Berberine Abstracts 8

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The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms

         (Abidi, Chen et al. 2006) Download

Our previous studies have identified berberine (BBR), an alkaloid isolated from the Chinese herb huanglian, as a unique cholesterol-lowering drug that upregulates hepatic low density lipoprotein receptor (LDLR) expression through a mechanism of mRNA stabilization. Here, we demonstrate that the root extract of goldenseal, a BBR-containing medicinal plant, is highly effective in upregulation of liver LDLR expression in HepG2 cells and in reducing plasma cholesterol and low density lipoprotein cholesterol (LDL-c) in hyperlipidemic hamsters, with greater activities than the pure compound BBR. By conducting bioassay-driven semipurifications, we demonstrate that the higher potency of goldenseal is achieved through concerted actions of multiple bioactive compounds in addition to BBR. We identify canadine (CND) and two other constituents of goldenseal as new upregulators of LDLR expression. We further show that the activity of BBR on LDLR expression is attenuated by multiple drug resistance-1 (MDR1)-mediated efflux from liver cells, whereas CND is resistant to MDR1. This finding defines a molecular mechanism for the higher activity of CND than BBR. We also provide substantial evidence to show that goldenseal contains natural MDR1 antagonist(s) that accentuate the upregulatory effect of BBR on LDLR mRNA expression. These new findings identify goldenseal as a natural LDL-c-lowering agent, and our studies provide a molecular basis for the mechanisms of action.


The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials

         (Dong, Zhao et al. 2013) Download

Clinical trials have reported lipid-lowering effects of berberine intake, but the findings have been inconsistent. The aim of this meta-analysis was to assess the safety of berberine and its effects on blood lipid profiles. A systemic review was designed, undertaken and reported in accordance with the PRISMA statement. Randomized controlled trials of the effects of berberine on blood lipids in adults were included. Study population characteristics and the main results, including changes in the levels of total cholesterol, triglycerides, low-density and high-density lipoprotein cholesterol, were extracted. Weighted mean differences were calculated for net changes in blood lipid concentrations using fixed-effect or random-effects models. After filtering, eleven randomized controlled trials (including a total of 874 participants) were included in this study. The methodological quality of these studies was generally low. The final analysis showed that administration of berberine produced a significant reduction in total cholesterol (mean difference - 0.61 mmol/L; 95 % confidence interval - 0.83 to - 0.39), triglycerides (mean difference - 0.50 mmol/L; 95 % confidence interval - 0.69 to - 0.31), and low-density lipoprotein cholesterol (mean difference - 0.65 mmol/L; 95 % confidence interval - 0.76 to - 0.54) levels, with a remarkable increase in high-density lipoprotein (mean difference 0.05 mmol/L; 95 % confidence interval 0.02 to 0.09). No serious adverse effects of berberine have been reported. In conclusion, berberine may have beneficial effects in the control of blood lipid levels. However, the efficacy of berberine in treating hyperlipidemia should be further evaluated by more randomized controlled trials in a larger population of patients.

Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model

         (Durairajan, Liu et al. 2012) Download

The accumulation of beta-amyloid (Abeta) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble beta-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.

Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats

         (Kalalian-Moghaddam, Baluchnejadmojarad et al. 2013) Download

Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property.


Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats

         (Lee, Sur et al. 2012) Download

We examine whether Phellodendron amurense (PA) and its major alkaloid compound, berberine (BER), improved memory defects caused by administering scopolamine in rats. Effects of PA and BER on the acetylcholinergic system and pro-inflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses for 14 days of PA (100 and 200 mg/kg, i.p.) and BER (20 mg/kg, i.p.) 30 min before scopolamine injection (2 mg/kg, i.p.). Daily administration of PA and BER improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test. Administration of PA and BER significantly alleviated memory-associated decreases in cholinergic immunoreactivity and restored brain-derived neurotrophic factor and cAMP-response element-binding protein mRNA expression in the hippocampus. PA and BER also decreased significantly the expression of proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha and cyclooxygenase-2 mRNA in the hippocampus. These results demonstrated that PA and BER had significant neuroprotective effects against neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that PA and BER may be useful as therapeutic agents for improving cognitive functioning by stimulating cholinergic enzyme activity and alleviating inflammatory responses.

Alteration of the intestinal barrier and GLP2 secretion in Berberine treated Type 2 diabetic rats

         (Shan, Yang et al. 2013) Download

Background and aims: For centuries, Berberine has been used in the treatment of enteritis in China and it is also known to have anti-hyperglycemic effects in Type 2 diabetic patients. However since Berberine is insoluble and rarely absorbed in gastrointestinal tract the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxiemia. Materials and methods: A high-fat-diet combined with low dose streptozocin was used to induce Type 2 diabetes in male Sprague-Dawley rats. 100 mg/kg of Berberine was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Results: Hyperinsulinemia and insulin resistance but not blood glucose improved in the Berberine group. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease of plasma lipopolysaccharide level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but restored by Berberine treatment. Glutamine induced glucagon like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group, but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma lipopolysaccharide level, and ZO1 expression were significantly correlated with GLP2 level. Conclusions: In Type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes, it is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability and improving endotoxiemia. Whether these effects are all mechanistically related will require further studies but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.


References

Abidi, P., W. Chen, et al. (2006). "The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms." J Lipid Res 47(10): 2134-47. [PMID: 16885565]

Dong, H., Y. Zhao, et al. (2013). "The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials." Planta Med 79(6): 437-46. [PMID: 23512497]

Durairajan, S. S., L. F. Liu, et al. (2012). "Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model." Neurobiol Aging 33(12): 2903-19. [PMID: 22459600]

Kalalian-Moghaddam, H., T. Baluchnejadmojarad, et al. (2013). "Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats." Eur J Pharmacol 698(1-3): 259-66. [PMID: 23099256]

Lee, B., B. Sur, et al. (2012). "Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats." Korean J Physiol Pharmacol 16(2): 79-89. [PMID: 22563252]

Shan, C., J. Yang, et al. (2013). "Alteration of the intestinal barrier and GLP2 secretion in Berberine treated Type 2 diabetic rats." J Endocrinol. [PMID: 23757509]