Chlorisondamine, a sympathetic ganglionic blocker, moderates the effects of whole-body irradiation (WBI) on early host defense to a live bacterial challenge.

There is a growing consensus that long-term deficits in the brain are due to dynamic interactions between multiple neural and immune cell types. Specifically, radiation induces an inflammatory response, including changes in neuromodulatory pro- and anti-inflammatory cytokine secretion. The purpose of this study was to establish that there is sympathetic involvement in radiation-induced decrements early in in vivo immune function host defense. Female, 8-9 week-old C57BL/6J mice were exposed to whole-body irradiation (WBI). There were 8 groups with radiation (0 vs. 3 Gy protons), immune challenge (Escherichia coli) and exposure to the sympathetic ganglionic blocker, chlorisondamine (1 mg/kg weight, i.p.), as independent variables. Ten days post-irradiation, mice were inoculated with E. coli intraperitoneally and sacrificed 90-120 min later. The data suggest that radiation-induced changes in immune function may in part be mediated by the sympathetic nervous system. Briefly, we found that radiation augments the bacteria-induced inflammatory cytokine response, particularly those cytokines involved in innate immunity. However, this augmentation can be reduced by the ganglionic blockade.

Minocycline modulates cytokine and gene expression profiles in the brain after whole-body exposure to radiation.

An effective countermeasure against radiation damage to normal tissues is urgently needed. The major goal of the present study was to determine if minocycline could modify the immunomodulatory effects of radiation on the brain. C57BL/6 mice were treated with minocycline intraperitoneally for 5 days beginning immediately before total-body exposure to 0, 1, 2 and 3 Gray (Gy) (60)Co γ-rays. Brains were collected on days 4 and 32 post-irradiation for cytokine and gene analyses. Minocycline treatment significantly increased the levels of interleukin (IL)-10, IL-15 and vascular endothelial growth factor (VEGF) in the brain on day 4 in one or more irradiated groups compared to radiation-alone (p<0.05). IL-10 is anti-inflammatory, IL-15 can prevent apoptosis and VEGF is nuroprotective. On day 32, the drug decreased IL-1ß in the 2- Gy group (p<0.05 vs. 2-Gy alone); this cytokine is implicated in immune-related central nervous system pathologies. Microarray analysis of brains on day 32 showed that while radiation increased expression of inflammatory genes such as Il1f10, Il17, Tnfrsf11b, Tnfsf12, Il12b and Il1f8, these were no longer up-regulated in the minocycline-treated groups. Similarly, the pro-apoptotic gene Bik and nitric oxide synthase producer (Nostrin) were no longer up-regulated in the drug-treated groups. Pathway analysis based on gene data suggested that catenin-ß1 and tumor suppressor-related transcription regulation were significantly activated by radiation and/or minocycline (activation z-score >2.0). Overall, the data warrant further testing of minocycline as a potential neuroprotectant against radiation-induced damage.

Effects of minocycline on hematopoietic recovery after whole-body irradiation.

BACKGROUND/AIM: We previously found that minocycline enhanced the levels of several leukocyte populations and had the capacity to induce secretion of certain cytokines early after irradiation. In the current study we further determined the drug's effect on hematopoietic recovery. MATERIALS AND METHODS: Minocycline was injected intraperitoneally into C57BL/6 mice for 5 days, beginning immediately before exposure to (60)Co γ-rays (1, 2, 3 Gy). Thirty-two days post-irradiation, spleen and blood were collected to quantify cell populations, cytokines in splenic T-cell supernatants after anti-CD3 activation, and chromosomic status based on spectral karyotyping. RESULTS: While radiation resulted in significantly lower B-cell counts at 3 Gy in both blood and spleen, minocycline treatment increased the counts and/or percentages of splenic B-cells at 2 Gy and 3 Gy. In spleen supernatants, the drug-alone increased the levels of cytokines, including interleukin-1α (IL-1α) and IL-6 that are radioprotective, as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF that accelerate neutrophil recovery. In addition, minocycline suppressed the production of interferon-γ that can prevent hematopoiesis. Dose-dependent radiation-induced chromosomic abnormalities were present in splenic leukocytes. CONCLUSION: The data indicate that minocycline exerts a relatively long-term effect on parameters that influence hematopoietic recovery. Further testing of this drug as a countermeasure for acute radiation syndrome, is necessary to determine its full potential.

Analysis of minocycline as a countermeasure against acute radiation syndrome.

BACKGROUND/AIM: To evaluate the impact of an antibiotic, minocycline, on several immune parameters in response to radiation in a mouse model. MATERIALS AND METHODS: C57BL/6 mice were treated with minocycline (i.p.) for 5 days, beginning immediately before radiation with 1-3 Gy (60)Co γ-rays. Spleen and blood were collected on day 4 post-irradiation. Cell populations were determined in the blood and spleen. Splenocytes were activated with anti-CD3 antibody for 48 h and cytokines were quantified. RESULTS: Minocycline increased the counts and/or percentages of splenic macrophages, granulocytes, natural killer, T- and CD8(+) T-cells (p<0.05 versus radiation alone). Minocycline significantly increased the expression of interleukin-1α and ß, which are radioprotective, as well as the ones of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, which accelerate neutrophil recovery (p<0.05 versus radiation alone), while suppressing cytokines that could prevent hematopoiesis, e.g. macrophage inflammatory protein-1α, tumor necrosis factor-α and interferon-γ. CONCLUSION: These data indicate that minocycline should be further tested for use in restoration of the hematopoietic system after radiation exposure.

Anomalous high pressure behaviour in nanosized rare earth sesquioxides.

We report Raman spectroscopic studies of the nanosized rare earth sesquioxides, namely yttrium sesquioxide (Y(2)O(3)), gadolinium sesquioxide (Gd(2)O(3)) and samarium sesquioxide (Sm(2)O(3)), under high pressure. The samples were characterized using x-ray diffraction, Raman spectroscopy and atomic force microscopy at atmospheric pressures. Y(2)O(3) and Gd(2)O(3) were found to be cubic at ambient, while Sm(2)O(3) was found to be predominantly cubic with a small fraction of monoclinic phase. The strongest Raman peaks are observed at 379, 344 and 363 cm(-1), respectively, for Y(2)O(3), Sm(2)O(3) and Gd(2)O(3). All the samples were found to be nanosized with 50-90 nm particle sizes. The high pressures were generated using a Mao-Bell type diamond anvil cell and a conventional laser Raman spectrometer is used to monitor the pressure-induced changes. Y(2)O(3) seems to undergo a crystalline to partial amorphous transition when pressurized up to about 19 GPa, with traces of hexagonal phase. However, on release of pressure, the hexagonal phase develops into the dominant phase. Gd(2)O(3) is also seen to develop into a mixture of amorphous and hexagonal phases on pressurizing. However, on release of pressure Gd(2)O(3) does not show any change and the transformation is found to be irreversible. On the other hand, Sm(2)O(3) shows a weakening of cubic phase peaks while monoclinic phase peaks gain intensity up to about a pressure of 6.79 GPa. However, thereafter the monoclinic phase peaks also reduce in intensity and mostly disordering sets in which does not show significant reversal as the pressure is released. The results obtained are discussed in detail.