Berberine is an active chemical compound which has the ability to affect cognition and behavior. Berberine is a chemical which can be found naturally in many plants, but it is difficult to acquire adequate dosages through diet alone, so it is low in bioavailability.
Typically, berberine extracts are used in experimental settings and are ordered from pharmaceutical companies, in order to be applied to research. Scientifically, berberine is classified as an isoquinoline alkaloid and has been used clinically as an anti-inflammatory and anti-diabetic supplement.[1]
Berberine is increasingly becoming a well-studied and understood supplement with the potential to be extended into the realm of Neuropsychopharmacology. In fact, many findings have already been gathered with regards to how berberine offers positive benefits to the brain. For example, berberine is neuroprotective against ischemia due to its antioxidant properties.[1]
In this article we will review how berberine impacts behavior and cognition, mainly focusing on depression and memory-related animal models, and taking special consideration of which mazes are most effective at examining particular aspects of behavior.
Berberine Protects Against Stress-Induced Depression
Dysregulation of the hypothalamic-pituitary axis (HPA) is somehow associated with major depression and berberine has been shown to be able to intervene in this interaction. A healthy, normal reaction to stress involves the release of glucocorticoids into the bloodstream, a response which is regulated by the brain’s glucocorticoid receptors. Although glucocorticoids are protective in nature and regulate the organism’s efficient use of energy and material metabolism, the glucocorticoid regulatory function can be damaged by chronic stress. Many studies have shown a relationship between depressive symptoms, very high concentrations of glucocorticoids, and impaired neurogenesis in the hippocampus.
So, to assess the impact of berberine in this chronic-stress related form of depression, a group of scientists used behavioral assays to measure the performance of berberine-treated and non-treated mice which prior to experimentation went through induction of depression via corticosterone injections.
Some of the experimental animals were given berberine hydrochloride supplements which the researchers obtained from a pharmaceutical company. To measure behavior, a Forced Swim Test was given to all of the animals, a test which lasts for 6 minutes and begins by placing the animals in the middle of the water, thus forcing them to swim. The researchers began recording instances of immobility during the last 4 minutes of the test. Immobility is a behavior which is defined as the mouse floating in the water without making any movement or fuss, only exerting minimal motions, in order to keep the head suspended above water.[2]
The mice that were given corticosterone injections, thus inducing depression, had a significantly longer instance of immobility than the control group did, indicating a higher frequency of depressive-like behaviors by being immobile for a prolonged period of time. Interestingly, berberine treatment reduced immobility time in depressed mice, performing at the level of fluoxetine, a commonly distributed anti-depressant (commercially known as Prozac among other trade-names) which is a selective serotonin reuptake inhibitor.
Depressed mice that received berberine were not as immobile as the corticosterone-injected mice which did not receive treatment, indicating less depressive behaviors in the berberine-treated group. The fact that the depressed mice receiving berberine treatment performed at a statistically similar level with mice on medication suggests that berberine can act on the brain in such ways that it affects behavior, cognition, and physiology.[2]
In addition to behavioral effects, neurochemical differences were also noted across groups. Biological differences were revealed following an array of neurochemical tests on the experimental animals’ physiology, required to assess protein concentrations, for example. The depressed mice that did not receive treatment had significantly lower mRNA expression of brain-derived neurotrophic factor (BDNF). The untreated mice also had lower BDNF protein levels in the hippocampus than the healthy controls did. This negative trend of BDNF protein levels and BDNF mRNA expression was reversed when the depressed mice were given supplements of berberine. Also, corticosterone levels decreased when the depressed mice were on the berberine supplementation scheme.[2]
Berberine’s Anxiety Reducing Effect on Behavior
In addition to being able to affect a depressed state, berberine may have the potential to reduce anxiety. To determine exactly the impact that berberine would have on anxious-like behaviors, a group of researchers administered berberine treatment to some mice while administering anxiolytic pharmaceutical medications (diazepam and buspirone) to other mice and then compared behavioral differences between the two conditions.
