By reducing acetylcholine demolition activity …
… while it demonstrates glucose-lowering effects very similar to
metformin, a first-line drug for the treatment of type 2 diabetes
By Will Block
uring the Zhou period of China (ca. 1100–256 BC)—as legend has it—a Taoist master named Liu Fenglin trained for 400 years on the sacred mountain of Mt. Songgao. Throughout this period, he attempted to concoct a “divine elixir” on three separate occasions, only to be foiled by “wicked creatures.” Fenglin then moved to Mt. Weiyu where, so the story continues, he is still living and is over 2,000 years
old, having gained his earthbound immortality
Chinese goldthread (huanglian or Coptis chinensis). However, because of his many failed trials, he has not ascended as a heavenly immortal. Was someone keeping track?
There is evidence that C. chinensis is medicinally important owing to the significant amounts of berberine that it contains. And scientific investigation is progressively reporting new findings about this natural isoquinoline alkaloid, isolated from the roots, rhizomes, stems, and bark of plants such as Oregon grape, barberry, tree turmeric, amur cork tree and Chinese goldthread.
Let Down Your Golden Braids
Of all of these sources of berberine, Chinese goldthread has the longest history, having been used for medicinal purposes for more than 2500 years in traditional Ayurvedic and Chinese medicines. Curiously, the early Taoist fables seem to embody a idea similar to one found in the well-known Rapunzel tale of the Brothers Grimm: “… let down your golden braids,” in order to ascend. This tale is not usually associated with herbal ingestion, but if we look further …
Rapunzel’s story has striking similarities to the tale of Rudabeh, which was a Persian fairytale later to assume the name of rapunzel, after the name of a plant. To make a long story short, this plant was longed for “to the point of death,” by the wife of a man who is eventually caught stealing it from the garden of an enchantress. In a plea bargain, a Faustian deal is made, and when the wife bears a daughter, owing in part to the enhanced fertility the rapunzel confers, Rudabeh is surrendered at birth to the magician. Rapunzel is the name for rampion, a garden vegetable possessing roots that are typically boiled tender like parsnips. They are thought to have anti-inflammatory benefits, which could be associated with a calmer pregnancy and more successful birth.
The story of Rudabeh dates back to the Shahnameh (“The Persian Book of Kings”), an enormous poetic opus written 1000 years ago by the Persian poet Ferdowsi, it tells of the mythical and historical past of Persia, and embraces some medical folklore. As the tale of Rudabeh goes on, the heroine offers to let her hair down from her tower so that her lover can climb up and ascend to her. But as with our Taoist master, efforts to achieve the immortality of love are thwarted in both the Rapunzel and Rudabeh stories. Both suitors are denied the heavenly bliss.
Of the sources of berberine, Chinese
goldthread has the longest history,
having been used for medicinal
purposes for more than 2500 years in
traditional Ayurvedic and
It is curious to note that the Iranian Berber people are thought to be descended from Chinese Mongols, and that barberries (the fruit of Berberis vulgaris, containing berberine) are harvested in the Iranian Province of Khorasan, where the Berbers are principally found. Barberries are known for their anti-inflammatory, antiarrhythmic, and sedative effects in Iranian traditional medicine. Although berberine is routinely prescribed in other Asian countries for its antimicrobial activity in the treatment of gastrointestinal infections and diarrhea, and usually used for the treatment of diabetes mellitus, interest in its beneficial effects in metabolic and cardiovascular diseases has been growing in the Western world over the last decade.
Reducing the Activity of Cholinesterase, a Memory Breakdown Enzyme
In new research done in India, berberine is reported to inhibit cholinesterase (ChE) activity and increase glucagon-like peptide (GLP-1) release. ChE is the enzyme that breaks down the memory molecule acetylcholine, a neurotransmitter that is crucial for the important memory activities of focus and concentration. GLP-1, as recent evidence suggests, plays an imperative role in diabetes, along with cognitive dysfunction, learning, and neuroprotection.
Based on the unavailability of prior research for the influence of berberine on streptozotocin (STZ)-induced, memory impairment, the researchers designed their study to investigate if there could be any benefits. To test berberine’s influence against cognitive dysfunction in STZ-induced diabetic rats, they chose to use the Morris water maze model as a measure of memory. In the Morris test, rats are trained to find a submerged platform in a tank of water. Around the sides of the tank are symbols, and the goal entails (pun intended) that the rats remember the location of the platform, to save themselves from exerting energy to stay afloat by refinding the platform and emerging from the water.
