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In prion diseases, the cellular prion protein (PrPC) forms an abnormal, infectious, and disease-causing form known as PrPSc. Inhibition of prion propagation is a key approach for the treatment of these diseases. We report on a curcumin-based compound, GT863 (formerly known as PE859) that displays therapeutic efficacy when administered orally. GT863 inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain dependent manner: effectively for RML prion and marginally for 22 L prion. Treatment with ad libitum GT863-containing feed prolonged the incubation period of intracerebrally RML prion infected Tga20 mice by 217% increase in mean. Although the 263 K prion-infected Tg7 mice were less sensitive to GT863 than RML prion infected Tga20, treatment with ad libitum GT863-containing feed prolonged the incubation period by 39% increase in mean. The mechanism of the anti-prion effectiveness in vivo needs to be elucidated and managed. Nevertheless, GT863 could inspire the development of oral chemotherapy for prion diseases. [ABSTRACT FROM AUTHOR]

The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2− and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS. [ABSTRACT FROM AUTHOR]

Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD. [ABSTRACT FROM AUTHOR]