First, the researchers subjected the mice to the Light/Dark Box, a standard test within the field of behavioral science for assessing anxiety-like behaviors in mice and rats. The Light/Dark Box has two compartments, one is closed off and dark and the other is open and bright because it receives a lot of light. Rodents naturally prefer dark, secluded areas because open, lighted areas are anxiety-invoking to them. The control mice spent more time in the dark compartment, as was expected. The experimental mice on berberine spent more time in the open component, indicating they had lower levels of anxiety than the controls. The mice that were given anxiolytic medications, diazepam and buspirone, performed at the level of the mice on berberine, indicating that these groups performed equally in the Light/Dark Box test.[3]
To further explore how berberine affects anxiety, experimental animals were subjected to the Elevated-Plus Maze, a test which is commonly used to measure rodents’ natural avoidance of open areas and heights. In the Elevated Plus-Maze, the researchers noted that berberine supplementation was associated with an increased time spent in the maze’s open arms, paired with a decreased time spent in the closed arms. Notably, the mice that were given berberine performed at the level of the mice that were supplemented with either buspirone or diazepam, both anxiolytic medications. Such findings are remarkable because it indicates that berberine can act on the level of pharmaceutical medications in certain regards.
In terms of neurochemical assessments, high dosages of berberine were associated with decreased levels of dopamine, norepinephrine, and 5-hydroxytryptamine (of which high levels are associated with anxiety) and increased the levels of vanillylmandelic acid, 5-hydroxy-indole-3-acetic acid, and homovanillic acid.[3]
Such a shift in neurochemical levels and displayed behaviors means that berberine-treated mice had reduced levels of anxiety.
Berberine Protects From Sporadic Alzheimer’s-like Dementia
The sporadic Alzheimer’s like dementia animal model is commonly used by scientists to study Alzheimer’s in animals and is induced methodologically through intracerebroventricular streptozotocin injections (ICV-STZ) via the lateral cerebral ventricles. The following characteristics have been observed in this model:
- Hyperphosphorylation of tau (impairing the ability to bind microtubules)
- Increased acetylcholinesterase (AChE) activity
- Increased oxidative stress
- Increased neuronal apoptosis and accumulation of Aβ peptides
- Insulin resistance and decreased brain glucose utilization
The Journal of Neurotoxicology published a scientific article reporting the results from an experiment that examined the protective role of berberine on memory and anxiety in a sporadic Alzheimer’s-like dementia animal model. The researchers used the Morris Water Maze to study the rodents’ learning and memory abilities. The test was administered to several experimental groups: the healthy control group (one receiving saline and the other berberine supplementation), the ICV-STZ rats receiving no treatment, and the ICV-STZ rats on berberine treatment.
When using the Morris Water Maze to assess learning and memory, it is generally expected to see that repeated trials lead to decreased latency time as a result of learning the hidden platform’s location. The ICV-STZ rats took a longer amount of time to learn the platform’s location and needed to travel a longer distance before reaching it when compared to the control group. This behavioral disadvantage, however, was significantly reduced in the ICV-STZ rats on berberine supplementation, indicating that berberine was able to preserve memory and learning in rats that would have otherwise been subjected to the neurocognitive deficits associated with Alzheimer’s disease.[4]
Since anxiety-like behaviors have been previously reported in the ICV-STZ animal model for sporadic Alzheimer’s-like dementia, the researchers also used the Elevated Plus Maze test to measure anxiety levels in the ICV-STZ rats. This maze is an industry standard for determining anxiety-like behaviors in animals. Researchers quantify behavior simply by counting the number of entries that the experimental animals make into the open or closed arms, as well as the time spent in the open or closed arms. Behaviorally, anxiety is denoted by the prolonged presence in the maze’s closed arms, due to the animals’ natural aversion to open spaces. When compared with the ICV-STZ rats that did not receive treatment, the ICV-STZ rats supplemented with berberine spent a significantly longer amount of time in the open arms of the maze and significantly decreased the amount of time in the closed arms.[4]
Berberine Increases Acetylcholine Levels
The researchers also quantified biological markers in the ICV-STZ rats’ brains, in order to find potential differences across groups as a result of treatment. One of the neurochemical characteristics of Alzheimer’s disease is a decreased concentration of acetylcholine in the cerebral cortex and the hippocampus. Recently, increased acetylcholinesterase activity has been reported in an Alzheimer’s model which would possibly explain the widely observed deficit in the cholinergic system.[4]
ICV-STZ rats had higher levels of AChE activity than the control group did, as was expected. Interestingly, the ICV-STZ rats which were treated with berberine had lower levels of AChE activity than the no treatment group with induced Alzheimer’s-like dementia. In the healthy control groups that received berberine supplements, their AChE levels were no different than those of the saline control group, implying that berberine’s effects become active in a pathophysiological environment.
Berberine Reduces Cognitive Impairment in Alzheimer’s Model
A different experiment, also focusing on Alzheimer’s and memory, utilized TgCRND8 mice, which are widely regarded by the scientific community as being a good transgenic mouse model for Alzheimer’s disease, to examine berberine’s potential as a therapeutic supplement.
