Skip to main content

Neuroprotective effects of berberine in animal models of Alzheimer’s disease: a systematic review of pre-clinical studies



Berberine is an isoquinoline alkaloid extracted from various Berberis species which is widely used in East Asia for a wide range of symptoms. Recently, neuroprotective effects of berberine in Alzheimer’s disease (AD) animal models are being extensively reported. So far, no clinical trial has been carried out on the neuroprotective effects of berberine. However, a review of the experimental data is needed before choosing berberine as a candidate drug for clinical experiments. We conducted a systematic review on AD rodent models to analyze the drug effects with minimal selection bias.


Five online literature databases were searched to find publications reporting studies of the effect of berberine treatment on animal models of AD. Up to March 2018, 15 papers were identified to describe the efficacy of berberine.


The included 15 articles met our inclusion criteria with different quality ranging from 3 to 5. We analyzed data extracted from full texts with regard to pharmacological effects and potential anti-Alzheimer’s properties. Our analysis revealed that in multiple memory defects animal models, berberine showed significant memory-improving activities with multiple mechanisms, such as anti-inflammation, anti-oxidative stress, cholinesterase (ChE) inhibition and anti-amyloid effects.


AD is likely to be a complex disease driven by multiple factors. Yet, many therapeutic strategies based on lowering β-amyloid have failed in clinical trials. This suggest that the threapy should not base on a single cause of Alzheimer’s disease but rather a number of different pathways that lead to the disease. Overall we think that berberine can be a promising multipotent agent to combat Alzheimer’s disease.

Peer Review reports


Alzheimer’s disease (AD) is a progressive degenerative disease of the central nervous system. Its main clinical manifestations are progressive declines in memory and cognitive function, accompanied by psychiatric symptoms and abnormal behavior. AD mostly occurs in elderly persons over 65 years of age. According to 2017 statistics, there are nearly 46 million AD patients worldwide [1, 2]. In the brain, senile plaques (SP) and neurofibrillary tangles (NFT) are the diagnostic hall markers of AD. Its other pathological features include diffuse atrophy of the cortex, widening of the sulcus, enlargement of the ventricles, loss of neurons and decreases in choline acetylase and acetylcholine levels. The etiology of AD is still elusive, and several hypotheses have been proposed to explain the pathogenesis of AD. The most prevalent hypotheses are the amyloid β-protein (Aβ) cascade hypothesis [3, 4], hyper-phosphorylated Tau hypothesis [4], the free radical theory [5], the inflammatory theory [6] and cholinergic hypothesis [7]. The diversity and uncertainty of the pathogenesis of AD have caused difficulties in the development of effective treatment, and most of the clinical trials performed in recent decades have failed.

Berberine is an isoquinoline alkaloid that is widely present in several medicinal plants, especially in those belonging to the Berberis genus (e.g., Berberis vulgaris L., Berberidaceae). It also occurs, for example, in Coptis chinensis Franch. (Ranunculaceae), a plant which is used in traditional Chinese medicine as an anti-diarrheal, anti-bacterial, anti-fungal, and anti-protozoal agent, particularly in combination with other herbs [8,9,10]. The chemical structure of berberine is shown in Fig. 1. In several years, accumulating evidence has revealed a wide variety of bioactivities of berberine such as antiviral, antibacterial and anti-inflammatory [11, 12].

Fig. 1
figure 1

Chemical structures of berberine

The pharmacological effect of berberine on the nervous system was first reported in the 1970s as sedation-inducing [13]. The therapeutic activity of berberine has been widely examined in various neurological conditions including cerebral ischemic injury, AD, Parkinson’s disease, depression, anxiety, Huntington’s disease, epilepsy and convulsions. Several studies have shown that berberine can alleviate AD pathology through various mechanisms, including inhibition of hyper-phosphorylation of Tau protein and Aβ production. Berberine can reduce the hyper-phosphorylation of Tau protein, and this reduction may be related to the activation of the phosphatidylinositol 3-kinase/protein kinase/glycogen synthase kinase 3 pathway to restore protein phosphatase 2A activity and reverse glycogen synthase kinase-3 (GSK-3) activation [14]. In addition, berberine can inhibit the expression of beta-secretase by activating the extracellular signal-regulated kinase 1/2 signaling pathway, thereby inhibiting the production of Aβ40/42 [15]. Moreover, researchers have recently revealed that, on a molecular basis, berberine exerts inhibitory effects on the four key enzymes in the pathogenesis of AD: acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A, and monoamine oxidase B [16].

