Pharmacological effects of berberine on mood disorders

Abstract Berberine, a natural isoquinoline alkaloid, is used in herbal medicine and has recently been shown to have efficacy in the treatment of mood disorders. Furthermore, berberine modulates neurotransmitters and their receptor systems within the central nervous system. However, the detailed mechanisms of its action remain unclear. This review summarizes the pharmacological effects of berberine on mood disorders. Therefore, it may be helpful for potential application in the treatment of mood disorders.

characteristic alkaloidal bitter taste. It is very slightly soluble in water and ethanol and is sparingly soluble in methanol. The chloride or sulphate salts of berberine are relatively more soluble and are used clinically. 12 Berberine has multiple therapeutic actions, including antioxidant, anti-inflammatory, antitumour, antimicrobial, hepatoprotective, hypolipidemic, and hypoglycemic actions. 13 The pharmacology of berberine is well documented; however, there is renewed interest in berberine because of its benefits in various neurodegenerative and neuropsychiatric disorders. 7 Wang et al reported that berberine could easily cross the blood-brain barrier on systemic administration 14 and recent studies show that berberine has a protective effect on central nervous system disorders, such as Alzheimer's, cerebral ischaemia, mental depression, schizophrenia, and anxiety. 7,12,15 Here, we review the pharmacology of berberine in detail and highlight its efficacy in the treatment of mood disorders.

| The effect of berberine on neurotransmitters in depression
The original monoamine hypothesis postulates that the dysregulation of serotonin, norepinephrine, and dopamine has been theorized to be a core pathogenic factor in depression. Dysregulation of neurotransmitters can cause depression. 16 Berberine can regulate brain neurotransmitters, especially biogenic amines. 12,17 Norepinephrine (NE), serotonin (5-HT) and dopamine (DA) are neurotransmitters released from neurons during synaptic transmission in the nervous system. 12 The studies demonstrated that berberine (10, 20 mg/kg, p.o.), dramatically reduced the immobility time during the forced swim test and the tail suspension test. 18 Either acute or chronic administration of berberine at low doses results in increased levels of NE, 5-HT, and DA in whole-brain samples. Kulkarni et al showed that acute administration of berberine (5 mg/kg, i.p.) in mice caused increased levels of norepinephrine (31%), serotonin (47%), and dopamine (31%). Chronic administration of berberine (5 mg/kg, ip) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%). 12 These increases in biogenic amine levels are attributed to the inhibition of monoamine oxidase by berberine. 19,20 Berberine can also inhibit the release of NE via activation of adrenergic α2 autoreceptors 21 and can affect DA in a manner that antagonizes D2 and agonizes D1 receptors. 22,23 Substance P shows a strong negative correlation with serum concentrations of the primary 5-HT metabolite, 5-hydroxyindoleacetic acid. 24 Berberine reverses the increase in substance P levels induced by reserpine in the cerebral cortex and hippocampus. 25 Sigma receptors play an important role in the modulation of various neurotransmitters. Sigma ligands can modulate the activity of the neurotransmitter systems, such as noradrenergic, serotonergic, dopaminergic, and glutamatergic ones. 26 Meurs et al reported that sigma 1 receptor-mediated increase in hippocampal extracellular dopamine. 27 Moreover, some sigma agonists are found to have antidepressant-like activity perhaps with fewer side-effects. 28 These receptors are a promising therapeutic target for neuropsychiatric disorders, in particular, for depression. Recent studies have provided further evidence for the involvement of sigma receptors in the pathophysiology of major depression psychiatric disturbances. [28][29][30][31] Berberine affects sigma receptor 1 similarly to many antidepressant drugs 32 indicating its potential for the treatment of major depression.

| The effect of berberine on antioxidation in depression
Clinical studies of patients with depression have shown disturbances to oxidation, such as elevated lipid peroxidation products and reduced levels of superoxide dismutase. 33 Patients with depression also accompanied changes in brain volume. Increases in reactive oxygen species (ROS) and decreased antioxidant defences may cause oxidative modifications of proteins and DNA. The damage of stability of proteins and DNA may result in apoptois, and in part explain the brain volumetric changes evident in depression. 34 Arora et al found that treatment with berberine (10 and 20 mg/kg) produced a significant reduction in lipid peroxide levels in the cerebral cortex of reserpine administered rats. 25 Berberine inhibits the generation of ROS by suppressing overexpression of the nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme complex. 35,36 Meanwhile, berberine treatment restored the levels of nonprotein thiols, superoxide dismutase and catalase, which were significantly decreased by reserpine in the cerebral cortex and hippocampus. 25,37 Lukic et al provided evidence that depression is characterized by up-regulation of nuclear transcription factor-κB (NF-κB). Major depressive disorder subjects exhibited higher levels of NF-κB compared to controls. 38 NF-κB activity is regulated at least in part by the intensity of intracellular oxidative stress. 39,40 Li et al reported that NF-κB can be activated by oxidative stress (such as by exposure to H 2 O 2 ). 41 Berberine interacts directly with nucleic acids, and with several proteins, including p53, NF-κB, and oestrogen receptors. [42][43][44] Arora et al also observed a significant increase in levels of NF-κB and caspase-3 in the cerebral cortex and hippocampus of reserpinetreated rats and treatment with berberine down-regulated the elevated levels of NF-κB and caspase-3. 25 Chronic berberine treatment inhibited NF-κB signalling pathway in the hippocampus and prevented the depressive deficits both in sucrose preference test and novelty-suppressed feeding test in mice induced by chronic unpredictable mild stress. 45 These studies indicate that berberine may be of use as an antidepressant through the NF-κB signalling pathway, which may be activated by oxidative stress.

