Azza Hassan

Doxorubicin (DOX) is a standard anticancer agent exerting devastating effects as nephrotoxicity, hepatotoxicity and cardiotoxicity. The purpose of this study was to increase the clinical use of DOX through decreasing its detrimental effects via combination with ACE inhibitors to ameliorate the induced acute kidney injury (AKI). AKI was induced by a single injection of DOX (7.5 mg/kg; i.p.) as Group 1; control (vehicle), Group 2; DOX (7.5 mg/kg; i.p.) single dose, Group 3 and 4; Lisinopril (Lis, 20 mg/kg) and Enalapril (Enal, 40 mg/kg) orally administration for 15 consecutive days after DOX injection, respectively. Serum samples were used to measure creatinine and BUN, tissue samples were extracted to determine myeloperoxidase (MPO), malondialdehyde (MDA), total antioxidant capacity (TAC) and kidney injury molecule (KIM-1) using ELISA technique. Heme oxygenase (HO-1) RNA expression was quantified in tissue using real time polymerase chain reaction (PCR). Parts of the kidney tissue were kept in formalin for immunohistochemical demonstration of Cleaved Caspase-3 and NF-κβ immune staining and the other part was used for pathological examination. Oral treatment with Lis (20 mg/kg) and Enal (40 mg/kg) for 15 consecutive days reversed DOX effects as they reduced the serum creatinine and BUN, kidney levels of MPO and MDA, whereas the drugs increased tissue TAC. The administration of Lis and Enal with DOX also reduced KIM-1and HO-1 RNA expression. A significant decrease in cleaved caspase-3 and NF-κβ immunostainings in conjunction with pronounced amelioration in pathologies in the rat kidney were observed. We concluded that DOX adverse effects can be controlled by Lis and Enal.

The extensive recorded environmental and occupational dispersal of hexavalent chromium (CrVI) dust contributes to an increased interest in its toxicological consequences. A previous study of our team described a brain injury induced by acute intranasal instillation of Cr(VI) in rats, which was characterized by oxidative stress and inflammation. This proposed a high risk of brain damage among Cr(VI) exposed individuals either environmentally or occupationally especially through the nasal cavity. Accordingly, the main aim of this study was to evaluate the effects of subacute/subsubacute/subchronic exposure to intranasal potassium dichromate (inPDC) solution in three dose levels (0.125, 0.25, or 0.5 mg/kg/day for five successive days/week) for 3 different intervals/dose: two weeks, one month, and two months, on the brain of rats. The rats were sacrificed 24 h following the last inPDC dose. The locomotor activity, motor coordination, and object recognition behavior of the rats have been measured. Evaluation of oxidative stress; evidenced by lipid peroxidation and reduced glutathione, and inflammatory markers; evidenced by interleukin 1-beta in the brain tissues, as well as the brain PI3K and PKB contents were performed. Furthermore, the brain anti-glial fibrillary acidic protein (GFAP); marker of neurotoxicity was assessed immunohistochemically. Brain histopathological alterations were also studied. The findings of the current study revealed a dose- and time-dependent inPDC-induced brain toxicity in rats, as displayed by the biochemical, immunohistochemical and histopathological evaluation. Behaviorally, the major toxic effects of inPDC were observed on the locomotor and cognition functions, however, minor effects were observed on the motor coordination. The results suggest that short-term exposure to intranasal Cr(VI), in theses doses, does not trigger a major brain injury in rats; however, observation of more toxic alterations in a time-dependent manner is a threat of more sever toxicity upon longer exposure.

Hepatic encephalopathy depicts the cluster of neurological alterations that occur during acute or chronic hepatic injury. Hyperammonemia, inflammatory injury, and oxidative stress are the main predisposing factors for the direct and indirect changes in cerebral metabolism causing encephalopathy. The aim of this study was to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg, p.o.) and l-carnosine (CAR; 200 mg/kg, p.o.) on hepatic encephalopathy that was induced by thioacetamide (TAA; 100 mg/kg, i.p.) administered three times weekly for six weeks. Behavioral changes, biochemical parameters, histopathological analysis, and immunohistochemical and ultrastructural studies were conducted 24 h after the last treatment. Combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by reduced locomotor activity and decline in motor skill performance, as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes and serum and brain levels of ammonia. In addition, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines, and cleaved caspase-3 expression. Furthermore, they succeeded in activating nuclear erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase-1 (HO-1) activity and ameliorating markers of hepatic encephalopathy, including hepatic necrosis and brain astrocyte swelling. This study shows that combining AG with CAR exerted a new intervention for hepatic and brain damage in hepatic encephalopathy due to their complementary antioxidant, anti-inflammatory effects and hypoammonemic effects via Nrf2/HO-1 activation and NO inhibition.