Ameliorative Potential of Donepezil with or without Prednisolone in Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of the Anti-Inflammatory, Antioxidant, and the Antifibrotic Pathways.

Background and Objectives: Bleomycin-induced pulmonary fibrosis is one of the serious complications that may limit the use of bleomycin in cancer therapy. To date, there is no effective remedy for the amelioration of this condition. Donepezil, an anti-Alzheimer's medication, has recently been proven to exhibit potent anti-inflammatory, antioxidant, and antifibrotic effects. To the best of our knowledge, this study represents the first study designed to investigate the prophylactic effects of donepezil, either alone or in combination with the classic anti-inflammatory drug prednisolone, in bleomycin-induced pulmonary fibrosis. Methods: This study was carried out on fifty rats, which were divided into five equal groups: control (Saline) group; bleomycin group; bleomycin + prednisolone group; bleomycin + donepezil group; and bleomycin + prednisolone + donepezil group. At the end of the experiments, bronchoalveolar lavage was performed to evaluate the total and differential leucocytic counts. The right lung was processed to assess the oxidative stress markers, proinflammatory cytokines, NLRP3 inflammasome, and transforming growth factor-beta1. The left lung was subjected to histopathological and immunohistochemical examination. Results: The administration of donepezil and/or prednisolone induced a significant amelioration of oxidative stress, inflammation, and fibrosis. In addition, these animals showed a significant amelioration of the histopathological changes of fibrosis, together with a significant decline in nuclear factor kappa B (p65) immunoexpression, compared to the group treated with bleomycin alone. However, the rats treated with the donepezil/prednisolone combination showed non-significant effects on the aforementioned parameters compared to the group treated with prednisolone alone. Conclusions: Donepezil may emerge as a promising drug that shows significant prophylactic effects against bleomycin-induced pulmonary fibrosis.

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice.

AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.

The possible anti-apoptotic and antioxidant effects of acetyl l-carnitine as an add-on therapy on a relapsing-remitting model of experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.