Abstract
Ionizing radiation (IR) acts as an external stimulating factor, when it acts on the body, it will activate NF-B and cause the up-regulation of inducible nitric oxide synthase (iNOS) and induce a large amount of nitric oxide (NO) production. NO and other reactive nitrogen and oxygen species (RNS and ROS) can cause damage to biological molecules and affect their physiological functions. Our study investigated the protective role of 2-amino-5,6-dihydro-4H-1,3-thiazine hydrobromide (2-ADT) and 2-acetylamino-5,6-dihydro-4H-1,3-thiazine hydrobromide (2-AADT), two nitric oxide synthase inhibitors, against radiation-induced hematopoietic and intestinal injury in mice. Pretreatment with 2-ADT and 2-AADT improved the survival of mice exposed to a lethal dose of radiation, especially, the survival rate of the 2-ADT 20 mg/kg group was significantly higher than that of the vehicle group (p < 0.001). Our findings indicated that the radioprotective actions of 2-ADT and 2-AADT are achieved via accelerating hematopoietic system recovery, decreasing oxidative and nitrosative stress by enhancing the antioxidant defense system and reducing NO as well as peroxynitrite (ONOO) content, and mitigating the radiation-induced DNA damage evaluated by comet assay. These results suggest that 2-ADT and 2-AADT may have great application potential in ameliorating the damages of radiotherapy.
Highlights
Radiotherapy is an important treatment modality for various malignancies and severe diseases [1], but these adverse side effects such as hematopoietic and gastrointestinal dysfunction even death caused by radiation reduce the patients’ quality of life and limit their radiation therapy
A considerable amount of literatures have shown that ionizing radiation can cause a large increase in nitric oxide (NO) levels, and its excessive production can lead to cytotoxic actions and mediate inflammation [27], and NO is a mediator of radiation-induced tissue damage and a negative regulator of hematopoietic stem cell activity [7,13]
Evidence suggests that NOS inhibitors can act as radioprotectors by attenuating radiation-induced elevation of NO or inducing hypoxia [2,12,14]. 2-ADT and 2-AADT are potent inhibitors of nitric oxide synthase and early study indicated that the radioprotective activity of 2-ADT was not attributable to the oxygen effect [28]
Summary
Radiotherapy is an important treatment modality for various malignancies and severe diseases [1], but these adverse side effects such as hematopoietic and gastrointestinal dysfunction even death caused by radiation reduce the patients’ quality of life and limit their radiation therapy. Evidence that the leading mechanism of the radioprotective effect of NOS inhibitors among isothiourea derivatives is the induction of hypoxia was provided by Filimonova MV in 2014 [14]. Drugs such as catecholamines, serotonin and other vasoactive agents provide radiation protection by inducing tissue hypoxia through their pharmacological activities in bone marrow or spleen [15,16,17]. The 30-day survival rate of mice, effects of 2-ADT and 2-AADT on hematopoietic system, antioxidant defense system, DNA damage, NO content, the crypt-villus structure of the small intestine and proliferation and differentiation of intestinal cells in irradiated mice were respectively assessed
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