matter necrosis.
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Although conclusive evidence has been obtained for the presence of radiation-induced bystander effects, the mechanisms that trigger and regulate these processes are still largely unknown. The bystander effect may play a critical role in determining the biological effectiveness of low-dose exposures, but questions on how to incorporate it into current models and extrapolate the risks of radiation-induced carcinogenesis are still open. The Gray Cancer Institute soft X-ray microbeam has been used to investigate the dose-response relationship of the bystander effect below 0.5 Gy. ⋯ This suggests that the event that triggers the emission of the bystander signal by the hit cell is an all-or-nothing process. Extrapolation of the data indicates that when a single fast electron traverses a V79 cell, there is a probability of approximately 0.3% that the cell will emit the bystander signal. The data presented in this paper have also been analyzed statistically to test the possibility that complex DNA double-strand breaks may be the initial critical event.
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Experiments have been performed to measure the response of a spherical tissue-equivalent proportional counter (TEPC) and a silicon-based LET spectrometer (RRMD-III) to protons with energies ranging from 50-200 MeV. This represents a large portion of the energy distribution for trapped protons encountered by astronauts in low-Earth orbit. The beam energies were obtained using plastic polycarbonate degraders with a monoenergetic beam that was extracted from a proton synchrotron. ⋯ The TEPC cannot measure the LET distribution directly. However, the frequency mean value of lineal energy, y(-)(f), provided a good approximation to LET. This is in contrast to previous results for high-energy heavy ions where y(-)(f) underestimated LET, whereas the dose-averaged lineal energy, y(-)(D), provided a good approximation to LET.
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The ability of thiol-containing reducing agents to activate transcription factors leading to changes in gene expression and enzyme activities provides an additional mechanism to potentially protect against radiation-induced cell killing. Manganese superoxide dismutase (Sod2) is one such gene whose expression levels have been shown to be elevated after exposure to the thiol compounds WR-1065 and N-acetyl-L-cysteine (NAC), resulting in an increase in radiation resistance. To further characterize this effect, SA-NH sarcoma cells, both wild-type and a clone stably transfected with a plasmid containing an IkappaBalpha gene mutated at serines 32 and 36, which prevents the inducible phosphorylation of these residues and the subsequent activation of NFkappaB (SA-NH+mIkappaBalpha1), were grown to confluence and then exposed to amifostine's free thiol WR-1065 at a concentration of 4 mM for 30 min. ⋯ All four thiols were protective if irradiation with 2 Gy occurred 24 h later; i.e. increases in survival of 1.40, 1.22, 1.35, and 1.25 times were found for WR-1065, captopril, mesna and NAC, respectively. This delayed radioprotective effect correlated with elevated Sod2 protein levels in wild-type SA-NH tumor cells but was not observed in SA-NH+mIkappaBalpha1 cells, indicating that interference with thiol-induced NFKB activation abrogates this delayed radioprotective effect. Because the delayed radioprotective effect is readily demonstrable at a radiation dose of 2 Gy 24 h after exposure to clinically approved thiol-containing drugs such as amifostine, captopril, mesna and NAC, it suggests a new potential concern regarding the issue of tumor protection and the use of these agents in cancer therapy.