Caffeic Acid Phenethyl Ester

Propolis: A useful agent on psychiatric and neurological disorders? A focus on CAPE and pinocembrin components

Cinthia C. S. Menezes da Silveira1 | Diandra A. Luz1 |
Carla C. S. da Silva1 | Rui D. S. Prediger2 |
Manoela D. Martins3 | Marco A. T. Martins3 |
Enéas A. Fontes‐Júnior1 | Cristiane S. F. Maia1
1Laboratory of Pharmacology of
Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, Pará, Brazil
2Department of Pharmacology, Biological Science Center, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
3Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Correspondence
Cristiane S. F. Maia, Laboratório de Farmacologia da Inflamação e do Comportamento, Instituto de Ciências da Saúde, Universidade Federal do Pará, Rua Augusto Corrêa 1, Campus do Guamá, Belém, Pará 66075‐900, Brazil.
Email: [email protected] and crismaia0301@ hotmail.com

Funding information
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Grant/Award Numbers: PROCAD/AMAZÔNIA, (CAPES‐FINANCE CODE 001); Brazilian National Council for Scientific and Technological
Development (CNPq)

Abstract
Propolis consists of a honeybee product, with a complex mix of substances that have been widely used in traditional medicine. Among several compounds present in propolis, caffeic acid phenethyl ester (CAPE), and pinocembrin emerge as two principal bioactive compounds, with bene- fits in a variety of body systems. In addition to its well‐explored pharmacological properties, neuropharma- cological activities have been poorly discussed. In an unprecedented way, the present review addresses the current finding on the promising therapeutic purposes of propolis, focusing on CAPE and pinocembrin, highlighting its use on neurological disturbance, as cerebral ischemia, neuroinflammation, convulsion, and cognitive impairment, as well as psychiatric disorders, such as anxiety and de- pression. In addition, we provide a critical analysis, dis- cussion, and systematization of the molecular mechanisms which underlie these central nervous system effects. We hypothesize that the pleiotropic action of CAPE and pi- nocembrin, per se or associated with other substances present in propolis may result in the therapeutic activities reported. Inhibition of the pro‐inflammatory cascade, an- tioxidant activity, and positive neurotrophic modulatory effects consist of the main molecular targets attributed to CAPE and pinocembrin in health benefits.

K E Y W O R D S
CAPE, neurological disorders, pinocembrin, propolis, psychiatric disorders

1| INTRODUCTION
Honeybee products, including honey, pollen, and propolis, have been widely used in traditional medicine and have increasingly aroused the interest of the pharmaceutical and food industries. In particular, propolis, a resinous product that is made from different plant parts mixed with salivary secretion and beeswax, represents a multimillion‐dollar market.1,2 In 2012, Brazil exported approximately 41,721 kg of propolis, an amount that corresponded to roughly $5,401,643.3
More than 2000 patents for propolis preparations have been registered; the majority are from Japanese and Chinese studies.3,4 Many products, such as tablets, capsules, ampoules, and syrups, are prepared with hydro- alcoholic extracts and used as agents with antimicrobial, anti‐inflammatory, healing, and antioxidant properties. These benefits are all the main targets of propolis research.1,3 Besides, propolis also has the potential to be explored by the food industry as a functional food.
Another aspect of propolis that should be examined is its neuropharmacological properties. Neurological diseases result from multifactorial causes. Some studies affirm that propolis can be utilized to treat these disorders due to its immunomodulatory and antioxidant activity, beyond the other potential actions of their chemical compounds.1 Thus, this study aims to discuss the potential neuropharmacological effects of propolis related to neurological and psychiatric diseases, with a focus on the two main components: caffeic acid phenethyl ester (CAPE) and pinocembrin. Therefore, we selected the works published in the last 17 years on scientific databases (i.e., PubMed, Web of Science, and Scopus), applying the keywords “propolis,” “CAPE,” and “pinocembrin” per se and associated with “cerebral ischemia,” “neuroinflammation,” “convulsion,” “cognitive impairment,” “anxiety,” and “depression.”

