Berberine

It is 6th January 2015, but the number of scientific publications concerning the therapeutic effects of berberine published this year already exceed 100. Diarrhoea, breast cancer, diabetes, hyperlipidaemia, leukaemia and quite a few more – all are possible targets for the chemical.

Berberine caught my attention with a paper (Bonon et al) from 2013 entitled “Berberine slows cell growth in autosomal dominant polycystic kidney disease cells”. The research, from an Italian university, was published in a rather specialist science journal and is not the easiest paper to read, BUT it concludes that berberine can reduce the rate of growth of cystic cells from both mouse and human ADPKD cell lines.

So what is BERBERINE?
Although I have not knowingly encountered it before, I have probably seen some of the plants in which it can be found – Oregon mountain grape, barberry, prickly poppy, berberis.

Berberis (from plantsystematics.org)

 

It is a plant alkaloid – a naturally occurring chemical, where a nitrogen atom is attached to four organic groups, specifically an isoquinoline quaternary alkaloid. Lots of medicinally active chemicals come from such groups – morphine, disinfectants, antimicrobials. Berberine is found in the roots, rhizomes, stems and bark, conferring a bitter unpleasant taste most probably designed to protect the plant. Despite one species having the common name “tree turmeric” it is not the same as turmeric – both are yellow and used in foods and dyes but they are different chemicals.

 

Why did the scientists even think of using it therapeutically?
For millennia berberine has been used in traditional Chinese medicine and Ayurvedic medicine with purported benefits in diarrhoea, infections and type2 diabetes. In the past decade western medicine has undertaken trials using it to lower lipids, treat cancers, suppress inflammation and, as is common with new therapeutic chemicals, as a cure-all for things from alzheimers to obesity. Within those trials berberine has shown some promise – one demonstrated it to be as effective as metformin in lowering blood sugar.

It is the effects in cancer cells that brought it to light as a potential method of slowing cyst growth in ADPKD. Berberine has been shown to slow the rate at which cells duplicate. It does this by prolonging one of the dormant phases of the cell cycle. It also inhibits protein synthesis at the ribosomes, a process involving activated protein kinase (AMPK). AMPK is an energy sensing system monitoring the cell’s energy a bit like an internal fuel gauge. Berberine triggers phosphorylation of AMPK as if it were telling the cell it can slow down on the production line. So if it can stop cancer cells from duplicating then why not cystic epithelial cells in ADPKD?

Chemical structure of berberine (image from PubChem)

 

 

What was the study?
The study was in vitro (test-tube and petri dish) using cultured cells from humans with ADPKD and mouse models of the illness. The comparison cells were normal renal tubular epithelium. The cells were treated with different doses of berberine and they used various methods to analyse the effects – direct cell counts, immunocytometry and DNA fragmentation. Specifically they were looking at cell proliferation and apoptosis (programmed cell death) and because they used several different techniques to measure each of these they have provided their own checks and controls.

The results demonstrated that berberine slows cell proliferation in a dose-dependent manner: at 10 mcg/ml it reduced cell growth in ADPKD cells only, while at higher concentrations both cystic and normal epithelial cells were affected.

When they looked closely at the cellular cycle they found a significant increase in cells in the G0/G1 phase – that is cells still alive but halted at a specific stage before they reach the point of duplicating. This too was dose-dependent with no effect at 1mcg/ml, optimum effect at 10mcg/ml and cell death at higher doses. Additional analyses pointed to specific chemical pathways, involving ERK and P70S6 kinases – getting a bit too technical for me, but their study here supports others on cancer cells in confirming the actual mechanisms of interference.

Cell Cycle: berberine increases the number of cells at G0/G1 phases

What does it mean?
Cyst growth in ADPKD involves the tubular lining epithelial cells multiplying in an uncontrolled fashion, losing their sense of which way up they are and forming ball-shapes rather than tube-shapes. Being able to slow or stop this process without actually killing the cells entirely or affecting other parts of the kidney is one approach to managing the disease. There are ongoing studies using drugs that theoretically could have such an effect, such as rapamycin (Sirolimus) – more on those in a later post – but so far the results have been unexciting. Finding new molecules with anti-proliferative properties is a huge step in the process of finding treatments for ADPKD.

This study demonstrates that berberine consistently slows the rate at which polycystic kidney cells grow and proliferate. It also suggests the appropriate concentration required to do this and that higher doses would affect normal cell lines.

What it doesn’t say is “berberine is a treatment for ADPKD” – so before we all rush to place a New Years order online we need to take a few steps back.

What else do we need to know about berberine?
While it can be purchased without a prescription, the concentrations of active ingredient vary from one preparation to another and the “recommended” doses also. This bothers me, where maximum safe doses have not been defined. Although in more recent years there has been more research on traditional Chinese medicine, the abundance of “papers” makes it so very hard to sift through to find the more useful ones as some turn out to be just advertising and not research.

What I have learned is that berberine hydrochloride is the more common form of the chemical. It has a half life of 3-4 hours which means to achieve a steady state one would need to take a dose three times a day. The common side effects are abdominal discomfort, wind and diarrhoea but these diminish after the first four weeks of treatment. It is NOT safe in pregnancy, high doses damage the foetus in the early stages and in newborns may cause brain damage through kernicterus.

On the benefits side however it is claimed to reduce blood glucose levels in type 2 diabetics, lower cholesterol levels, act as a mild antidepressant, reduce fat accumulation in the liver, suppress inflammatory cytokines, and even help with weight loss in obesity. Some of these effects have studies to back the claims, but it is beginning to sound suspiciously like the “new aspirin” – a cure-all where “nothing works faster” (sarcasm for the older British reader who recalls the Anadin advert of the 1970s)

Despite all the positive, I could find only two patents for potential new drugs containing berberine – one for reducing lipids and one for alleviating weight gain with antipsychotic drugs. So there is a long way to go before this research translates into a treatment.

Shows promise but not yet a recommended treatment

References:

Bonon A, Mangolini A, Pinton P, Del Senno L, Aguiari G. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells. Biochem Biophys Res Commun. 2013;441(3):668–674.

Dong H, Zhao Y, Zhao L, Lu F. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 2013 Apr;79(6):437-46. doi: 10.1055/s-0032-1328321. Epub 2013 Mar 19.