The early Taoist fables seem to
embody a idea similar to
one found in the well-known
Rapunzel tale of the Brothers Grimm:
“… let down your golden braids.”
Also, lipid peroxidation and glutathione levels (as parameters of oxidative stress) and ChE activity (as a marker of cholinergic function) were assessed in the cerebral cortex and hippocampus. The greater the activity of ChE, the less effective is the cholinergic system, as ChE breaks down acetylcholine. Thirty days after diabetes induction with STZ, rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity.
In contrast, diabetic rats treated chronically with orally administered berberine at doses of 25, 50, or 100 mg/kg, but especially the 50 and 100 mg dose, twice daily for 30 days, and then subjected to the Morris water maze test, were all found to have improved cognitive performance, along with lowered hyperglycemia, oxidative stress, and ChE activity. Also administered were vitamin C (100 mg/kg) or metformin (500 mg/kg) or vehicle (1 ml/kg), twice daily. Both vitamin C and metformin were comparable in effects to berberine.
Diabetes Implicated in Cognitive Dysfunction
Prior studies have identified that when memory impairment is induced in rats, changes consequently occur in the central nervous system that are secondary to hyperglycemia, including impaired oxidative stress, cholinergic dysfunction, and changes in GLP-1. Indeed, in a model of treatment that uses antihyperglycemics, antioxidants, and cholinergic agonists, beneficial effects have been produced.
In the second leg of the Indian study, 30 days after confirmation of diabetes, berberine was given at the same dose range during training trials in the Morris water maze that lasted 5 days (days 31–35). Alternatively, vitamin C at 100 mg/kg or metformin at 500 mg/kg, or donepezil at 3 mg/kg or placebo at 1 ml/kg were also used. The result for berberine was improved learning and memory, with lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C, or metformin, or donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In a prior study with berberine, its effects were found to be very similar to metformin, and this was upheld in the current study.
Note: For those readers who require more science, and are willing to wade through the technicalities …Other Possible Mechanisms
Suggested by the Findings
The Indian study explored findings demonstrating that diabetes reduced learning and memory performance. It is important to note that the impaired performance of diabetic rats is related to cognitive impairment rather than to sensory and motor brain deficits, since performance of diabetic rats were similar to non-diabetic rats in the task with the visible platform of the Morris water maze test.
The restoration of cognitive function
observed in diabetic rats in
the current study may be due to
the ability of berberine to
In the first experiment, the mean escape latencies in all the groups were similar, implying that their motor performance (ability to swim) was unaffected by the persistent hyperglycemia and/or berberine treatment. The beneficial effects of berberine observed in the present study could be related to a number of variables. Most of the diabetes complications, including cognitive impairments, are caused by protracted hyperglycemia, and antihyperglycemics and insulin-sensitizing agents, which are reported to reduce memory deficit in diabetic condition. Indeed, an exhaustive review suggested that better glycemic control improves cognition and that there is a cognitive benefit to restricting hyperglycemic episodes in diabetes. In the present study, berberine treatment significantly reduced blood glucose levels which is well in accordance with earlier studies. Therefore, the restoration of cognitive function observed in diabetic rats in the current study may be due to the ability of berberine to reduce hyperglycemia. This is also supported by observations in the present study that metformin, a known antihyperglycemic, improves performance of diabetic rats in the Morris water maze test.
Treatment with berberine returned
the levels of lipid peroxides and
reduced glutathione towards their
control values in diabetic rats.
An increase in reactive species production (ROS) due to oxidative stress seems to play a key role in neuronal damage. Elevated intracellular glucose oxidation is responsible for glucotoxicity in the neurons. Oxidative damage to the rat synapse in the cerebral cortex and hippocampus has been previously reported to contribute to the deficit of cognitive functions. In addition, it is reported that antioxidants prevent diabetes-induced cognitive dysfunction. Also, lipid peroxidation levels were significantly increased, whereas reduced glutathione activity was markedly decreased in the cerebral cortex and the hippocampus brain regions of diabetic rats—this is well in accordance to earlier reports. Treatment with berberine returned the levels of lipid peroxides and reduced glutathione towards their control values in diabetic rats.
Berberine might protect
diabetes-associated memory decline
by reducing oxidative stress in rats.
Treatment with vitamin C also showed berberine-like effects on these parameters. In one of the study’s segments, berberine reduced malondialdehyde (a product of lipid peroxidation) along with superoxide anion activity, while increasing superoxide dismutase levels. It was also shown that berberine inhibited ROS generation. Therefore, berberine might protect diabetes-associated memory decline by reducing oxidative stress in rats.
