Background/Objectives: The clinical efficacy of cyclophosphamide, a commonly used chemotherapeutic drug, is often restricted by off-target neurotoxicity, which is primarily caused by oxidative stress, neuroinflammation, and apoptosis. With the aim of finding natural neuroprotective agents, pterostilbene was investigated in this study, either in conventional form or when solubilized as a nanoemulsion, for its neuroprotective potential against cyclophosphamide-induced neurotoxicity. Methods: Female Wistar rats were orally administered pterostilbene, either in its conventional form (50 mg/kg p.o) or nanoemulsion form (25 and 50 mg/kg p.o), for 15 days. Cyclophosphamide was injected once on day 14 (200 mg/kg ip). Results: Our findings revealed that administering pterostilbene as a nanoemulsion or in its conventional powder form managed to counteract the cyclophosphamide-induced intoxication features via disrupting the oxidative stress–inflammasome–cytokine axis; by upregulating cortical and hippocampal PPAR-γ, Nrf2, HO-1, BCL2 levels and the BCL2/Bax ratio; and downregulating NLRP3, IL-1β, COX-2, Bax and GFAP levels. Further histopathological and immunohistochemical evaluation confirmed the improved neuronal morphology, reduced degeneration and apoptosis, restoration of cortical and hippocampal architecture, and normalization of GFAP expression levels, approaching those of the control group upon treatment with either conventional or nanoformulated pterostilbene. Conclusions: The promising nature of the nanoemulsion formulation, particularly when administered at the high dose level, was evidenced, hence emphasizing the important role of proper formulation of natural bioactives such as pterostilbene in maximizing their therapeutic potential.
R. Ahmed, Hadir Farouk, Y. A. Hussien et al.· Biomedicines· 0 citations
Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with oxidative stress, neuroinflammation, and hyperammonaemia secondary to hepatic dysfunction. This study aimed to investigate dapagliflozin's effects (DAPA) against HE induced by thioacetamide (TAA) in rats and to elucidate the roles of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathways. HE was induced by injection of TAA (200 mg/kg) intraperitoneally 2 times every other day. Two groups were pretreated with DAPA at 5 and 10 mg/kg for 15 days; on the 13th day, rats were given TAA (200 mg/kg, i.p.) twice, 2 days apart. Behavioral assessments, including object recognition and rotarod tests, were conducted, and serum and tissue samples were collected for biochemical and molecular analyses. DAPA pretreatment ameliorated TAA effects, improved recognition memory, enhanced muscular tone and motor coordination. DAPA also reduced ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ammonia serum levels. Additionally, it restored antioxidant balance, decreased malonaldehyde (MDA) and increased reduced glutathione (GSH). Moreover, it reduced tissue inflammation and inhibited apoptosis; where tumor necrosis factor-alpha (TNF-α) and caspase-3 expression were suppressed. DAPA was associated with increased Nrf2/HO-1 pathway-related protein expression while decreasing pERK/total ERK and pJNK/total JNK ratios, along with nuclear factor kappa-light-chain-enhancer of activated B cells, p65 subunit (NF-κB-p65) protein expression. Histopathologically, DAPA improved hepatic and brain architecture. Collectively, DAPA exhibits hepatoprotective and neuroprotective effects against TAA-induced HE accompanied by modulation in oxidative-, inflammatory-, and apoptotic-related protein expression, highlighting its therapeutic potential in hepatic encephalopathy.
Hadir Farouk, Salma A. El-Marasy, M. S. Khattab et al.· Toxicology Mechanisms and Me...· 0 citations
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