Berberine is a Multipotent Anti-Alzheimer’s Weapon

Along with use for diabetes, dyslipidemias, and cardiovascular conditions …

Berberine is as near to an armamentarium as you can get 
for addressing the diseases of accelerated aging

Life is that which must overcome itself again and again. 
— Friedrich Nietzsche

Accelerated aging is a new term that is circulating in the longevity community. Essentially, it refers to a disease in which various tissues, organs, or systems of the human body age prematurely. Each accelerated aging disease displays different aspects of aging, yet never every aspect. Consequently, biogerontologists often call such diseases segmental progerias.* One of these is the disease known as Alzheimer’s (DA), which has become one of the most threatening diseases in the elderly. DA accelerates aging of the mind.

*Progeria (also known as Hutchinson–Gilford Progeria Syndrome) is an extremely rare genetic condition wherein symptoms resembling multiple aspects of aging are manifested at an early age.

A Full Armamentarium

In medicine, an armamentarium is the collection of resources that comprise the material and equipment used by healthcare professionals in their practices. There has been no truly efficient therapeutic agent to combat DA, let alone an armamentarium. That said, a growing body of knowledge about the plant derivative berberine is finding that this natural isoquinoline alkaloid possesses a wide range of pharmacological effects, and in fact is as near to an armamentarium as you can get with regard to diseases of accelerating aging, including DA.

Alzheimer’s accelerates 
aging of the mind.

In a new study, conducted at Shandong University of Technology in China, researchers have reviewed berberine’s multiple activities including its antioxidant, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory, monoamine oxidase inhibitory, amyloid-beta (Aβ) peptide-level reducing, and cholesterol-lowering activities.¹ In other words, berberine helps prevent oxidation damage to biomolecules in the brain, inhibits enzymes which breakdown important memory molecules, reduces peptides that interfere with proper memory function, and lowers lipids that interfere with cerebral blood flow. Together, these capacities suggest that berberine may act as a promising multipotent agent to combat DA, one of the most threatening diseases in the elderly with the accelerated aging of human society.

Berberine is isolated from the Chinese herb Rhizoma coptidis, which has been widely used in Chinese herbal medicine. It is also found in such plants as Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (Barberry), and Berberis aristata(Tree Turmeric)], Hydrastis canadensis (Goldenseal), Phellodendron amurense (Amur Cork Tree, Huang Bai, Huang Po, Po Mu), Coptis chinensis (Chinese Goldthread, Huang-Lian, Huang-Lien), and Tinospora cordifolia, as well as other plants. Berberine is usually found in the roots, rhizomes, stems, and bark.

Growing Biomedical Attention Paid to Berberine

In recent years, berberine has gained much attention owing to its multiple biochemical and pharmacological effects, including anticancer, antiviral, antifungal, and antibacterial activities. And more … . Evidence is amassing that berberine also possesses significant potential to treat DA. A recent study has found that the accumulation of Aβ peptide derived from amyloid precursor protein (APP) is a triggering event leading to the pathological cascade of DA.² Thus, the inhibition of Aβ production should be a rational therapeutic strategy in the prevention and treatment of DA. The paper went on to report that berberine reduces Aβ levels by modulating APP processing in human neuroglioma* cells without cellular toxicity. This alone indicates that berberine would be a promising candidate for the treatment of DA.

*A tumor formed of overgrowth of the neuroglia; a glioma.

Evidence is amassing that berberine 
also possesses significant potential to 
treat Alzheimer’s disease.

In another recent study, it was demonstrated that administration of berberine (50 mg/kg)^† once daily for 14 days significantly reduced spatial memory impairment in a rat-DA model.³ Indeed, in the past decade (1999–2008), there have been more than 2,000 published papers studying the clinical application, pharmacodynamic mechanism, and structure-activity relationship of berberine and its derivatives.⁴ Of these, a significant number have studied berberine’s effects on cerebral ischemia mental disease, DA, etc., demonstrating that berberine has wide physiologic functions and great potential for structural modifications.

†The human equivalent would be 689 mg/day for a 187 lb person.

Berberine has also been found to 
inhibit lipid peroxidation, thus 
showing protective effects against 
low-density lipoprotein (LDL-C, the 
“bad” cholesterol) oxidation.

Aluminum toxicity has long been associated with DA, certainly with neural toxicity. A rat brain damage model was established via administration of 400 mg/kg of elemental aluminum once a day, 5 days a week for 12 weeks.⁵ When either the rhizome of C. chinensis (a plant containing berberine) or berberine was administered 4 hours after each aluminum administration for 12 weeks, the morphological changes of the neurons of the rat hippocampus and the changes of rat learning and memory functions were observed. Both were found to have protective effects on neurodegeneration induced by aluminum overload.