2| CHEMICAL PROPERTIES
Propolis is a stiff and brittle material at a low temperature. However, after warming (25–45°C), it becomes smooth, ductile, and sticky. The melting point ranges from 60 to 100°C. The solvents most commonly utilized for propolis are water, methanol, ethanol, chloroform, dichloromethane, ether, and acetone.2 Propolis is a complex mix of substances, and thus the solvent employed to extract its constituents should be appropriate for the polarity of the chemical component of interest.
Like most natural products, the chemical composition of propolis can be influenced by environmental condi- tions, including season, collection origin, and local flora.5 According to Bankova et al.,6 the knowledge of the vegetal source of propolis can be important for its chemical standardization. Wagh et al.2 summarized and correlated the chemical constitution and demonstrated that there are variations in the major compounds from propolis depending on the country of origin as well as the plant source of the propolis (Table 1).
These authors also reported the substances that were obtained with distinct solvents. These data reinforce the influence of these properties on the chemical profile of propolis (Table 2).2 Moreover, these variations are responsible for the distinct colorations of propolis samples, which can be red, brown, green, or yellow.
Several phytochemical studies were performed to identify the metabolites present in different propolis types. In general, propolis is composed of 50% plant resins, 30% waxes, 10% essential and aromatic oils, 5% pollens, and 5% other organic substances.7 Other metabolite classes include tannins, alkaloids, terpenoids, sterols, and sapo- nins, among others, all of which are known to promote beneficial effects on the central nervous system (CNS).8 Moreover, propolis compounds possess lipophilic properties, which are particularly important to cross the blood–brain barrier (BBB) and access the brain. Vitamins, minerals, sugars, enzymes, aldehydes, ketones, and
3,9‐11
alcohols have also been detected in propolis samples.
Polyphenols, aromatic acids, and triterpenes, among others, constitute important propolis compounds with regard to the management of CNS disorders. In fact, polyphenolic compounds are the metabolites most frequent detected in propolis samples, and they are proposed as a biomarker for its antioxidant capacity.2 Quercetin and its derivates (1), kaempferol and related compounds (2), and pinocembrin (3) are valorous members of this class. They seem to exert anti‐inflammatory and antioxidant effects, as well as modulate neurological disorders.12,13 Additionally, pinocembrin exhibits neuroprotective actions (Figure 1).14
Caffeic acid (CA; 4), CAPE (5), and vanillin (6) are important aromatic acids that are found in propolis. CA has been investigated for its antioxidant, immunomodulatory, and antitumor effects; recently, its ability to improve
17‐19memory has been explored.16 Vanillin was studied as an antimutagenic, antioxidant, and anticonvulsant drug. Lupeol (7), a triterpene detected in propolis samples, is another important compound with regard to CNS effects.11 Research has indicated that this substance displays anxiolytic, antidepressant, and anticonvulsant activities.8,20 Besides, CAPE presents antioxidant and neuroprotective activities through mechanisms that will be discussed in subsequent sections (Figure 1).21,22

3| NEUROPHARMACOLOGICAL EFFECTS
3.1| Neurological disturbance
Pharmacological effects have been described for propolis and its constituents. These studies have assigned great prominence to potential CNS activity and have suggested new therapeutic targets. Oxidative stress and neu- roinflammation have emerged as important mechanisms that are involved in neurological disorders.