Before this, several experiments have been performed to evaluate the anti-AD properties of berberine. However, these pre-clinical studies have not been systematically analyzed to provide a whole picture and un-biased understanding of the therapeutic potential of berberine for AD. The aim of this systematic review is to summarize the current evidence and analyze that evidence as to what it reveals about the underlying mechanism of the protective effects of berberine in animal AD models. We hope to provide more insightful information for future clinic trials.

To perform the systematic review, we searched the literatures and selected the studies passing our selection criteria for data extraction and analysis. Our search of electronic databases returned a total of 91 articles. After deleting 16 which contained duplicated experimental data, we had a total of 72 references. After reading the titles and abstracts, we deleted 57 papers for the following reasons: (1) Not including experiments on animal models; (2) Not directly administering berberine; (3) No experimental details provided. Thus, finally, we had 15 articles that reported the efficacy of berberine in AD animal models; this review is based on these articles (Fig. 2).

Fig. 2
figure 2

Research methodology for review process


Literature search

A careful literature search was performed to find publications reporting studies of the effect of berberine treatment on animal models of AD. Online literature databases (PubMed, Google scholar, PsychINFO, Embase and Web of Science) were searched up to March 2018 using search terms for English or Chinese publications. The following search strategy was used for each database.

  1. 1.


  2. 2.

    Alzheimer’s Disease

  3. 3.

    Alzheimer Disease

  4. 4.


  5. 5.


  6. 6.

    1 and 5

Inclusion/exclusion criteria and screening

Inclusion criteria

  1. (1)

    Berberine was administered alone.

  2. (2)

    Experimental AD was induced in rodents (i.e., rats or mice).

  3. (3)

    AD treatment group was treated with a pharmacological agent, and a control group was administered a placebo after injury.

  4. (4)

    Article was published in English or Chinese.

Exclusion criteria

  1. (1)

    Not an original paper (review or letter etc.);

  2. (2)

    Berberine was not administered alone.

  3. (3)

    Absence of a correct control group.

  4. (4)

    Other types of animals (e.g., sheep, cats, and dogs) were used.

  5. (5)

    Duplicate publications.

Data extraction and quality assessment

Data extraction

Two investigators independently screened papers and listed them based on publication year, the first author’s name and experimental models. Using a structured form, they extracted individual data on study characteristics, methods and outcome measures. The differences in papers selected were resolved through discussion. Finally, the methodological quality of the included basic research was assessed by applying six correction scales.


The search strategy retrieved 91 papers through online literature databases (PubMed, Google scholar, PsychINFO, Embase and Web of Science), 15 papers met our selection criteria. These 15 studies evaluated in this review involved animals from two species and four varieties: TgCRND8 mice, APP/PS1 mice, Sprague Dawley rats and Wister rats. The scales of the studies varied, from 6 to 104 animals in a single study. Rat and mouse weights were 200–300 g and 20–55 g, respectively. Eleven studies used male animals, and 1 study used female rats. After selecting and classifying these 15 studies, 3 were diabetic rat models with memory-impairment, 2 were 3 × Tg-AD mice models, 2 were Aβ infused rats models, 1 was an APP/PS1 mice model, 1 was a (Pilo)-induced epilepsy rat model, 1 was an ibotenic acid (ibo)-induced rat model and 5 memory-impairment models induced by Scopolamine, ICV-STZ, ethanol and D-galactose respectively. The research parameters evaluated in the 15 studies included the Morris water maze, immunohistochemistry (IHC), Western blot, RT-PCR (reverse transcription-polymerase chain reaction) and ELISA. The Morris water maze, a behavior test, was used to evaluate memory function. The IHC method as a molecular biology technique was used to investigate neuroprotective effects. Western blot, ELISA and RT-PCR techniques were used to measure potential genetic and proteins markers involved in Alzheimer’s disease. Table 1 lists the basic characteristics of the 15 studies.

