Vol. 2, 2017



Masatsugu Ohgami, Nobuhiko Takai, Masahiko Watanabe, Koichi Ando, Akiko Uzawa, Ryoichi Hirayama

Pages: 6-10

DOI: 10.21175/RadProc.2017.02

The intestinal crypt stem cells in gut have a high growth potential and radiosensitivity, it is dose-dependently reduced by heavy-ion irradiation and intestinal death occurs by arrest of epithelial cells supply in high dose area. The radiation to abdominal cancer, for example uterus and bladder, could give impairments not only on tumor, but also on gut nearby target. Therefore, the development of radioprotective agents for gut may contribute to more effective and less harmful heavy-ion therapy. N-methyl-D-aspartate receptor (NMDAR) is one of glutamate receptors and NMDAR antagonist has been reported to prevent the radiation-induced injuries in the central nervous system. Thus, we examined whether the peripheral NMDAR activation is a possible cause of gut injuries in mice irradiated with carbon-ion beam. We compared the dose-dependent change in the number of crypts after irradiation between treated MK-801 (0.1 mg/kg), a noncompetitive NMDAR antagonist, and untreated mice in order to confirm a MK-801 radioprotective effect on crypts. Compared with the sham group, the number of crypts in MK-801 group was significantly increased at 12.0 Gy or over. The radiolabeled [3H]MK-801 was intravenously injected with C3H female mice received 9 Gy whole body irradiation (290 MeV/u, 20 keV/μm). The significant increase was observed in [3H]MK-801 at 24 hr and 48 hr after irradiation, followed by decrease thereafter. These results suggest that intestinal NMDAR are most activated at 48 hr after carbon-ion irradiation. Thus, we suggested that radiation-induced gut injuries could be suppressed by NMDAR antagonists as radioprotective agents until 48 hr after carbon-ion exposure.
  1. T. Kamada, “Outline of Heavy Ion Radiotherapy,” in Proc. 2nd Int. Symp. on Heavy-Ion Radiotherapy and Advanced Technology, Tokyo, Japan, 2016, pp. 1-4
    Retrieved from: http://www.nirs.qst.go.jp/rd/reports/proceedings/pdf/2nd_International_Symposium_2016.pdf
    Retrieved on: Feb. 01, 2017
  2. Y. Yoshida et al., “Evaluation of therapeutic gain for fractionated carbon-ion radiotherapy using the tumor growth delay and crypt survival assays,” Radiother. Oncol, vol. 117,no. 2, pp. 351–357, Nov. 2015.
    DOI: 10.1016/j.radonc.2015.09.027
    PMid: 26454348
  3. T. Ohno, “Particle radiotherapy with carbon ion beams,” EPMA J, vol. 4,no. 9, Mar. 2013.
    DOI: 10.1186/1878-5085-4-9
  4. A. Dubois, R. I. Walker, “Prospects for Management of Gastrointestinal Injury Associated with the Acute Radiation Syndrome,” Gastroenterology, vol. 95,no. 2, pp. 500–507, Aug. 1988.
    Retrieved from: http://www.sciencedirect.com/science/article/pii/0016508588905124
    Retrieved on: Feb. 01, 2017.
  5. M. M. Bismar, F. A. Sinicrope, “Radiation enteritis,” Curr. Gastroenterol. Rep., vol. 4,no. 5, pp. 361–365, Oct. 2002.
    DOI: 10.1007/s11894-002-0005-3
    PMid: 12228037
  6. C. G. Rousseaux, “A Review of Glutamate Receptors I: Current Understanding of Their Biology,” J Toxicol. Pathol., vol. 21,no. 1, pp. 25–51, Apr. 2008
    DOI: 10.1293/tox.21.25
  7. S. F. Traynelis et al., “Glutamate Receptor Ion Channels: Structure, Regulation, and Function,” Pharmacol. Rev., vol. 62,no. 3, pp. 405–496, Sep. 2010.
    DOI: 10.1124/pr.109.002451
    PMid: 20716669
    PMCid: PMC2964903
  8. K. G. Dickman et al., “Ionotropic Glutamate Receptors in Lungs and Airways,” Am. J. Respir. Cell Mol. Biol., vol. 30,no. 2, pp. 139–144, Feb. 2004.
    DOI: 10.1165/rcmb.2003-0177OC
    PMid: 12855408
  9. J. W. Olney, “Excitotoxic Amino Acids and Neuropsychiatric Disorders,” Annu. Rev. Pharmacol. Toxicol., vol. 30, pp. 47–71, Apr. 1990.