3.1.1| Cerebral ischemia
Since 2003, bioactive components that are present in propolis have been proposed for the treatment of neuro- logical disorders. For example, CAPE studies have reported that this compound is a neuroprotector in a cerebral inflammatory model.24 CAPE administered either before or after a hypoxic‐ischemic (HI) injury in neonatal rats prevents HI‐induced damage in the cortex, hippocampus, and thalamus. In addition to blocking HI‐induced caspase‐ 3 activation, CAPE also inhibits the HI‐mediated expression of inducible nitric oxide synthase (iNOS) and caspase‐1 in vivo and potently blocks NO‐induced neurotoxicity in vitro. In fact, CAPE mitigates the glutamate‐ induced excitotoxicity that plays a vital role in ischemia‐induced damage, specifically by modulating glutamate‐ induced caspase‐3 activation and blocking p38 phosphorylation. Furthermore, CAPE directly inhibits Ca2+‐induced cytochrome c release from isolated brain mitochondria.25
Similar to these results, CAPE reduces the total infarct volume and the percentage of infarction after focal permanent cerebral ischemia in a murine model. These effects are related to antioxidant activity and/or upregu- lation of NO production.26,27 Altug et al.27 also showed that CAPE attenuates the elevation of plasma mal- ondialdehyde (MDA), catalase (CAT), and xanthine oxidase (XO) contents, whereas it increases the levels of plasma glutathione (GSH) and NO. These findings suggest that CAPE mainly provides neuroprotection against cerebral ischemia injury via antioxidant properties,28 as well as anti‐inflammatory effects that will be discussed below (Figure 3).29
In addition to CAPE, other propolis phenolic components have positive effects on cerebral ischemia. Another study evaluated the effect of water‐extracted brown propolis (WEBP), from two regions of Iran, against cerebral‐ ischemia‐induced oxidative injury in a mouse model of stroke. The major WEBP components were 3,7‐dihydroxy‐5‐ methoxy‐flavanones, pinobanksin‐3‐acetates, pinobanksin‐3‐butanoate, cinnamic acid, benzoic acid, quercetin, naringenin, butanedioic acid, and propionic acid; they seem to exert synergistic activity on the CNS.30 WEBP treatment restores the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), and leads to a subsequent decrease in the lipid peroxidation index (MDA content). Functionally, the infarct volume is ameliorated, and sensory–motor impairment and neurological deficits are improved. Notably, even in the absence of CAPE, WEBPs promote brain restoration. This finding indicates that there are other bioactive compounds with good antioxidant activity present in propolis.
Liu et al.31 investigated the neuroprotective effect of pinocembrin on ischemia/reperfusion insults. Pino- cembrin administration protects the brain against injury caused by focal cerebral ischemia/reperfusion in rats. It increases neuronal viability through an antioxidative pathway (as well as antiapoptotic mechanisms) by down- regulation of NO synthesis, inhibition of ROS overproduction through the upregulation of GSH and scavenging activity, and reduction of caspase‐3 expression. Oliveira et al.32 explored oxidative stress induced by methylglyoxal and postulated that pinocembrin provides mitochondrial protection through the activation of the nuclear factor E2‐related factor 2 (Nrf2) in an extracellular‐related kinase (Erk1/2) signaling‐dependent manner. This Erk1/
