Combination of metformin and hesperidin mitigates cyclophosphamide-induced hepatotoxicity. Emerging role of PPAR-γ/Nrf-2/NF-κB signaling pathway.

Cyclophosphamide (CP) is widely used as an immunosuppressive and chemotherapeutic drug. However, its therapeutic application is restricted by its adverse effects, particularly hepatotoxicity. Both metformin (MET) and hesperidin (HES) have promising antioxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, the principal aim of the current study is to investigate the hepatoprotective effects of MET, HES, and their combinations on the CP-induced hepatotoxicity model. Hepatotoxicity was evoked by a single (I.P) injection of CP (200 mg/kg) on day 7. For this study, 64 albino rats were randomly categorized into eight equal groups; naïve, control vehicle, untreated CP (200 mg/kg, IP), and CP 200 groups treated with MET 200, HES 50, HES 100 or a combination of MET 200 with HES 50 and HES 100 respectively orally daily for 12 days. At the end of the study, the liver function biomarkers, oxidative stress, inflammatory parameters, histopathological and immunohistochemical analysis of PPAR-γ, Nrf-2, NF-κB, Bcl-2, and caspase3 were assessed. CP significantly increased serum ALT, AST, total bilirubin, hepatic MDA, NO content, NF-κB, and TNF-α. Otherwise, albumin, hepatic GSH content, Nrf-2, and PPAR-γ expression decreased considerably compared to the control vehicle group. The combinations of MET200 with HES50 or HES100 induced pronounced hepatoprotective, anti-oxidative, anti-inflammatory, and anti-apoptotic effects on CP-treated rats. The possible explanation of such hepatoprotective effects may be mediated via upregulation of Nrf-2, PPAR-γ, Bcl-2 expression, hepatic GSH content, and marked suppression of TNF-α and NF-κB expression. In conclusion, the current study showed that combining MET and HES revealed a remarkable hepatoprotective effect against CP-induced hepatotoxicity.

Celecoxib and omega-3 fatty acids alone and in combination with risperidone affect the behavior and brain biochemistry in amphetamine-induced model of schizophrenia.

The implications of oxidative stress and neuro-inflammation in the pathogenesis of schizophrenia have been elucidated. Despite their effectiveness against positive symptoms of schizophrenia, antipsychotics have limited effectiveness against negative and cognitive symptoms and are associated with remarkable adverse effects. The use of celecoxib or omega-3 in schizophrenia may have beneficial effects. This study aimed to evaluate the possible efficacies of celecoxib, omega-3 or the combination of celecoxib+risperidone and omega-3+ risperidone compared to risperidone on the behavior and brain biochemistry in rats. In the present study, an amphetamine-induced model of schizophrenia in adult male rats was used to evaluate the effects of celecoxib, omega-3, celecoxib+risperidone and omega-3+ risperidone on the behavior of animals and on brain lipid peroxidation or tumor necrosis factor-alpha. In the water maze task, celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone significantly decreased the latency time compared to amphetamine-treated group. Celecoxib, omega-3, celecoxib+risperidone, omega-3+risperidone also significantly reversed the decreased spontaneous alternation induced by amphetamine in the Y-maze task. In the social interaction task, groups treated with celecoxib, omega-3, celecoxib+risperidone, omega-3+ risperidone spent less time to recognize foreign animals than animals in the amphetamine-treated group. Increased brain MDA and TNF-α levels due to amphetamine were significantly reduced in groups treated with celecoxib+risperidone or omega-3+ risperidone. The present findings showed that celecoxib or omega-3 can attenuate amphetamine- induced behavioral impairment and these effects may be associated with their ability to decrease lipid peroxidation and cytokine release. Celecoxib or omega-3 may be promising candidates as adjuvant therapy for schizophrenia.