Table 1 Basic information of included studies

Methodological quality

We assessed the scores of the quality according to these 6 points:

A: peer reviewed publication; B: random allocation to group; C: blinded assessment of outcome; D: a sample size calculation; E: compliance with animal welfare regulations; F: a statement of a potential conflict of interest.

The quality items scored in the included studies ranged from 3 to 5 out of a total of 6 points as shown in the Table 2. Two of the studies (13.3%) achieved 3 points; seven studies (46.7%) achieved 4 points; and Six studies (40%) achieved 5 points.

Table 2 Methodological quality of included studies

Table 2 shows the Methodological quality of the 15 reviewed studies.

Anti-Alzheimer’s disease mechanisms of berberine

Table 3 shows the main outcomes and results of the included studies. Twelve studies investigated whether berberine improved cognitive abilities; four studies examined hippocampal cells of CA1 region and apoptosis of pyramidal neurons in the CA1 area. The changes in oxidative stress and acetylcholinesterase (AChE) activity were examined in 8 studies. Three studies tested NF-kB signaling. In addition, one study reported that berberine induced autophagy to reduce the APP and BACE1 levels. The above proposed neuroprotective mechanisms of berberine are summarized in Fig. 3.

Table 3 Anti-AD effects and underlying mechanisms after berberine treatment of included studies
Fig. 3
figure 3

Reported potential mechanisms underlying anti-AD property of berberine


Potential mechanisms underlying anti-Alzheimer’s disease properties of berberine

The neuroprotective effects of berberine have been extensively studied in different animal experimental models and we summarized the studies which include a rat model of amyloid beta induced-Alzheimer’s disease, a memory impairment model induced by ethanol in rats, a D-galactose-induced memory deficits model in rats, a pilocarpine (Pilo)-induced epilepsy model in rats, a scopolamine and streptozotocin-induced memory impairment model in rats, a memory-deficient rat model induced by stereotaxic injection of ibotenic acid into entorhinal cortex (Ibo model), and the transgenic mouse model of Alzheimer’s disease. Interestingly, berberine displayed significant effects in preventing memory impairment in these mechanistically different animal models, suggesting an over-all improvement of memory function by berberine. Indeed, mechanistic studies showed that berberine modulated a wide range of biological functions to exert neuroprotection and the detailed mechanisms are discussed in the following part.

  1. (a)

    Antioxidant properties of berberine

Alzheimer’s disease is characterized by extensive evidence of oxidative stress which is the result of uncontrolled production of reactive oxygen species (ROS) [35]. ROS has been regarded as a critical factor in the neuron dysfunction or death of neuronal cells that contribute to the pathogenesis of the disease [36]. Under normal conditions, the damage caused by oxygen free radicals can be controlled through a series of reactive antioxidant systems. However, under pathological conditions, the balance between oxidants and antioxidants is disturbed such that active oxygen production exceeds cellular antioxidant defenses. The antioxidant activity of berberine has been widely demonstrated [34, 37,38,39]. For instance, berberine displayed peroxynitrite (ONOO) scavenging activity and total ROS inhibitory capacities [37]. Bhutada et al. [27] showed that berberine treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats.