Other studies have found that berberine has multiple neuropharmacological properties, such as neuroprection, anti-neuronal apoptosis, and the ability to improve cerebral microcirculation and DA.⁶ In another study, when the effects of six protoberberine alkaloids were evaluated, the results indicated that C. chinensis alkaloids have a strong potential of inhibition and prevention of DA mainly through both cholinesterase and Aβ pathways, and additionally through antioxidant capacities.⁷

Many berberine studies show that 
berberine exerts inhibitory effects 
against AChE.

Antioxidant Activity

Oxidative damage has been shown to play an important role in the pathogenesis of DA.⁷ Cellular oxidative stress and/or nitrosative stress, including augmentation of protein oxidation, protein nitration, lipid peroxidation, and glycoloxidation are involved in DA. In many studies, the antioxidant activity of berberine has been widely demonstrated. Initially, it was reported that berberine can scavenge reactive oxygen species and reactive nitrogen species. For instance, among the reactive nitrogen species, peroxynitrites generated through the reaction between nitric oxide and superoxide anion radical in vivo has been implicated in Aβ formation and accumulation. Prior studies have shown that berberine can scavenge both nitric oxide and peroxynitrites. Berberine has also been found to inhibit lipid peroxidation, thus showing protective effects against low-density lipoprotein (LDL-C, the “bad” cholesterol) oxidation. Plus, researchers have found that berberine can bind catalyzing metal ions, thus reducing the concentration of metal ions that promote lipid peroxidation.

Curiously, berberine has been 
demonstrated to inhibit both MAO-A 
and MAO-B.

AChE and BChE Inhibitory Activity

In the central nervous system, AChE is abundantly present where its main role is to catalyze the hydrolysis of the neurotransmitter acetylcholine (ACh) to choline, thus returning an activated cholinergic neuron to its resting state. It should come as no surprise to readers of this publication that DA is associated with a deficiency in the brain of ACh. Accordingly, because AChE is an important pathogenic factor of DA, most pharmacological studies that screen agents to combat DA have focused on AChE inhibitors (such as galantamine) to alleviate cholinergic deficit and improve neurotransmission. As well, BChE plays an important role in the etiology (causality) and disease progression of DA beyond regulation of synaptic ACh levels. Indeed, Aβ neurotoxicity is amplified when BChE is added to Aβ in tissue culture. Findings such as these support a probable role for BChE inhibition in DA.

Berberine’s Non-Anti-Alzheimer’s Benefits Berberine has been tested and used successfully in experimental and human diabetes mellitus, both type 2 and type 1 (see “Berberine Gives Diabetes the 1–2 Punch” in the August issue). In this metabolic disease, it has been shown to lower elevated blood glucose as effectively as metformin (see “Berberine is Superior to Metformin” in the July, 2011 issue). Berberine works in several ways. First, by inhibiting of aldose reductase, it induces glycolysis, thus preventing insulin resistance by increasing insulin receptor expression and acting like incretins (gastrointestinal hormones that cause an increase in the amount of insulin). One new study proffered the idea that berberine may overcome insulin resistance via modulating key molecules in the insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells. In this way, berberine may modulate glucokinase activity, rendering pancreas β cells more sensitive to glucose fluctuation and to respond more effectively to glucose challenge. As well, berberine seems to inhibit hyperglycemic factors and suppress intestinal disaccharidases with beneficial metabolic effects in diabetic states. A recent comprehensive metabolic analysis applied to 60 type 2 diabetics suggested that the administration of berberine down-regulates the high level of free fatty acids, which are known to be toxic to the pancreas and cause insulin resistance. Also, berberine has been shown to boost the effects of the diabetic drugs metformin and 2,4-thiazolidinedione (THZ), and can partly replace these commercial drugs, which could lead to a reduction in toxicity and side effects associated with the drugs. Then, berberine inhibits FoxO1, which integrates insulin signaling with mitochondrial function. FoxO1 is a member of the forkhead family of transcription factors and among its functions, it is believed to induce insulin resistance. Inhibition of FoxO1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome. Lipids Improving Effects Also, berberine lowers total cholesterol, LDL-C, triglycerides, and atherogenic apolipoprotein B (Apo B), but its mechanism of action is distinct from statins. This is complicated. Berberine reduces LDL-C by up-regulating LDL receptor (LDL-R) mRNA expression while down-regulating a natural inhibitor of (LDL-R), and increasing in the liver the expression of LDL-Rs through the extracellular signal-regulated kinase signaling pathway. Statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reductase. This rate-controlling enzyme of the mevalonate pathway interferes with CoQ10 metabolism. Berberine doesn’t use this pathway, explaining why it does not cause some of the side effects typical of statins. Finally, berberine seems to improve the arterial endothelial function in humans by activating AMP-activated protein kinase (AMPK)—specifically extracellular signal-regulated kinases (ERK)—which plays a central role in glucose and lipid metabolism, suppresses proinflammatory cystokines, and reduces matrix metallopeptidase enzymes and metalloproteinase protein expression, which are all beneficial changes for heart health.

