Evaluation of neurotoxicity of artificial dura mater and poly(lactic-glycolic acidcaprolactone) co-oligomer containing dibutyltin or tin (II) octylate in rats

  • Tsuji Masayoshi
    Department of Hygiene and Preventive Medicine, Fukushima Medical University School of Medicine
  • Tsunoda Masashi
    Department of Preventive Medicine, Kitasato University School of Medicine
  • Sugaya Chiemi
    Department of Preventive Medicine, Kitasato University School of Medicine
  • Inoue Yoko
    Graduate School of Medical Sciences, Kitasato University
  • Hirano Sachiko
    Kanagawa Prefectural Office
  • Katagiri Hiroshi
    Department of Public Health, Kitasato University School of Allied Health Sciences
  • Akita Hisanao
    Department of Physiology, Kitasato University School of Allied Health Sciences
  • Saji Makoto
    Department of Physiology, Kitasato University School of Allied Health Sciences
  • Yuba Toshiyasu
    Kawasumi Laboratories, Inc.
  • Fukushima Tetsuhito
    Department of Hygiene and Preventive Medicine, Fukushima Medical University School of Medicine
  • Tsuchiya Toshie
    Division of Medical Devices, National Institute of Health Sciences
  • Aizawa Yoshiharu
    Department of Preventive Medicine, Kitasato University School of Medicine

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Objectives: A synthetic biodegradable artificial dura mater (DM) can provide benefits such as helping to avoiding viral infections. The major component of this artificial DM is poly (lactic-glycolic acid-caprolactone) co-oligomer (PLGC). For synthesis of the DM, a catalyst containing dibutyltin (DBT) and tin (II) octylate (OT) is used. DBT and OT remain in the DM. To establish a model for the evaluation of the safety of the DM, after intracranial implantation of each 1-cm-diameter disk, the maximum size for rats, the neurotoxic effects of the DM and a PLGC containing 100 ppm DBT (DBT-PLGC) or 200 ppm OT (OT-PLGC) were evaluated.<br>Methods: A circular disk of cranial bone of 1 cm in diameter was cut from each rat's skull. The artificial DM, DBTPLGC, or OT-PLGC was implanted onto the surface of the brain of each rat (the DM, DBT-PLGC, and OT-PLGC groups). The control group underwent a sham operation. Four weeks after the implantation, prepulse inhibition (PPI) and open field tests were performed. The neurotransmitters in discrete brain regions were determined by highperformance liquid chromatography.<br>Results: There was severe damage to the brains of several rats. There were no significant differences among the groups in any indexes in the PPI or open field tests. The mean value of dopamine in the hypothalamus in the DM group was significantly higher compared to that in the other groups. The mean 5-HIAA/5-HT in the midbrain of the DM group was significantly higher than that in the control group.<br>Conclusion: Although the effects of DM after the implantation were slight under the current protocol, further studies are required because of the severe damage most likely induced by the implantation. As an experimental model, if the circular cranial bone disk cut out were 8 mm in diameter, it may provide better results with less damage to the brain.

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