  1. (b)

    Anti-inflammatory properties of berberine

In the brain of patients with Alzheimer’s disease, chronic inflammation has been well described. On the histological level, this inflammation is characterized by activated microglia, reactive astrocytes and increased inflammatory cytokines release [33]. This observation has led to the hypothesis that brain inflammation is a cause of neuronal damage in AD and anti-inflammatory drugs may be used as protective agents. Chen et al. [18] studied the functions of berberine involved in anti-inflammation and the amelioration of insulin resistance in the prefrontal cortex of diabetic rats. They found that intragastric administration of berberine (187.5 mg/kg/d) inhibited inflammation mediator release and insulin resistance in the mPFC of diabetic rats. Finally, it relieved the impairment of cognitive function in diabetic rats. The promising effect of Phellodendron amurense (PA) and its major alkaloid compound, berberine, on memory dysfunction has also been studied in scopolamine-induced memory deficient rats [26]. A two-week administration of 20 mg/ kg of berberine improved memory impairment as measured by the passive avoidance test, and it reduced the escape latency for finding the platform in the Morris water maze test.

  1. (c)

    Anti-cholinesterase activity of berberine

The cholinergic hypothesis was initially presented several years ago, then several studies demonstrated the adverse effects of anticholinergic drugs on memory [40], the low intracerebral cholinergic activity in patients with Alzheimer’s disease (AD) [41, 42] and the association of AD with cholinergic transmission disorders [43]. This hypothesis suggests that decreased cholinergic activity is associated with the AD symptoms and the improvement of cholinergic activity will relieve the AD symptoms. The cholinesterase (ChE) is the major enzyme for acetylcholine destruction and its inhibition results in increasing acetylcholine level in the brain. Therefore, many anti-AD pharmacological studies have focused on cholinesterase (ChE) inhibitors to ameliorate the cognitive symptoms [44]. Several studies have been performed to examine the effect of berberine on the ChE activity. For example, chronic treatment with berberine (25–100 mg/kg) lowered oxidative stress and ChE activity in ethanol treated rats [21]. A similar promising effect of one-month treatment with berberine on streptozotocin-induced memory impairment in rats has been reported [20]. In another set of experiments, berberine (100 mg/kg) treatment during training trials also improved learning and memory and lowered hyperglycemia, oxidative stress, and ChE activity [27].

  1. (d)

    Anti-amyloid activity of berberine

The 42-amino acid amyloid beta (Aβ) is released from cleavage of the amyloid precursor protein by β-secretase and γ-secretase [45]. The Aβ sequenced from the meningeal blood vessels of AD patients and individuals with Downs’ syndrome is highly aggregated, and spontaneously assumes the β-sheet conformation and polymerizes into oligomers, fibrils, fibrils and plaques [46]. Berberine has been shown to ameliorates β-amyloid pathology and cognitive impairment in an AD transgenic mouse model [19]. After berberine treatment, the levels of extracellular and intracellular Aβ1–42 were decreased, mediated by increased autophagy activity.

With advances in science, there is increasing interest in another constituent of neurofibrillary tangles(NFTs), hyper-phosphorylated Tau protein. He et al. found that berberine improved learning and memory in APP/PS1 mice, decreased hyper-phosphorylated Tau protein and lowered the activity of NF-kB signaling in the hippocampus of APP/PS1 mice [17]. Berberine administration promoted the activity of glutathione (GSH) and inhibited lipid peroxidation in the hippocampus of AD mice. They concluded that berberine attenuated cognitive deficits and limited hyper-phosphorylation of Tau via inhibiting the activation of the NF-kB signaling pathway and by retarding oxidative stress and neuro-inflammation.

Opportunities and challenges

Berberine is a natural product with a definite structure and a wide range of pharmacological effects. Berberine displays many biological functions and potential therapeutic applications in neurological diseases. Animal research is an essential early step toward evaluating and developing an intervention for clinical trials in humans [31]. This systematic review has examined high quality animal studies on the anti-AD effects of berberine and finds a consistent effect of berberine in improving the memory defects in multiple animal models, indicating the therapeutic potential of berberine for treating AD. While the effects are clear, the mechanism is not; further research is needed to determine the details of the biochemical mechanisms and specific drug target(s). Meanwhile, perhaps the greatest barrier to the pharmaceutical development of berberine is its naturally low bioavailability. More effort, for example, in structural modification and/or pharmaceutical processing, is needed for berberine to achieve its full potential in clinical use [32]. The following suggestions are worth considering: 1. The feasibility of targeted drug delivery should be explored. It is difficult to achieve effective concentrations, especially in the brain, by oral administration so targeted administration is worth considering; 2. The effects of berberine in combination with other drugs for AD treatment can be tested. 3. The possibility of toxic effects of berberine during long-term drug administration must be considered, and thoroughly studied.


