Protection of radiation-induced damage to the hematopoietic system, small intestine and salivary glands in rats by JNJ7777120 compound, a histamine H4 ligand.
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.
Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Diego J
DJ
Martinel Lamas
Eliana
E
Carabajal
Juan P
JP
Prestifilippo
Luis
L
Rossi
Juan C
JC
Elverdin
Susana
S
Merani
Rosa M
RM
Bergoc
Elena S
ES
Rivera
Vanina A
VA
Medina
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006413:Hematopoietic System / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D008024:Ligands; D008297:Male; D009153:Mutagens / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012469:Salivary Glands / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D013438:Sulfhydryl Compounds / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014916:Whole-Body Irradiation
C498828:Hrh4 protein, rat; D007211:Indoles; D008024:Ligands; D009153:Mutagens; D010879:Piperazines; D011837:Radiation-Protective Agents; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine