Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptor α / 中国天然药物

Nonalcoholic fatty liver disease (NAFLD) is regarded as the most common liver disease with no approved therapeutic drug currently. Silymarin, an extract from the seeds of Silybum marianum, has been used for centuries for the treatment of various liver diseases. Although the hepatoprotective effect of silybin against NAFLD is widely accepted, the underlying mechanism and therapeutic target remain unclear. In this study, NAFLD mice caused by methionine-choline deficient (MCD) diet were orally administrated with silybin to explore the possible mechanism and target. To clarify the contribution of peroxisome proliferator-activated receptor α (PPARα), PPARα antagonist GW6471 was co-administrated with silybin to NAFLD mice. Since silybin was proven as a PPARα partial agonist, the combined effect of silybin with PPARα agonist, fenofibrate, was then evaluated in NAFLD mice. Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARα and its targets. As expected, silybin significantly protected mice from MCD-induced NAFLD. Furthermore, silybin reduced lipid accumulation via activating PPARα, inducing the expression of liver cytosolic fatty acid-binding protein, carnitine palmitoyltransferase (Cpt)-1a, Cpt-2, medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1, and suppressing fatty acid synthase and acetyl-CoA carboxylase α. GW6471 abolished the effect of silybin on PPARα signal and hepatoprotective effect against NAFLD. Moreover, as a partial agonist for PPARα, silybin impaired the powerful lipid-lowering effect of fenofibrate when used together. Taken together, silybin protected mice against NAFLD via activating PPARα to diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARα agonists for NAFLD therapy.

Activity of tongqiao huoxue decoction on the memory and learning ability and fluorescence intensity of intracellular calcium concentration of hippocampal neurons of vascular dementia rats / 中国药学杂志

OBJECTIVE: To study activity of tongqiao huoxue decoction (TQHXD) on memory and learning ability of rats with vascular dementia (VD) and its influence on fluorescence intensity of intracellular calcium concentration of hippocampal neurons. METHODS: Vascular dementia model was established by using improved bilateral carotid artery ligation method. The Morris water maze experiment was adopted to evaluate the ethology of VD rats. The fluorescence intensity of hippocampus intracellular calcium was detected by flow cytometry. RESULTS: Compared with the model group, high, middle and low dose group of TQHXD significantly reduce the time of escape latency and the distance of climbing on the platform (P < 0.01). The entries in the second quadrant, the times in the second quadrant and the distance in the second quadrant in relation to high, middle and low dose groups of TQHXD were increasing significantly (P < 0.05) and the latency to first entry in the second quadrant was shorten (P < 0.05). The fluorescence intensity of intracellular calcium in hippocampal neurons of the high, middle and low dose groups of TQHXD was lower than that of the model group (P < 0.01, P < 0.05). CONCLUSION: TQHXD can improve the memory and learning ability of rats with VD significantly. The mechanism may be related to reduce the intracellular calcium concentration in the hippocampus, thereby the damage of nerve cells is reduced.

Tongqiao Huoxue Decoction ameliorates learning and memory defects in rats with vascular dementia by up-regulating the Ca(2+)-CaMKII-CREB pathway / 中国天然药物

The present study was aimed at determining the effects of Tongqiao Huoxue Decoction (TQHXD) on the Ca(2+)-CaMKII-CREB pathway and the memory and learning capacities of rats with vascular dementia (VD). The rat VD model was established by using an improved bilateral carotid artery ligation method. The Morris water maze experiment was used to evaluate the ethology of the VD rats following treatments with TQHXD at 3.01, 6.02, and 12.04 g·kg(-1) per day for 31 days. At the end of experiment, the hippocampus were harvested and analyzed. Western blotting and RT-PCR were used to measure the expression levels of calmodulin-binding protein kinase II(CaMKII), protein kinase A(PKA), cAMP-response element binding protein(CREB), and three N-methyl-D-aspartic acid receptor subunits (NR1, NR2A, and NR2B). Our results revealed that TQHXD could alleviate the loss of learning abilities and increase the memory capacity (P < 0.05 and P < 0.01 vs the model group, respectively). The treatment with 6.02 and 12.04 g·kg(-1) of TQHXD significantly up-regulated the Ca(2+)-CaMKII-CREB pathway in the hippocampus. In conclusion, TQHXD showed therapeutic effects on a bilateral carotid artery ligation-induced vascular dementia model, through the up-regulation of calcium signalling pathways.

Activity of tongqiao huoxue decoction on the learning and memory ability of rats with vascular dementia in rats / 中国药学杂志

OBJECTIVE: To study the activity of TQHXD on the learning and memory ability of rats with vascular dementia(VD) and its effects on the content of Ach in cerebral cortex. And to investigate the action mechanism of TQHXD on VD in rats. METHODS: VD model was made by common carotid artery injection of a co-thrombus inducer. The 8-arm radial maze experiment was adopted to evaluate the times of working memory errors and reference memory errors. The changes of the pathological area in hippocampus CA1 were observed by optical microscope. Enzyme-linked immunosorbent assay was used to determine the concentration of Ach in rats cerebral cortex. RESULTS: High and middle dose of TQXHD significantly reduce the times of working memory errors and reference memory errors (P<0.01), definitely improved the anormalies of pathological area in hippocampal CA1, and significantly increased the content of Ach in cerebral cortex (P<0.01). CONCLUSION: TQHXD can significantly ameliorate the learning and memory ability of in VD rats. The mechanism may be related to the improvement of the vertebral body cells anomalies in the hippocampal CA1 region and increasing the content of the Ach in cerebral cortex. Copyright 2012 by the Chinese Pharmaceutical Association.