title: Short-term inhibition of ADP-induced platelet aggregation by clopidogrel ameliorates radiation-induced toxicity in rat small intestine.
abstract: Endothelial dysfunction and increased platelet aggregation may be involved in the pathogenesis of normal tissue radiation toxicity. This study assessed clopidogrel, an inhibitor of ADP-induced platelet aggregation, as a modulator of intestinal radiation injury (radiation enteropathy). Rat small intestine was exposed to 21 Gy X-radiation. Clopidogrel (20 mg/kg/day) or vehicle was administered from 2 days before to 10 days after irradiation. Structural radiation injury, neutrophil infiltration, smooth muscle cell proliferation, collagen content, and TGF-beta1 expression were assessed 2 weeks (early phase) and 26 weeks (delayed phase) after irradiation, using quantitative histology and immunohistochemistry, morphometry, and real-time fluorogenic probe RT-PCR. Irradiated intestine exhibited significant histopathologic injury, reduced mucosal surface area, vascular sclerosis, intestinal wall fibrosis, increased collagen content, and increased TGF-beta1 expression. Clopidogrel reduced ADP-induced platelet aggregation by 93% and significantly attenuated the severity of post-radiation vascular sclerosis (p = 0.004 and p = 0.02) and the loss of mucosal surface area (p = 0.0008 and p = 0.003) at both 2 and 26 weeks. Clopidogrel also ameliorated overall histopathologic injury (p = 0.02), relative intestinal collagen content (p = 0.03), and collagen III immunoreactivity levels 2 weeks after irradiation, and caused a borderline reduction in the radiation-induced increase in extracellular matrix-associated TGF-beta immunoreactivity at 26 weeks (p = 0.04). The effects of clopidogrel on steady-state TGF-beta1 mRNA levels and neutrophil infiltration were not statistically significant. Short-term clopidogrel administration affords protection against early and, to a lesser extent, delayed radiation enteropathy. Modulation of platelet aggregation should be subject to further studies as a potential method to increase safety and efficacy of radiation therapy.
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Albertson
authors.forename: Huaien
authors.initials: H
authors.lastname: Zheng
authors.forename: Louis M
authors.initials: LM
authors.lastname: Fink
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D000077144:Clopidogrel; D003094:Collagen / Q000032:analysis; D004730:Endothelium, Vascular / Q000473:pathology / Q000528:radiation effects; D004751:Enteritis / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000737:chemistry / Q000473:pathology; D005355:Fibrosis; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D009130:Muscle, Smooth / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D013988:Ticlopidine