A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.
Aim: 1,1′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(piperidin-1-yl)propan-1-one)dihydrochloride (DL0410) is a novel synthetic dual acetylcholinesterase (AChE)/butyrocholinesterase (BuChE) inhibitor, which has shown a potential therapeutic effect on Alzheimer's disease (AD). In this study we examined whether DL0410 produced neuroprotective effects in an AD cellular model and an Aβ 1-42 -induced amnesia mouse model. Methods: The in vitro inhibitory activities against AChE and BuChE were estimated using Ellman's assay. Copper-induced toxicity in APPsw-SY5Y cells was used as AD cellular model, the cell viability was assessed using MTS assay, and cell apoptosis was evaluated based on mitochondrial membrane potential detection. Aβ 1-42 -induced amnesia mouse model was made in male mice by injecting aggregated Aβ 1-42 (2 μg in 2 μL 0.1% DMSO) into the right cerebral ventricle. Before and after Aβ 1-42 injection, the mice were orally administered DL0410 (1, 3, 9 mg·kg -1 ·d -1 ) or rivastigmine (2 mg·kg -1 ·d -1 ) for 3 and 11 d, respectively. Memory impairments were examined using Morris water maze (MWM) test and passive avoidance test. The expression levels of APP, CREB, BDNF, JNK and Akt in the mouse brains were measured with either immunohistochemistry or Western blotting. Results: DL0410 exhibited in vitro inhibitory abilities against AChE and BuChE with IC 50 values of 0.286±0.004 and 3.962±0.099 μmol/L, respectively, which were comparable to those of donepezil and rivastigmine. In APPsw-SY5Y cells, pretreatment with DL0410 (1, 3, and 10 μmol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copperstimulated Aβ 1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Aβ 1-42 -treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410 administration markedly decreased Aβ 1-40/42 deposits in mouse cerebral cortices, and significantly up-regulated neurotrophic CREB/BDNF. Meanwhile, Akt/JNK signaling pathway may play a key role in the neuroprotective effect of DL0410. Conclusion: DL0410 ameliorates cognitive deficit and exerts neuronal protection in AD models, implicating this compound as a candidate drug for the prevention and therapy of AD.
The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC–MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0–t) values ranged from 1.75 to 11.80 (mg·h/L). J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.
Aim: To investigate the effects of the novel N6-substituted adenosine derivative {(2R,3S,4R,5R)-3,4-dihydroxy-5- [6-[(4-hydroxy-3-methoxybenzyl)amino]-9H-purin-9-yl]tetrahydrofuran-2-yl} methyl decanoate (WS0701) on stress-induced excessive fear, anxiety, and cognitive deficits in a mouse model of posttraumatic stress disorder (PTSD). Methods: Male mice underwent a conditioned foot shock and single prolonged stress procedure to induce PTSD. Contextual/cued fear, elevated plus-maze, open field and novel object recognition tests were conduced to assess PTSD-like behaviors. From d 1, the mice were orally administered WS0701 (7.5, 15, or 30 mg·kg -1 ·d -1 ) or paroxetine (10 mg·kg -1 ·d -1 ) for two weeks. Apoptosis of hippocampal neurons was detected using flow cytometry and TUNEL staining, and expression of Bcl-2 and Bax in the hippocampus was measured with Western boltting and qPCR assays. Results: WS0701 administration significantly alleviated fear, anxious behaviors and memory deficits in the mouse model of PTSD. Furthermore, WS0701 administration significantly reduced the stress-induced apoptosis of hippocampal neurons, and increased the Bcl-2/Bax ratio in the hippocampus. The positive control drug paroxetine exerted similar effects on PTSD-like behaviors and hippocampal neuron apoptosis in the mouse model of PTSD, which were comparable to those caused by the high dose of WS0701. Conclusion: WS0701 effectively mitigates stress-induced PTSD-like behaviors in mice, partly via inhibition of neuronal apoptosis in the hippocampus.
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