| The effect of berberine on nitric oxide synthesis in depression
Systemic inhibition of nitric oxide synthase induces antidepressantlike effects in the rat hippocampus. The neuronal nitric oxide synthase inhibitor significantly decreased immobility time. 46 Pharmacological manipulation of nitric oxide pathway by berberine can be observed in a reserpine-induced model of depression. Berberine (5 and 10 mg/kg, ip) reversed the increased of immobility period induced by reserpine. 12 Evidence has suggested that neuronal nitric oxide synthase inhibition increases serotonin signalling and activaties prosencephalic 5HT1A receptors. 47 There is also a close connection between adenosine monophosphate-activated protein kinase (AMPK) pathway and nitric-oxide synthesis. AMPK plays an important role in regulating NO synthesis in endothelial cells. 48 The activity of AMPK pathway is regulated by berberine. 49 AMPK is an upstream kinase of endothelial nitric oxide synthase (eNOS) that promotes eNOS phosphorylation, complex formation between eNOS and heat shock 90 kDa protein, and nitric oxide (NO) production. 50,51 Recent evidence has shown that reduced nitric oxide levels can induce antidepressant-like effects. 50 Moreover, the L-arginine-NO-cyclic guanosine monophosphate signalling pathway is important in the antidepressant action of berberine chloride. 46 Excessive levels of cyclic guanosine monophosphate can produce a depression-like state, while reduced levels can produce antidepressant-like actions. 52

| The effect of berberine on neuroinflammation in depression
Neuroinflammation may have a role in the pathogenesis of depression. 37,53 Inflammation-associated disorder of serotonergic and glutamatergic neurotransmission ultimately induces depression-like behaviour. 54 Mice induced by chronic unpredictable mild stress display enhanced levels of pro-inflammatory cytokines, including interleukin-6, interleukin-1-beta, and tumour necrosis factor β in hippocampus. Then the increased pro-inflammatory cytokines were decreased by orally administration berberine. 45 In addition, treatment with berberine attenuated the increased levels of the interleukin-1-beta in reserpine-treated rats. 25 It has been suggested that pro-inflammatory cytokines may affect the catabolism and disposition of various neurotransmitters through activation of indoleamine 2,3-dioxygenase (IDO). 55,56 Increased IDO activity may also decrease tryptophan availability, impacting serotonergic neurotransmission. 57 Berberine, a newly identified IDO inhibitor, significantly decreased the production of kynurenine in A549 cells. 58 Increased kynurenine may metabolize to neurotoxic metabolites, such as quinolinic acid, thereby, influencing glutamatergic neurotransmission. 57

| The effect of berberine on neurotrophic factors in depression
Nerve growth factor plays a role in the modulation of synaptic function and plasticity in the CNS. 58 Berberine potentiates nerve growth factor (NGF) activity, which can increase NGF-induced neurite outgrowth in a dose-dependent manner. 59 In some depression models, berberine decreased ROS levels, 36 and increased NGF-mediated neurite outgrowth via the phosphoinositide 3-kinase/protein kinase B/nuclear factor-E2-related factor 2-dependent pathway. 36 In addition, berberine has a neuroprotective effect in a dose-dependent manner, low-dose berberine significantly increased cell viability, while highdose berberine inhibited cell viability. 60 An antidepressant effect of berberine results from elevation of brainderived neurotrophic factor (BDNF) levels. 17,61 Bombi et al reported that berberine restored the decreased level of BDNF mRNA in the rat hippocampus following withdrawal from repeated morphine injection. 17 Our recent study indicated that berberine exerts antidepressant-like effects in ovariectomized mice, partly through the effects of berberine on BDNF-cyclic adenosine monophosphate (cAMP) response elementbinding protein and eukaryotic elongation factor 2 (eEF2) pathways. 61 The BDNF-cAMP-response element binding protein (CREB) pathway is a well-established antidepressant pathway which is critical for antidepressant action. Furthermore, eEF2 is involved in the actions of rapidonset antidepressants. 62,63 The reductions of hippocampal BDNF and phosphorylated eEF2 levels in ovariectomized mice are reversed by berberine treatment. 61 These studies suggest that berberine may rapidly produce antidepressant-like behaviour.

| The effect of berberine on hormonal regulation in depression
Hormonal imbalance can cause a variety of neurological disorders.

