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In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer's disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by enhancing the inhibition of Aβ1–42 self-induced aggregation. Moreover, 7b also had potent protective effects against glutamate-induced cell death without significant cell toxicity in mouse hippocampal neuronal HT22 cells and 10c effectively scavenged diphenylpicrylhydrazyl free radicals. Collectively, these data strongly encourage further optimisation of 7b as a new hit to develop multifunctional agents for the treatment of AD. [ABSTRACT FROM AUTHOR]

Aims Oxidative stress ( OS) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease ( AD). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine-3-caffeic acid (T3 CA), a novel promising multifunctional anti-Alzheimer's dimer, against OS-induced neuronal death. Methods and Results T3 CA protected HT22 cells against high-concentration-glutamate-induced cell death in time- and concentration-dependent manners and potently attenuated glutamate-induced intracellular reactive oxygen species ( ROS) production as well as mitochondrial membrane-potential (ΔΨ) disruption. Besides, T3 CA significantly induced nuclear factor erythroid 2-related factor 2 ( Nrf2) nuclear translocation and increased its transcriptional activity, which were demonstrated by Western blotting, immunofluorescence, and antioxidant response element ( ARE)-luciferase reporter gene assay. Further studies showed that T3 CA potently up-regulated heme oxygenase-1 ( HO-1), an endogenous antioxidative enzyme and a downstream effector of Nrf2, at both mRNA and protein levels. The neuroprotective effects of T3 CA were partially reversed by brusatol, which reduced protein level of Nrf2, or by inhibiting HO-1 with si RNA or Zn PP- IX, a specific inhibitor of HO-1. Conclusions Taken together, these results clearly demonstrate that T3 CA protects neurons against OS-induced cell death partially through Nrf2/ ARE/ HO-1 signaling pathway, which further supports that T3 CA might be a promising novel therapeutic agent for OS-associated diseases. [ABSTRACT FROM AUTHOR]

Aims Oxidative stress is frequently implicated in the pathology of neurodegenerative diseases. This study aimed to investigate the effects and their underlying mechanism(s) of edaravone upon hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in HT22 cells, a murine hippocampal neuronal model. Methods HT22 cells were treated with H2O2 in the presence of various concentrations of edaravone or in its absence. A CCK-8 assay, Hoechst 33342 staining, and flow cytometry were used to detect cytotoxicity and apoptosis. In addition, the levels of reactive oxygen species ( ROS) and the expression of Bcl-2, Bax, p- ERK 1/2, p- JNK, and p-P38 proteins in HT22 cells were examined. Results Exogenous H2O2 decreased cell viability in a concentration-dependent manner and was associated with increased apoptosis and ROS production. Moreover, H2O2 significantly activated and upregulated the expression of p- ERK 1/2, p- JNK, and p-P38, while edaravon protected HT22 cells against H2O2-induced injury by inhibiting the production of ROS and activating the MAPK signaling pathway. Conclusions Our results provide the first evidence that edaravone can protect H2O2-induced cell injury in HT22 neurons via its antioxidant action. These findings suggest that edaravone may be useful in the treatment of neurodegenerative disorders in which oxidative stress has been principally implicated. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the protective effects of lipoic acid-niacin (N2L) dimers against blue light (BL)-induced oxidative damage to human retinal pigment epithelium (hRPE) cells in vitro., Methods: hRPE cells were divided into a control group (CG), a BL group, an N2L plus BL irradiation group, an α-lipoic acid (ALA) plus BL group, an ALA-only group, and an N2L-only group. hRPE cellular viability was detected by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide assays, and apoptosis was evaluated by annexin-V-PE/7-AAD staining followed by flow cytometry. Ultrastructural changes in subcellular organelles were observed by transmission electron microscopy. Reactive oxygen species formation was assayed by flow cytometry. The expression levels of the apoptosis-related proteins BCL-2 associated X protein (BAX), B-cell leukmia/lymphoma 2 (BCL-2), and caspase-3 were quantified by Western blot analysis., Results: BL exposure with a light density of 4±0.5 mW/cm 2 exceeding 6h caused hRPE toxicity, whereas treatment with a high dose of N2L (100 mol/L) or ALA (150 mol/L) maintained cell viability at control levels. BL exposure caused vacuole-like degeneration, mitochondrial swelling, and reduced microvillus formation; however, a high dose of N2L or ALA maintained the ultrastructure of hRPE cells and their organelles. High doses of N2L and ALA also protected hRPE cells from BL-induced apoptosis, which was confirmed by Western blot analysis: BCL-2 expression significantly increased, while BAX and caspase-3 expression slightly decreased compared to the CG., Conclusion: High-dose N2L treatment (>100 mol/L) can reduce oxidative damage in degenerating hRPE cells exposed to BL with an efficacy similar to ALA.