Radioprotective efficacy of GSH based peptidomimetic complex of manganese against radiation induced damage: DT(GS)2Mn(II)

Free Radic Biol Med. 2019 Dec:145:161-174. doi: 10.1016/j.freeradbiomed.2019.09.023. Epub 2019 Sep 21.

Abstract

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn2+ in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)2Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)2Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)2Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ± 0.14) compared to radiation alone group (1.60 ± 0.07) was observed. DT(GS)2Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)2Mn(II) with an average of 1546 ± 61 μm versus 763 ± 154 μm for radiation alone group. The present findings suggested DT(GS)2Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.

Keywords: DT(GS)(2)Mn(II); Glutathione; Manganese; Radiation; Radioprotection; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Radiation-Induced / drug therapy*
  • Abnormalities, Radiation-Induced / metabolism
  • Abnormalities, Radiation-Induced / pathology
  • Acetylcysteine / metabolism
  • Animals
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • DNA Damage / drug effects
  • DNA Damage / radiation effects
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Glutathione / chemistry
  • Glutathione / pharmacology*
  • Humans
  • Manganese / chemistry
  • Manganese / metabolism
  • Mice
  • Oxidative Stress / drug effects
  • Oxidative Stress / radiation effects
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Radiation, Ionizing
  • Radiation-Protective Agents / chemistry
  • Radiation-Protective Agents / pharmacology*

Substances

  • Peptidomimetics
  • Radiation-Protective Agents
  • Manganese
  • Glutathione
  • Acetylcysteine