One of the most common examples is the link between diabetes and
major depressive disorder. 64,65 A growing number of studies have demonstrated that berberine can affect mood by regulating plasma corticosterone levels. Palmatine, a quaternary protoberberine alkaloid, produced antidepressant-like activity by decreasing plasma corticosterone levels. 66 Phellodendron, which is rich in berberine, reduced the effects of cortisol exposure and perceived daily stress. 67 Treatment with berberine attenuated the depressive-like behaviour induced by repeated corticosterone injection. 68 Fluctuations in gonadal hormone levels are believed to contribute to these depressive conditions. 69 Although, some studies show an effect of berberine on gonadal hormone levels, it is not known whether the antidepressant effects of berberine involve gonadal hormonal regulation.

| New perspectives of berberine action in depression
Studies in humans have shown an association between irritable bowel syndrome and depression. 70   been reported to participate in the processing of neuropeptide precursors. 73 Moreover, neuroprotective effects of POPs inhibitors have been reported in experimental animals. 74,75 Berberine inhibits POPs in a dose-dependent manner. 72 However, few studies have reported the effects of berberine in bipolar disorder. As noted below, some neurotransmitters such as dopamine, glutamate, and γ-aminobutyric acid (GABA) are responsible for mood cycling, while, dopamine and glutamate increase transmission during the manic phase. 76,77 More evidence is required to substantiate a relationship between bipolar affective disorder and berberine.

| PHARMACOLOGICAL EFFECT OF BERBERINE ON ANXIETY
Anxiety is an aversive emotional state that affects approximately oneeighth of the worldwide population. 78  It is worth noting that berberine regulates biogenic amines in a concentration-dependent manner. At a low dose, berberine (10 and 20 mg/kg) is effective in depression by increasing levels of NE, 5-HT and DA. 18 In contrast, high doses of berberine (100, 500 mg/kg) decreased concentrations of biogenic amines. 18,79 Furthermore, berberine increased the concentrations of their metabolites in the brain stem. The anxiolytic mechanism of berberine might be related to the increased turnover rates of monoamines in the brain stem and decreased serotonergic system activity. Moreover, berberine decreased serotonergic system activity via activation of somatodendritic 5-HT1A autoreceptors and inhibition of post-synaptic 5-HT1A and 5-HT2 receptors. 79 Berberine also has an inhibitory effect on glutamate receptors and can reduce glutamate, 5-HT and NE levels. 80,81 Extensive comorbidity among depressive disorders and anxiety disorders indicates related disease etiologies. 82,83 Dysregulation of GABA in anxiety has been reported in a number of studies. 84  Although the antioxidant effect of berberine has been confirmed, 87 it has not been reported in animal models of anxiety. Further studies are warranted to validate this link and to understand the pathogenic mechanisms involved.

| TOLERABILITY AND SAFETY
Berberine has been used in the clinic for several decades. 88,89 It displays various pharmacological effects, including efficacy against gastroenteritis, abdominal pain, and diarrhoea. It also has anti-microbial, anti-diabetic, and anti-inflammatory properties. 88,90 Chronic administration of berberine (1200-2000 mg/d) for at least 2 months significantly decreased total cholesterol levels and low-density lipoprotein cholesterol without major adverse effects. 91 Yin et al and Dong et al studied the anti-diabetic properties of berberine (500-1500 mg daily for 3 months) 92 and they hypothesized that berberine induces a significant reduction in postprandial glucose levels. In addition, in patients randomized to receive 800 mg of berberine hydrochloride daily for 2 months, a trend of improvement was observed for IBS symptom scores compared with placebo. 74 Berberine does not display any genotoxic, cytotoxic, or mutagenic activity. 7 However, berberine has remarkable cytotoxicity on T A B L E 1 Berberine in various mood disorders and its mechanism of action

| CONCLUSION
Based on the published findings, we conclude that berberine may be a potential treatment for mood disorders. Berberine in various mood disorders and its mechanism of action are summarized in Table 1. Schematic representation of the mechanism of berberine involved with depression is shown in Figure 1. Further research into the safety profile of berberine is required before its clinical application.

ACKNOWLEDG EMENTS
This work was supported by grants from the Natural Science Foundation of China (NSFC) (31571126 and 31300850).

CONFLI CTS OF INTEREST
The authors declare no conflict of interest.