In this paper, we have reviewed 15 high-quality animal studies on the neuroprotective effects of berberine against AD, with systematic evaluation of its efficacy and pharmacology mechanisms. Berberine has showed significant memory-improving activities in multiple memory defects animal models; common properties, including anti-oxidation, anti-inflammation and anti-ChE activity were revealed. So far, no clinical trial has been carried out on the neuroprotective effects of berberine. Considering the positive results from animal studies and the relatively low toxicity of berberine, the performance of clinical trials to evaluate the anti-AD effect of berberine on human patients appears justified.





Alzheimer’s disease


β-site amyloid precursor protein cleaving enzyme 1




Cyclic adenosine monophosphate


CD45 Antigen


Field excitatory postsynaptic potential


Glial fibrillary acidic protein


Intracerebroventricular streptozotocin


Interleukin 1 beta


Mitogen-activated protein kinases


The medial prefrontal cortex


Morris water maze


Nuclear factor kappa-light-chain-enhancer of activated B cells


Positron-Emission Tomography


Protein kinase C epsilon type


Protein kinase C-eta type


Reverse Transcription Polymerase Chain Reaction


Tumor necrosis factor alpha

WB analysis:

Western Blot analysis


  1. Krantic S. Editorial (thematic issue: from current diagnostic tools and therapeutics for Alzheimer's disease towards earlier diagnostic markers and treatment targets). Curr Alzheimer Res. 2017;14:2–5.

    Article  CAS  Google Scholar 

  2. Association As. 2017 Alzheimer's disease facts and figures. Alzheimers Dement. 2017;13:325–73.

    Article  Google Scholar 

  3. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991;12:383–8.

    Article  CAS  Google Scholar 

  4. Mudher A, Lovestone S. Alzheimer's disease–do tauists and baptists finally shake hands? Trends Neurosci. 2002;25:22–6.

    Article  CAS  Google Scholar 

  5. Su B, Wang X, Nunomura A, Moreira PI, Lee H-g, Perry G, Smith MA, Zhu X. Oxidative stress signaling in Alzheimer's disease. Curr Alzheimer Res. 2008;5:525–32.

    Article  CAS  Google Scholar 

  6. Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK. New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-α inhibitors, and GLP-1 receptor agonists. Ann N Y Acad Sci. 2004;1035:290–315.

    Article  CAS  Google Scholar 

  7. Terry AV, Buccafusco J. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821–7.

    Article  CAS  Google Scholar 

  8. Mirska I, Kedzia H, Kowalewski Z, Kedzia W. The effect of berberine sulfate on healthy mice infected with Candida albicans. Arch Immunol Ther Exp. 1972;20:921–9.

    CAS  Google Scholar 

  9. Yamamoto K, Takase H, Abe K, Saito Y, Suzuki A. Pharmacological studies on antidiarrheal effects of a preparation containing berberine and geranii herba. Nihon yakurigaku zasshi Folia pharmacologica Japonica. 1993;101:169–75.

    Article  CAS  Google Scholar 

  10. Ou M. Chinese–English manual of common used in traditional Chinese medicine. Hong Kong: Guangdong Science and Technology Publishing House. In: Joint Publishing (HK); 1999.

  11. Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res. 2008;22:999–1012.

    Article  CAS  Google Scholar 

  12. Kuo C-L, Chi C-W, Liu T-Y. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004;203:127–37.

    Article  CAS  Google Scholar 

  13. Shanbhag S, KULKARNI HJ, Gaitonde B. Pharmacological actions of berberine on the central nervous system. Jpn J Pharmacol. 1970;20:482–7.