The Alzheimer’s disease mice were subjected to the Morris Water Maze and behavioral tendencies were measured across conditions, comparing treated and untreated mice. Experimental results revealed that the TgCRND8 mice which received berberine supplementation had better learning skills and shorter travel distance than the non-treated TgCRND8 control mice. Also, the treated TgCRND8 mice performed better in the probe trial, indicating stronger spatial memory retention than the untreated TgCRND8 control mice.[5] Such behavioral differences mean that berberine can significantly, positively impact the Alzheimer’s mouse model.
Berberine Can Decrease β-amyloid Plaque Concentration
Physiologically, after 4 months of treatment with berberine, the TgCRND8 mice were sacrificed and β-amyloid (Aβ) plaque pathology (biological markers of Alzheimer’s) from the hippocampus and cerebral cortex were closely analyzed. The Aβ plaques’ size and concentration both decreased as a result of berberine treatment.[5]
In a different study, berberine was tested on APP/PS1 mice which are also oftentimes used by researchers as an Alzheimer’s animal model.[6] When given berberine, these mice performed better on the Morris Water Maze and had limited hyperphosphorylation of the tau protein due to the inhibition of the NF-κB signaling pathway.
The administration of berberine has been demonstrated to impact behaviors and brain physiology related to memory and learning in various Alzheimer’s animal models.
Berberine Improves Memory in Diabetes Animal Model
Diabetes comes with an array of problems, including memory dysfunction. A common animal model for inducing diabetes in animals is through streptozotocin administration. In this animal model, memory dysfunction is a result of central nervous system changes, in addition to chronic hyperglycemia, cholinergic dysfunction, prolonged oxidative stress, and alterations in the glucagon-like peptide (GLP).
In a study focusing on the effects of berberine supplementation in streptozotocin-induced diabetes in rats, memory skills were assessed using a Morris Water Maze. When compared to the untreated diabetic rats, those receiving berberine supplementation had decreased escape latency time during the learning period on days 2, 3, 4, and 5. During the probe trial, the treated diabetic rats spent a longer period of time in the target quadrant than the untreated group, indicating that berberine supplementation prevented the memory impairment associated with diabetes in this particular animal model.[7]
Neurochemical analysis revealed that berberine had an impact on the brain’s physiology and composition. Treated diabetic rats had lower cholinesterase activity in the cerebral cortex than their untreated equivalents, a positive outcome given that overactivity of cholinesterase is thought to be responsible for the pathology behind the memory-related cognitive dysfunction. Furthermore, the untreated rats had higher lipid peroxidation levels (high levels are associated with cell damage).
Conclusion
Future research should continue investigating the interactions between berberine and cognition across various animal models. Also, berberine is known to interact with other medicines, but the research available on how this ends up affecting cognition is still limited. In this article, the effects of berberine on a variety of animal models were reviewed, mainly focusing on depression, anxiety, and the memory-related symptoms of Alzheimer’s disease. Also, special consideration was given to how berberine neurochemically affects the brain. Aβ proteins were observed to decrease as a result of berberine administration. Also, it was established that berberine can decrease acetylcholinesterase levels and thereby increases acetylcholine levels, an effect which is quite important in the context of Alzheimer’s animal models.
References
- Ye, Minzhong, et al. “Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research.” Journal of Pharmacy and Pharmacology 61.7 (2009): 831-837.
- Shen, Ji-duo, et al. “Berberine up-regulates the BDNF expression in hippocampus and attenuates corticosterone-induced depressive-like behavior in mice.” Neuroscience letters 614 (2016): 77-82.
- Peng, Wen-Huang, et al. “Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: interaction with drugs acting at 5-HT receptors.” Life Sciences 75.20 (2004): 2451-2462.
- de Oliveira, Juliana Sorraila, et al. “Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death.” Neurotoxicology 57 (2016): 241-250.
- Durairajan, Siva Sundara Kumar, et al. “Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model.” Neurobiology of Aging 33.12 (2012): 2903-2919.
- He, Wenbo, et al. “Berberine attenuates cognitive impairment and ameliorates tau hyperphosphorylation by limiting the self-perpetuating pathogenic cycle between NF-κB signaling, oxidative stress and neuroinflammation.” Pharmacological Reports 69.6 (2017): 1341-1348.
- Bhutada, Pravinkumar, et al. “Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes.” Behavioural brain research220.1 (2011): 30-41.