Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
PLoS One. 2013 Jul 26;8(7):e69106. doi: 10.1371/journal.pone.0069106. Print 2013.
Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation-induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg) starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG) function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240±8 vs. 165±10, P<0.01). This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27±8 vs. 149±22, in 1,000 erythrocytes, P<0.01). JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy.
基于先前关于组胺对高度敏感组织的放射防护作用的数据，本研究旨在研究 H4R 配体 JNJ7777120 对电离辐射诱导的小肠、唾液腺和造血组织损伤和遗传毒性损伤的放射防护潜力。为此，将大鼠分为 4 组。JNJ7777120 和 JNJ7777120-照射组在照射前 24 小时开始每天接受一次皮下 JNJ7777120 注射（10mg/kg）。照射组接受全身单次 5Gy 的铯-137 源照射，并在照射后 3 或 30 天处死。取出组织，固定，用苏木精和伊红或 PAS 染色染色，并评估组织学特征。通过免疫组织化学研究增殖和凋亡标志物，通过微核试验评估 DNA 损伤。通过乙酰甲胆碱诱导的唾液分泌评估颌下腺（SMG）功能。结果表明，JNJ7777120 治疗减少了辐射暴露后的粘膜萎缩和绒毛保留以及隐窝数量（240±8 对 165±10，P<0.01）。这种作用与肠隐窝中凋亡和 DNA 损伤的减少有关。JNJ7777120 减少了辐射引起的再生障碍，保留了骨髓成分，减少了微核的形成，并且加速了骨髓再填充。此外，它还降低了外周血中的微核频率（1000 个红细胞中 27±8 对 149±22，P<0.01）。JNJ7777120 完全逆转了辐射引起的唾液分泌减少，保持了腺体质量的正常组织学外观，并减少了 SMG 的凋亡和萎缩。JNJ7777120 对小肠、SMG 和造血组织的辐射诱导细胞毒性和遗传毒性损伤具有放射防护作用，因此对接受放射治疗的患者可能具有临床价值。