    Article  CAS  Google Scholar 

  14. Yu G, Li Y, Tian Q, Liu R, Wang Q, Wang J-Z, Wang X. Berberine attenuates calyculin A-induced cytotoxicity and tau hyperphosphorylation in HEK293 cells. J Alzheimers Dis. 2011;24:525–35.

    Article  CAS  Google Scholar 

  15. Durairajan SSK, Liu L-F, Lu J-H, Chen L-L, Yuan Q, Chung SK, Huang L, Li X-S, Huang J-D, Li M. Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model. Neurobiol Aging. 2012;33:2903–19.

    Article  CAS  Google Scholar 

  16. Ji H-F, Shen L. Molecular basis of inhibitory activities of berberine against pathogenic enzymes in Alzheimer's disease. Sci World J. 2012;2012.

  17. He W, Wang C, Chen Y, He Y, Cai Z. Berberine attenuates cognitive impairment and ameliorates tau hyperphosphorylation by limiting the self-perpetuating pathogenic cycle between NF-κB signaling, oxidative stress and neuroinflammation. Pharmacol Rep. 2017;69:1341–8.

    Article  CAS  Google Scholar 

  18. Chen Q, Mo R, Wu N, Zou X, Shi C, Gong J, Li J, Fang K, Wang D, Yang D. Berberine ameliorates diabetes-associated cognitive decline through modulation of aberrant inflammation response and insulin signaling pathway in DM rats. Front Pharmacol. 2017;8:334.

    Article  Google Scholar 

  19. Huang M, Jiang X, Liang Y, Liu Q, Chen S, Guo Y. Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of β-amyloid in APP/tau/PS1 mouse model of Alzheimer's disease. Exp Gerontol. 2017;91:25–33.

    Article  CAS  Google Scholar 

  20. de Oliveira JS, Abdalla FH, Dornelles GL, Adefegha SA, Palma TV, Signor C, da Silva BJ, Baldissarelli J, Lenz LS, Magni LP. 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. 2016;57:241–50.

    Article  Google Scholar 

  21. Patil S, Tawari S, Mundhada D, Nadeem S. Protective effect of berberine, an isoquinoline alkaloid ameliorates ethanol-induced oxidative stress and memory dysfunction in rats. Pharmacol Biochem Behav. 2015;136:13–20.

    Article  CAS  Google Scholar 

  22. Haghani M, Shabani M, Tondar M. The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity. Eur J Pharmacol. 2015;758:82–8.

    Article  CAS  Google Scholar 

  23. Zhan P-Y, Peng C-X, Zhang L-H. Berberine rescues D-galactose-induced synaptic/memory impairment by regulating the levels of arc. Pharmacol Biochem Behav. 2014;117:47–51.

    Article  CAS  Google Scholar 

  24. Gao F, Gao Y, Liu Y-F, Wang L, Li Y-J. Berberine exerts an anticonvulsant effect and ameliorates memory impairment and oxidative stress in a pilocarpine-induced epilepsy model in the rat. Neuropsychiatr Dis Treat. 2014;10:2139.

    Article  Google Scholar 

  25. Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A. Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol. 2013;698:259–66.

    Article  CAS  Google Scholar 

  26. Lee B, Sur B, Shim I, Lee H, Hahm D-H. Phellodendron amurense and its major alkaloid compound, berberine ameliorates scopolamine-induced neuronal impairment and memory dysfunction in rats. Korean J Physiol Pha. 2012;16:79–89.

    Article  CAS  Google Scholar 

  27. 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;220:30–41.

    Article  CAS  Google Scholar 

  28. Lim JS, Kim H, Choi Y, Kwon H, Shin KS, Joung I, Shin M, Kwon YK. Neuroprotective effects of berberine in neurodegeneration model rats induced by ibotenic acid. Anim Cells Syst. 2008;12:203–9.

