Role of nitric oxide donor in methotrexate-induced testicular injury via modulation of pro-inflammatory mediators, eNOS and P-glycoprotein.

Methotrexate (MTX) is a widely used chemotherapeutic agent but its clinical use is challenged with different forms of toxicities including testicular injury. The aim of the current study was to evaluate the potential protective effect of potassium channel opener, nicorandil (NIC) (3 and 10 mg/kg/day) on MTX-induced testicular injury in a rat model. Rats were randomly divided into four groups (nine rats each) and treated for 2 weeks as follows: (I) normal control (CON group) received vehicle, (II) model group (MTX group) given MTX (20 mg/kg) single intraperitoneal (i.p.) injection dose on 11th day, (III) MTX + NLD group treated with NIC (3 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. dose on 11th day, and (IV) MTX + NHD group treated with NIC (10 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. injection on the 11th day. The testicular injury was assessed biochemically via serum testosterone, total antioxidant capacity, testicular oxidative stress parameters, P-glycoprotein, tumor necrosis factor-alpha, and interleukin-1ß. Furthermore, histopathological evaluation, endothelial nitric oxide synthase (eNOS) immunoexpression, and detection of p53 expression level using Western blotting were performed. Results showed that MTX induced testicular injury which was proved by both biochemical and histopathological evaluations. Our results concluded that NIC pretreatment attenuated MTX-induced testicular injury via significantly increased eNOS immunoexpression, antiapoptotic, anti-inflammatory, and antioxidant properties. Interestingly, NIC high dose is more protective than low dose.

Purine versus non-purine xanthine oxidase inhibitors against cyclophosphamide-induced cardiac and bone marrow toxicity in rats.

BACKGROUND AND AIM: Cancer is a fatal and serious disease. Cyclophosphamide (CYC) is a commonly used anticancer drug. Cardiotoxicity and myelotoxicity are life-threatening side effects of CYC treatment. We aimed to evaluate the effect of the xanthine oxidase (XO) inhibitors, allopurinol (ALL) and febuxostat (FEB), on CYC-induced cardio- and hematopoietic toxicity in rats. METHODS: ALL (100 mg/kg/day) or FEB (10 mg/kg/day) were administered orally to rats in the presence and absence of CYC (200 mg/kg kg i.p. single dose) treatment. Serum creatine kinase-MB creatine kinase myocardial band (CK-MB) and lactate dehydrogenase (LDH) activities were estimated. Complete blood counting (CBC), cardiac and bone marrow XO activity, malondialdehyde level, and superoxide dismutase activity were determined. Cardiac and bone marrow histopathological changes were also evaluated. RESULTS: ALL and FEB significantly decreased CK-MB and LDH induced by CYC. Disturbed levels of XO, oxidative stress parameters, and CBC were also corrected by both XO inhibitors tested, with amelioration of cardiac histopathological changes caused by CYC. Treatment with FEB, but not ALL, prior to CYC challenges normalized bone marrow histopathological changes. CONCLUSION: These results suggest that both XO inhibitors tested; ALL and FEB can ameliorate CYC-induced cardiotoxicity. However, only FEB can protect against CYC-induced myelotoxicity, whereas ALL, to the contrary, might aggravate it.

Evaluation of the rivastigmine role against botulinum toxin-A-induced osteoporosis in albino rats: A biochemical, histological, and immunohistochemical study.

The present study aimed to evaluate the role of rivastigmine against the effect of a single unilateral botulinum toxin-A (BTX-A) injection on the bone and bone marrow of adult albino rats 4 weeks after injection. Twenty-four Wistar albino rats were divided into four equal groups: group I, which received distilled water; group II, which received rivastigmine (0.3 mg/kg daily, intraperitoneally for 4 weeks); group III, which received BTX-A (4 IU in 0.2 mL physiological saline) single dose, intramuscularly; and group IV, which received BTX-A + rivastigmine. The results revealed that BTX-A induced a significant decrease in the calcium level with a significant increase in the phosphorus, alkaline phosphatase, C-reactive protein, and tumor necrosis factor α levels in serum. Furthermore, a significant increase in malondialdehyde with a significant decrease in reduced glutathione activities in both bone and bone marrow. Histologically, a distortion and thinning out of the compact bone and trabeculae of cancellous bone of the rat femur in the BTX-A group with an increase in adipocytes in adjacent bone marrow were detected. Immunohistochemically, Cluster of Differentiation 68 (CD68) showed a significant increase in both osteoclasts and bone marrow macrophage. Rivastigmine treatment could relieve the toxic effects induced by BTX-A. In conclusion, rivastigmine has a protective effect against the hazardous effects of BTX-A on bone and bone marrow.