2–Nrf2 pathway upregulation induces the augment of the antioxidant enzymes expression, preventing or miti- gating oxidative harmful events. Finally, studies have proposed a neuroprotective activity for pinocembrin through the inhibition of autophagy after ischemic brain injury.33,34 Autophagy occurs after a stroke as a neuroprotective mechanism in response to the damage; however, excessive autophagy activation leads to neuronal death.35 Thus, pinocembrin acts on autophagy processes, namely by regulating the overexpression of several members of the autophagy protein family (i.e., LG3‐II) and its regulators (i.e., beclin1).34,36,37
In thromboembolic brain stroke, pinocembrin reduces BBB damage through tight junction protein dete- rioration and platelet‐derived growth factor (PDGFs)‐CC from the endothelium and astrocytes and a signaling reduction in its alpha receptors.38 With regard to synthesis, pinocembrin has been proposed as a valuable sub- stance for cerebral stroke adjuvant therapy based on its pleiotropic effects, including its antioxidant activity and ability to abrogate the mitochondrial apoptotic pathway, regulate autophagy, and protect/maintain the BBB
FIGURE 3 A hypothetical scheme showing generation of reactive oxygen species (ROS) and neuroprotective effects of propolis against cell injury in neurological disorders. Enzymes: 1, peroxidase; 2, superoxide dismutase; 3, catalase; and 4, glutathione reductase. Stimulation of NF‐кB by ROS helps in its translocation to the nucleus where it not only facilitates the transcription of sPLA2, COX‐2, NOS, and SOD genes, but also upregulates expression of pro‐inflammatory cytokines as well as IFN‐β genes in the nucleus. Propolis also inhibits translocation of HIF‐α (hypoxia‐inducible factor 1‐alpha) to the nucleus. A1, agonist; CD14, protein encoded by CD14 gene is a component of innate immune system; COX‐2, cyclooxygenase‐2; cPLA2, cytosolic phospholipase A2; GSH, reduced glutathione; GSSG, oxidized glutathione; H2O2, hydrogen peroxide; HIF‐1α, hypoxia‐inducible transcription factor 1 alpha; IFN, type 1 interferon genes; IL‐1β, interleukin‐1beta; IRAK, IL‐1 receptor associated kinase; IRF3, interferon regulatory transcription factor; LOX; lipoxygenase; MAL, MYD88‐adaptor like; MYD88, myeloid differentiation primary‐response protein‐88; NF‐кB, nuclear transcription factor kappa B; NF‐кB‐RE, nuclear factor kappa B response element; NO, nitric oxide; NOS, nitric oxide synthase; OONO-, peroxynitrite; R1, receptor; SOD, superoxide dismutase; sPLA2, secretory phospholipase A2; TIR, toll/interleukin (IL‐1) receptor; TLR, toll‐like receptor; TNF‐α, tumor necrosis factor‐alpha; TRAF6, TNF receptor‐associated factor 6; TRAM, TRIF‐related adaptor molecule; TRIF, TIR domain containing adaptor inducing IFNβ; VHL, von Hippel‐Lindau protein [Color figure can be viewed at wileyonlinelibrary.com]function (Figure 3). In fact, in 2008, pinocembrin was approved for therapeutic use in stroke by the China Food and Drug Administration.39
We hypothesize that the presence of CAPE and pinocembrin in propolis intensifies their antioxidant and antiapoptotic properties, which is related to the one of the pathological mechanisms displayed by cerebral ischemia. In addition, the pinocembrin activities described above highlight the other positive effects of propolis on cerebral stroke, findings that reinforce its use as a valuable nutraceutical (Figure 3).