    DOI: 10.1146/annurev.pa.30.040190.000403
    PMid: 2188577
  10. D. W. Choi, “Excitotoxic cell death,” J. Neurobiol., vol. 23,no. 9, pp. 1261–1276, Nov. 1992.
    DOI: 10.1002/neu.480230915
    PMid: 1361523
  11. Y. M. Lu, “Ca2+-Permeable AMPA/Kainate and NMDA Channels: High Rate of Ca2+ Influx Underlies Potent Induction of Injury,” J. Neurosci., vol. 16,no. 17, pp. 5457–5465, Sep. 1996.
    Retrieved from: http://www.jneurosci.org/content/jneuro/16/17/5457.full.pdf
    Retrieved on: Feb. 01, 2017.
  12. C. G. Rousseaux, “A Review of Glutamate Receptors II: Pathophysiology and Pathology,” J. Toxicol. Pathol., vol. 21,no. 3, pp. 133–173, Oct. 2008.
    DOI: 10.1293/tox.21.133
  13. L. Tenneti et al., “Role of Caspases in N-Methyl-D-Aspartate-Induced Apoptosis in Cerebrocortical Neurons,” J. Neurochem., vol. 71,no. 3, pp. 946–959, Sep. 1998.
    DOI: 10.1046/j.1471-4159.1998.71030946.x
    PMid: 9721720
  14. T. Fuchigami et al., “Development of PET and SPECT probes for glutamate receptors,” Scientific World Journal, vol. 2015,no. 716514, Mar. 2015.
    DOI: 10.1155/2015/716514
  15. J. A. McRoberts et al., “Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats,” Gastroenteoloy, vol. 120,no. 7, pp. 1737–1748, Jun. 2001.
    DOI: 10.1053/gast.2001.24848
  16. H. Chen et al., “Identification of a homocysteine receptor in the peripheral endothelium and its role in proliferation,” J. Vasc. Surg., vol. 41,no. 5, pp. 853–860, May. 2005.
    DOI: 10.1016/j.jvs.2005.02.021
  17. H. Wang et al., “Peripheral NMDA receptors contribute to activation of nociceptors: a c-fos expression study in rats,” Neurosci Lett, vol. 221,no. 2-3, pp. 101–104, Jan. 1997.
    DOI: 10.1016/S0304-3940(96)13299-7
  18. C. G. Parsons, “NMDA receptors as targets for drug action in neuropathic pain,” Eur. J. Pharmacol., vol. 429,no. 1-3, pp. 71–78, Oct. 2001.
    DOI: 10.1016/S0014-2999(01)01307-3
  19. A. B. Petrenko et al., “The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review,” Anesth. Analg., vol. 97,no. 4, pp. 1108–1116, Oct. 2003.
    DOI: 10.1213/01.ANE.0000081061.12235.55
    PMid: 14500166
  20. W. Rzeski et al., “Glutamate antagonists limit tumor growth,” Proc. Natl. Acad. Sci. USA, vol. 98,no. 11, pp. 6372–6377, May. 2001.
    DOI: 10.1073/pnas.091113598
  21. G. A. Mickley et al., “Serial injections of MK 801 (Dizocilpine) in neonatal rats reduce behavioral deficits associated with X-ray-induced hippocampal granule cell hypoplasia,” Pharmacol. Biochem. Behav., vol. 43,no. 3, pp. 785–793, Nov. 1992.
    DOI: 10.1016/0091-3057(92)90409-9
  22. E. H. Wong et al., “The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist,” Proc. Natl. Acad. Sci. USA, vol. 83,no. 18, pp. 7104–7108, Sep. 1986.
    Retrieved from: http://www.pnas.org/content/83/18/7104.full.pdf
    Retrieved on: Feb. 01, 2017.
  23. J. F. MacDonald et al., “Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones,” J. Pysiol., vol. 432,no. 1, pp. 483–508, Jan. 1991.
    DOI: 10.1113/jphysiol.1991.sp018396
  24. A. Uzawa et al., “Comparison of biological effectiveness of carbon-ion beams in Japan and Germany,” Int. J. Radiat. Oncol. Biol. Pys., vol. 73,no. 5, pp. 1545–1551, Apr. 2009.
    DOI: 10.1016/j.ijrobp.2008.12.021
    PMid: 19306751
  25. A. Balla et al., “Continuous phencyclidine treatment induces schizophrenia-like hyperreactivity of striatal dopamine release, Neuropsychopharmacol., vol. 25,no. 2, pp. 157–164, Aug. 2001.
    DOI: 10.1016/S0893-133X(01)00230-5
  26. J. A. Harder et al., “Learning impairments induced by glutamate blockade using dizocilpine (MK-801) in monkeys,” Br. J. Pharmacol., vol. 125,no. 5, pp. 1013–1018, Nov. 1998.
    DOI: 10.1038/sj.bjp.0702178
    PMid: 9846639
    PMCid: PMC1565679