At the same time, many berberine studies show that berberine exerts inhibitory effects against AChE. One study reported that berberine can inhibit AChE with relatively small amounts of berberine. Regarding the molecular mechanisms underlying the inhibition of AChE with berberine, another paper proposed that the binding of berberine to AChE is principally driven by a favorable entropy increase and that the inhibition of AChE with berberine consists of the main contributions of interaction as well as minor conformation change of AChE induced by berberine. Also, berberine is found to be a BChE inhibitor at low amounts. Berberine acts as a dual inhibitor of AChE and BChE.

MAO Inhibitory Activity

There are two isoforms of monoamine oxidase (MAO) inhibitors in humans, MAO-A and MAO-B. MAO-A inhibitors have proven to be effective antidepressants, but they are no longer in widespread use. MAO-B inhibitors are potential agents used to combat neurodegenerative diseases, including DA and Parkinson’s disease. Deprenyl (selegeline) is such an inhibitor. Curiously, berberine has been demonstrated to inhibit both MAO-A and MAO-B.

Aβ Level-Reducing Activity

When Aβ accumulates and aggregates in the brain, it represents a central event in the pathogenesis of DA. Aβ is generated from amyloid precursor protein (APP), and consequently the inhibition of Aβ generation would seem to be a promising strategy for treating DA. And guess what? Berberine has been reported to reduce Aβ levels by altering APP processing in human neuroglioma cells that stably express a certain type of APP at a low range concentration and without cellular toxicity.

Cholesterol-Lowering Activity

An epidemiologic study has indicated that cholesterol-lowering drugs are associated with a decreased prevalence of DA. In an investigation of how cholesterol might modulate Aβ deposit formation, researchers proposed that decreased neuronal cholesterol levels can inhibit the Aβ-forming amyloidogenic pathway, possibly by removing APP from membrane microdomains and reduce the ability of Aβ to act as a seed for further fibril formation.

Moreover, when other researchers reviewed the molecular mechanisms underlying the cholesterol-DA relationship, they too proposed that cholesterol-lowering agents have great potential to combat DA. Indeed, the oral administration of berberine can effectively reduce serum cholesterol and LDL-C levels in hyperlipidemic hamsters and human hypercholesterolemic patients. Once again, the mechanisms of berberine in these regards are different than those of the statin drugs.

Berberine has a positive 
safety profile and is generally 
considered to be non-toxic at doses 
used in clinical situations.

Other Anti-DA Activities

Could there be more? Yes. Emerging evidence indicates that diabetes can be a risk factor for DA. This is most likely because it is associated with an impairment of insulin signaling in the brain. A recent study found that the diabetes drug liraglutide proved to prevent key neurodegenerative developments in a mouse model of DA. In tandem, the efficacy and safety of berberine for the treatment of type 2 diabetes have been reported. This reinforces berberine’s anti-DA potential, which is further supported by the recently reported beneficial effect of berberine in ameliorating memory dysfunction in a rat model of streptozotocin-induced diabetes (see “Berberine Goldthread Enhances Memory” in the April, 2011 issue).

Also, it has been found that glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide and has been recognized as an attractive agent to treat type 2 diabetes (see “Berberine is Superior to Metformin” in the July, 2011 issue). It has been proven that GLP-1 protects neurons from toxic effects and proposed as a novel therapeutic target for intervention in DA. And former studies have found that berberine treatment can increase GLP-1 amide secretion in streptozotocin-induced diabetic rats and that it can also modulate GLP-1 release as demonstrated both in vivo and in vitroexperiments. Berberine’s effects on GLP-1 may also contribute its anti-DA potential.

Berberine May Empower Mitochondria

Continuing, mitochondria have been found to be central players in mediating neuronal stress relevant to the pathogenesis of DA. Indeed, mitochondrial dysfunction and energy deficiency are an early feature of DA. One report found that berberine is accumulated by the mitochondria of a mouse melanoma cell line, leading to mitochondrial fragmentation and dysfunction. Yet, while in isolated mitochondrial fractions, berberine is toxic to mitochondria. Whether the mitochondrial effect of berberine is beneficial to DA treatment is not clear and requires more study.

Berberine can effectively reduce 
serum cholesterol and LDL-
cholesterol levels in hyperlipidemic 
hamsters and human 
hypercholesterolemic patients.

When taken all together, berberine possesses multiple activities which are involved in anti-DA potential. These activities include antioxidant activity, AChE and BChE inhibitory activity, MAO inhibitory activity, and berberine’s abilities to reduce Aβ level and to lower cholesterol. What’s more, berberine has a positive safety profile and is generally considered to be non-toxic at doses used in clinical situations. It also lacks genotoxic, cytotoxic or mutagenic activity and can be administered orally while it can pass through the blood-brain barrier. Therefore, a strong case cann be made that berberine is a potential multipotent agent for combating DA. This is a very promising supplement that slings its own armamentarium in the battle for significantly better memory health. Berberine is a supplement you should pay more attention to, and perhaps as a consequence be more able to do so.

References

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