3.1.2| Neuroinflammation
Several studies have reported peripheral anti‐inflammatory properties for propolis.23,40 In the CNS, CAPE has emerged as a useful bioactive compound due to its potent anti‐inflammatory activity; it acts on several pathways to counteract neuroinflammation. In addition to its antioxidant activity, CAPE reduces lipid peroxidation and ara- chidonic acid release by inhibiting cyclooxygenase (COX)‐2 overproduction that is mediated by arachidonic acid, as well as nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) transcription (Figure 4).41,42FIGURE 4 Hypothetical representation antineuroinflammatory mechanisms of propolis active constituents caffeic acid phenethyl ester (CAPE) and pinocembrin. (+) stimulation, induction, or activation; (-) inhibition, blockage, or reduction; Akt, protein kinase B; AP‐1, activator protein 1; AMPKa, AMP‐activated protein kinase; COX‐2, cyclooxygenase‐2; HO‐1, heme oxygenase; IKK, IκB kinase; IkBa, IkB alfa; IL‐1b, interleukin‐1b; IL‐6, interleukin‐6; iNOS, induced nitric oxide synthase; JNK, Jun amino‐terminal kinases; Keap1, Kelch‐like ECH‐ associated protein 1; M1, microglia M1 phenotype; M2, microglia M2 phenotype; Mk2, MAPK‐activated protein kinase 2; MyD88, myeloid differentiation protein; p38MAPK, mitogen‐activated protein kinases p38; Nrf2, nuclear factor E2‐related factor 2; PI‐3K, phosphatidylinositol 3ʹ‐kinase; PKC‐d, protein kinase C delta type; SAPK, stress‐ activated protein kinases; TNF‐a, tumor necrosis factor alpha; TLR‐4, toll‐like receptor 4 [Color figure can be viewed at wileyonlinelibrary.com]Microglia protect the CNS against deleterious stimuli. CAPE exerts anti‐inflammatory activities in the CNS by directly interacting with microglia. CAPE reduces the microglial activation induced by neuroinflammatory pro- cesses. Such activity modulates the expression of microglial pro‐inflammatory cytokines on circulating blood (i.e., iNOS, COX‐2, interleukin (IL)‐6, and IL‐1β).43 In addition, HO‐1 and erythropoietin (EPO) expression regulate microglial activation.42 In turn, HO‐1 inhibits iNOS expression and, consequently, NO production, as well as other pro‐inflammatory mediators, for example, tumor necrosis factor (TNF)‐α and IL‐6. EPO upregulates HO‐1, an action that augments the anti‐inflammatory effects of HO‐1 in the CNS.42,44 Thus, HO‐1 and EPO upregulation elicited by CAPE and its derivative relies on protein kinase C‐delta (PKCδ) activation that upregulates HO‐1.42 Notably, PKCδ is modulated by 5ʹAMP‐activated protein kinase (AMPK) expression,45 and thus the AMPKα pathway is responsible for the CAPE anti‐inflammatory responses in the CNS.42 In fact, CAPE can reverse the imbalance between pro‐inflammatory and anti‐inflammatory molecules.43
Pinocembrin, one of the main flavonoids in propolis, has been described as an antioxidant and anti‐ inflammatory compound with effects in the CNS. In an Alzheimer’s disease (AD) model, which displays several pro‐ inflammatory processes, pinocembrin elicits anti‐inflammatory effects, namely by acting on the mitogen‐activated protein kinase (MAPK) signaling cascade.46 Doses under 30 µM can block phosphorylated p38 MAPK/MK2, as well as the SAPK/JNK‐c‐Jun pathways. The doses starting at 30 µM also inhibit extracellular signal‐regulated kinase (ERK)1/2 phosphorylation in brain endothelial cells.46 Besides, pinocembrin also promotes the reduction of IKKα/
IKKβ phosphorylation, which diminishes IκBα degradation. These pinocembrin‐mediated effects also modulate NF‐κB to prevent overstimulation. NF‐κB is directly blocked by pinocembrin, with a consequent reduction in the overproduction of pro‐inflammatory mediators, that is, TNF‐α, IL‐1β, and IL‐6.46,47 Specifically, pinocembrin reduces IκBα degradation, which is a crucial step for NF‐κB‐p65 nuclear translocation (Figure 4).46,47
With regard to the immune response, pinocembrin reduces toll‐like receptor 4 (TLR4) expression, an action that minimizes microglial M1 polarization.47 In addition to this effect, the decreased TLR4 expression elicited by pinocembrin minimizes NF‐κB overproduction. This activity displays a synergistic mechanism with the molecular anti‐inflammatory actions discussed above.47 The effects of pinocembrin on microglial M2 polarization, which can increase the expression of anti‐inflammatory mediators and promote beneficial effects beyond blocking pro‐inflammatory biomolecules, requires further investigation (Figure 4).47