Berberine might ameliorate
the pathologies of diabetes-induced
cognitive dysfunction through
inhibiting ChE activity.
Cholinergic neurotransmission is a crucial process underlying memory and cognitive function. Cholinergic basal forebrain neurons in the nucleus basalis magnocellular innervate the cerebral cortex, amygdaloid complex, and the hippocampus. These are essential for learning and memory formation. One of the most important mechanisms responsible for correct cholinergic function is performed by ChE. Indeed, several prior studies had found that an increase in ChE activity in the brain is associated to cognitive impairments in diabetics, which is further supported by observation in the present study that donepezil—an AChE inhibitor—improved the diabetes-induced cognitive dysfunction. In support, treatment with berberine restored the increased levels of ChE in diabetic rats. Interestingly, berberine is reported to non-competitively inhibit ChE activity, so berberine might ameliorate the pathologies of diabetes-induced cognitive dysfunction through inhibiting ChE activity.
The finding that berberine
improve pathologies of diabetes-
induced cognitive dysfunction may
involve GLP-1 receptor modulation.
Recently gathering evidence suggests that GLP-1 plays an important role in diabetes and Alzheimer’s disease. In fact, it has been demonstrated that the GLP-1 receptor is involved in learning and neuroprotection. Elsewhere, it was reported that GLP-1 knockout mice exhibited impairment in acquisition and recognition during the Morris water maze task and clearly demonstrated that GLP-1 receptor function in the brain affects synaptic plasticity and cognitive processes. Moreover, GLP-1 enhances glucose-dependent insulin secretion and lowers blood glucose in type 2 diabetes and, currently, an exenatide-GLP-1 receptor agonist is approved for the treatment in type 2 diabetics.
Berberine exerts its beneficial effects
on SI memory dysfunction due to its
antidiabetic, antioxidant, and ChE
Another study also reported that berberine enhances GLP-1 release and biosynthesis. So the finding that berberine improves pathologies of diabetes-induced cognitive dysfunction may involve GLP-1 receptor modulation. More data would be of value to confirm the role of GLP-1 modulation for the effects of berberine.
In conclusion, the findings of the present investigation suggest that berberine exerts its beneficial effects on STZ-induced memory dysfunction due to its antidiabetic, antioxidant, and ChE inhibition activities, which could find clinical use in treating cognitive and neural dysfunction in diabetics. To elucidate the exact mechanism of these modulatory effects, and to examine its potential therapeutic effects, furthers studies are needed.
Diabetes May Double Alzheimer’s Disease Probability
A growing body of literature suggests that diabetes-related cognitive dysfunction is largely a consequence of changes within the CNS that are secondary to chronic hyperglycemia. The cerebrovascular changes, oxidative stress, increased advanced glycation end products, and impairments in cerebral insulin signaling systems are thought to be the underlying causes for diabetic dementias. Furthermore, diabetes seems to double the probability of developing Alzheimer’s disease and other dementias.
As stated above, anti-oxidants, antihyperglycemics, and insulin-sensitizing agents are reported to reduce cognitive dysfunction in diabetes. And recent evidence suggests that GLP-1 plays an important role in diabetes and cognitive dysfunction. As mentioned, it has also been demonstrated that GLP-1 is involved in learning, and neuroprotection. However, at present there are no specific treatments available for the management and/or prevention of cognitive dysfunction in type 2 diabetes.
Berberine for Memory Impairment in Diabetes
In summary, the Indian study demonstrates that treatment with berberine prevents changes in oxidative stress and ChE activity, and as a consequence memory impairment in diabetic rats. STZ-induced diabetes produced marked impairment in cognitive function which was associated with a significant increase in ChE activity and increased oxidative stress in the brain. Chronic treatment with berberine significantly and dose dependently ameliorated cognitive deficits, cholinergic dysfunction, and oxidative stress markers in diabetic rats.
Berberine significantly and dose
cognitive deficits, cholinergic
dysfunction, and oxidative
stress markers in diabetic rats.
Additionally, short-term treatment with berberine significantly reversed behavioral and biochemical changes in STZ-induced diabetic rats, a well-documented model of experimental diabetes. STZ produced significant weight loss, but treatment with berberine restored the same, which is in accordance with earlier reports. Morris-water maze performance in diabetic rats was severely impaired as compared with non-diabetic rats, confirming earlier findings.