    Article  CAS  Google Scholar 

  29. Zhu F, Qian C. Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease. BMC Neurosci. 2006;7:78.

    Article  Google Scholar 

  30. Peng W-H, Hsieh M-T, Wu C-R. Effect of long-term administration of berberine on scopolamine-induced amnesia in rats. Jpn J Pharmacol. 1997;74:261–6.

    Article  CAS  Google Scholar 

  31. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.

    Article  Google Scholar 

  32. Silverman RB, Holladay MW. The organic chemistry of drug design and drug action: academic press; 2014.

    Google Scholar 

  33. Rogers J, Webster S, Lue L-F, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P. Inflammation and Alzheimer's disease pathogenesis. Neurobiol Aging. 1996;17:681–6.

    Article  CAS  Google Scholar 

  34. Sarna LK, Wu N, Hwang S-Y, Siow YL, O K. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can J Physiol Pharmacol 2010; 88: 369–378.

  35. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000;71:621S–9S.

    Article  CAS  Google Scholar 

  36. Markesbery WR. The role of oxidative stress in Alzheimer disease. ARCH Neurol-Chicago. 1999;56:1449–52.

    Article  CAS  Google Scholar 

  37. Jung HA, Min B-S, Yokozawa T, Lee J-H, Kim YS, Choi JS. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull. 2009;32:1433–8.

    Article  CAS  Google Scholar 

  38. Yokozawa T, Ishida A, Cho EJ, Kim HY, Kashiwada Y, Ikeshiro Y. Coptidis Rhizoma: protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components. J Pharm Pharmacol. 2004;56:547–56.

    Article  CAS  Google Scholar 

  39. Hsieh Y-S, Kuo W-H, Lin T-W, Chang H-R, Lin T-H, Chen P-N, Chu S-C. Protective effects of berberine against low-density lipoprotein (LDL) oxidation and oxidized LDL-induced cytotoxicity on endothelial cells. J Agric Food Chem. 2007;55:10437–45.

    Article  CAS  Google Scholar 

  40. Drachman DA, Leavitt J. Human memory and the cholinergic system: a relationship to aging? Arch Neurol-Chicago. 1974;30:113–21.

    Article  CAS  Google Scholar 

  41. Bowen D, Allen S, Benton J, Goodhardt M, Haan E, Palmer A, Sims N, Smith C, Spillane J, Esiri M. Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease. JNeur. 1983;41:266–72.

    Article  CAS  Google Scholar 

  42. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Sci. 1982;217:408–14.

    Article  CAS  Google Scholar 

  43. Coyle JT, Price DL, Delong MR. Alzheimer's disease: a disorder of cortical cholinergic innervation. Sci. 1983;219:1184–90.

    Article  CAS  Google Scholar 

  44. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry. 2000;157:4–15.

    Article  CAS  Google Scholar 

  45. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. BBRC. 1984;120:885–90.

    CAS  PubMed  Google Scholar 

  46. Cai X-D, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Sci. 1993;259:514–6.

    Article  CAS  Google Scholar 

Download references


Not applicable.


This study was supported by the Grants of China NSFC-31500831, Macau government grants FDCT-022/2015/A1, FDCT-024-2017-AMJ, and SKL-QRCM-2014-2016, and the University of Macau grant MYRG2016-0019-ICMS-QRCM, and the joint grant EF001/ICMS-LJH/2016/HKBU awarded to Jiahong Lu.

Availability of data and materials

The datasets and materials supporting the conclusions of this article are presented in this main paper.

Author information

Authors and Affiliations



All listed authors worked collectively on the design of the study and development of the review instruments. YNN and CCZ carried out article reviews, data extraction, analysis of the data, and drafted the manuscript. WMY carried out article reviews and worked on the paper search methodology. SHX oversaw the database searches, and carried out all the article tabulation. ML and LJH participated in development of the review instruments and advised on statistical conduct of the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jia-Hong Lu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, NN., Cai, CZ., Wu, MY. et al. Neuroprotective effects of berberine in animal models of Alzheimer’s disease: a systematic review of pre-clinical studies. BMC Complement Altern Med 19, 109 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: