Raspberry Ketones Attenuate Cyclophosphamide-Induced Pulmonary Toxicity in Mice through Inhibition of Oxidative Stress and NF-ΚB Pathway

Abstract

Cyclophosphamide (CP) was found to have a potential toxic effect on lung tissues. Raspberry ketones (RKs) are natural antioxidant chemicals isolated from red raspberries (Rubus ideaus). They are commonly used for weight loss and obesity. The current study aimed to evaluate the possible protective effects of RKs against lung toxicity induced by CP. Mice were allocated into six groups: (1) control group; (2) CP group: received a single intraperitoneal dose of CP (150 mg/kg, i.p.); and (3–6) mice were pre-treated orally with different doses of RKs (25, 50, 100, and 200 mg/kg) for 14 consecutive days, respectively, before the administration of an intraperitoneal dose of CP (150 mg/kg, i.p.). Mice were then sacrificed under anesthesia, then lungs were removed for histopathological and biochemical investigations. A single dose of CP markedly altered the levels of some oxidative stress biomarkers and resulted in the fragmentation of DNA in lung homogenates. Histological examination of CP-treated mice demonstrated diffuse alveolar damage that involved apparent hyalinization of membranes, thickening of inter alveolar septa, and proliferation of type II pneumocytes. The immunohistochemical results of CP-treated mice revealed strongly positive Bax and weakly positive proliferating cell nuclear antigen (PCNA) staining reactivity of the nuclei of the lining epithelium of the bronchioles and alveoli. CP activated the cyclooxygenase-2/nuclear factor-kappa B pathway. However, pre-treatment with RKs significantly attenuated CP-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. RKs may be suggested to be a potential candidate to ameliorate CP-induced pulmonary toxicity.