The Ascendancy to Higher Brain Power
What if the rats in the Indian experiments had more than a triangle and a circle Morris water maze to help them locate the submerged platform, say a dangling goldthread braid? Then perhaps, as per did Rapunzel’s and Rudabeh’s lovers, they could have ascended from the tank. But that would have voided the experiment. However, they did receive goldthread as berberine, demonstrating that what they required is an ascendency in their brains or cognitive enhancement, something that we all could use.
- Eskildsen S. Asceticism in early taoist religion. New York: State University of New York Press, 1998.
- Bhutada P, Mundhada Y, Bansod K, Tawari S, Patil S, Dixit P, Umathe S, Mundhada D. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 2011 Jan 22. [Epub ahead of print]
- Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61:661–6.
- Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74.
- Messier C. Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging. Neurobiol Aging 2005:S26–30,26S.
Also more technical Berberine Directly Inhibits
Glucose Formation in the Liver
At The Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China, researchers studied berberine, a compound originally identified in a Chinese herbal medicine huanglian (Coptis chinensis), based on previous findings that it improves glucose metabolism in type 2 diabetic patients.
Established berberine mechanisms that reduce blood glucose involve activation of an enzyme that plays a role in cellular energy homeostasis, adenosine monophosphate activated protein kinase (AMPK), and improvement of insulin sensitivity. However, it is not clear if berberine works through other mechanisms.
Pursuing this question in their study, the scientists examined the liver response to berberine in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. It was observed that berberine decreased fasting glucose significantly, along with gluconeogenic genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. Also, liver steatosis was also reduced by berberine and the expression of fatty acid synthase was inhibited in liver.
Also, the activities of transcription factors including Forkhead transcription factor O1, sterol regulatory element-binding protein 1c, and carbohydrate responsive element-binding protein were decreased.
However, the insulin signaling pathway was not altered in the liver. In cultured liver cells, berberine inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) levels.
Altogether, the data suggest that berberine improves fasting blood glucose by direct inhibition of gluconeogenesis (the formation of glucose) in the liver, an action that is independent of insulin activity. This inhibition, the researchers concluded, is likely a result of berberine’s ability to inhibit mitochondria, thus supporting the idea that berberine improves glucose metabolism through an insulin-independent pathway.
- Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011 Feb 3;6(2):e16556.
Berberine, Cinnamon, and Metformin:
Adding to One Another
Recently, at the Institute of Integrative Traditional Chinese & Western Medicine at Huazhong University of Science & Technology in Wuhan, China, researchers studied the effects of a formulation containing berberine (as Rhizoma Coptidis), cinnamon, and metformin, via gastric perfusion along with its individual components on ectopic (outside the usual location) fat accumulation in rats with type 2 diabetes mellitus.
Using a type 2 diabetes rat model, diabetes was induced by injection of streptozotocin, and five groups were formed, one model group and four treated respectively with the combination formulation and its single components, Meanwhile, a normal control group was also set up.
Body weight (BW), liver index (LI), levels of fasting plasma glucose (FPG), fasting serum insulin (FINS) and insulin resistance index (HOMA-IR), plasma activities of liver associated enzymes (LAE), triglyceride (TG) contents and pathological changes of liver, heart and muscle were determined before and after a 8-week treatment.
In the diabetes-induced model rats, as compared with the normal rats, BW, LI, LAE activities, HOMA-IR, TG contents of the liver, heart and muscle were all increased, with pathologic appearance of fatty degeneration in different degrees.
In the treated groups, as compared with the model groups, LI, LAE, HOMA-IR, and TG contents in the liver, heart and muscle tissues were decreased in different extents in the four treated groups, and the histology of tissues in them was restored to near normal.
In the combination formulation treated group, compared with the metformin treated group, the hepatic and muscular TG contents decreased. In the berberine group, the muscular TG content was lower. Also, in the combination-formulation treated group, the gamma-GT level was the lowest in the three Chinese drugs treated groups.
In conclusion, glucose and lipid metabolism disturbances and abnormality of liver function in type 2 diabetes rats were improved by the combination formulation along with its single components. The mechanisms involved might be related to their effects in improving insulin resistance and reducing ectopic fat accumulation. They are likely to be additive.
- Gong YL, Lu FE Dong H. Effects of jiaotai pill and its single components on ectopic fat accumulation in rats with type 2 diabetes mellitus. Zhongguo Zhong Xi Yi Jie He Za Zhi 2010 Dec;30(12):1297-301.
Will Block is the publisher and editorial director of Life Enhancement magazine.