3.1.3| Convulsion
The anticonvulsant effects of propolis have been proposed; however, there are few studies on its anticonvulsant activity. In 2004, Kwon et al.48 investigated the anticonvulsant activity of propolis in a kainic acid‐induced seizure model. These authors postulated the potential anticonvulsant action of propolis through its antioxidant properties, as well as its ability to modulate the A1 receptor in the purinergic system. This anticonvulsant effect was also reported by Zárraga‐Galindo et al.49 in a pentylenetetrazole‐induced seizure model in rats. Therefore, the propolis components responsible for such effects were not explored.
Research has also implicated CAPE as an enhancer of the large conductance Ca2+‐activated K+ (BKCa) channels, which reduce neuronal activity.50 In turn, the BKCa channel plays a fundamental role in seizure occurrence because it contributes to the excitatory versus inhibitory CNS balance (for a review, see N’Gouemo51). In this regard, we hypothesize that the anticonvulsant activity of propolis might be related to CAPE, specifically its ability to elevate the BKCa channel activity, since no study has yet attributed anticonvulsant effects to pinocembrin.

3.1.4| Cognitive impairment
Studies have suggested that propolis represents a natural product that can modulate mnemonic processes. Chen et al.52 were the first group that attributed anti‐amnestic activity for propolis; they examined learning and memory impairment using an anticholinergic‐induced model in rats. These authors found that the water‐soluble derivative of propolis (WSDP) mitigated the mnemonic impairment displayed by scopolamine administration, primarily through inhibition of acetylcholinesterase (AChE). Although the WSDP possesses elevated levels of flavonoids and phenolic compounds, including the CAPE precursor CA, this Chinese propolis lacked CAPE and pinocembrin. Such work was the first reference for the potential propolis effects on cognitive function.
Our group employed a yellow propolis, rich in terpenoids, for mnemonic evaluation.20 We observed a positive effect for this natural product on the short‐term memory paradigm. Similar to Chen et al.,52 CAPE and pinocembrin were not constituents of the investigated yellow propolis.
Bioactive compounds that can improve cognitive function are the therapeutic targets for neurodegenerative diseases, including AD. In fact, dementia is the principal symptom that reduces the quality of life of AD patients (for a review, see Müller et al.53). Thus, AD paradigm models have been employed to explore mnemonic effects of therapeutic agents in rodents. In that scenario, propolis has emerged as a promising nutraceutical product that can mitigate learning and memory deficits induced by the AD paradigm model through multiple mechanisms of action, that is, AChE blockade, as well as positive modulation of brain‐derived neurotrophic factor (BDNF) and oxidative stress.54 These propolis‐mediated mechanisms elevate brain catecholamines (i.e., noradrenaline, dopamine, and serotonin), increase acetylcholine pathway activity, reduce brain cell loss, and improve neurogenesis.
In addition, the propolis‐induced BDNF increase upregulates activity‐regulated cytoskeleton‐associated pro- tein (Arc) expression, which improves synaptic plasticity and mnemonic processes through antioxidant activity and suppresses IL‐1β and microglial activation.55 However, the phosphoinositide 3‐kinase (PI‐3K) signaling pathway represents the principal mechanism that mediates the propolis‐induced BDNF increase.23 The cumulative effect of these mechanisms enhances cognitive function (Figure 5). In the study by Nanaware et al.,54 both CAPE and pinocembrin were the major constituents of the investigated Indian propolis.
Research has implicated CAPE as a therapeutic agent for mnemonic disturbance. In a pharmacological‐induced dementia model, CAPE minimizes and prevents memory disruption.56,57 The molecular mechanisms related to CAPE‐induced improvement in cognitive function are associated with a decrease in oxidative damage, which results in neuronal protection and direct inhibition on AChE activity.58 Besides, CAPE increases the phosphor- ylation and subsequent upregulation of the protein kinase A (PKA)‐cyclic AMP response element binding protein (CREB) pathway that represents a fundamental step to cognitive processes (Figure 5).56
In addition, Kumar and Bansal59 postulated that PI3K plays a pivotal role in the CAPE‐mediated mnemonic effects. In fact, CAPE reduces AChE activity, an action that triggers cholinergic transmissions that in turns activates PI3K that phosphorylates protein kinase B (Akt). Upregulation of the PI3K/Akt pathway displays several down- stream effects, including (1) a reduction in the levels of pro‐inflammatory molecules, that is, TNF‐α, NFκB, etc.; and (2) a decrease in oxidative stress.59 Interestingly, CAPE reduces glycogen synthase kinase‐3 beta (GSK3β) in- hibitory phosphorylation that in turn regulates—and is regulated by—Akt signaling.
FIGURE 5 Hypothetical representation of the main mechanisms by which propolis and its active constituents caffeic acid phenethyl ester (CAPE) and pinocembrin promotes improvement in the mnemonic process. (+) stimulation, induction, or activation; (-) inhibition, blockage, or reduction; Akt, protein kinase B; AMPKa, AMP‐ activated protein kinase; AP‐1, activator protein 1; COX‐2, cyclooxygenase‐2; HO‐1, heme oxygenase; iNOS, induced nitric oxide synthase; IKK, IκB kinase; IkBa, IkB alfa; IL‐1b, interleukin‐1b; IL‐6, interleukin‐6; JNK, Jun amino‐terminal kinases; Keap1, Kelch‐like ECH‐associated protein 1; M1, microglia M1 phenotype; M2, microglia M2 phenotype; Mk2, MAPK‐activated protein kinase 2; Nrf2, nuclear factor E2‐related factor 2; p38MAPK, mitogen‐activated protein kinases p38; PI‐3K, phosphoinositide 3‐kinases; PKC‐d, protein kinase C delta type; SAPK, stress‐activated protein kinases; TNF‐a, tumor necrosis factor alpha [Color figure can be viewed at wileyonlinelibrary.com]widespread modulatory activities, for example, synaptic plasticity regulatory effects, that are crucial for cognitive functions (for a review, see Beurel et al.60). In the study by Morroni et al.,61 GSK3β activation modulates the redox imbalance and induces the HO‐1 protective effects.
Equally important, CAPE also modulates crucial molecules that are involved in several homeostatic activities. Nrf2 is a transcription factor that is liberated from cytoplasmic repressor protein Kelch‐like ECH associated protein 1 (Keap1). Nrf2 is translocated to the nucleus, an action that subsequently improves the expression of several protective genes.62 CAPE activates the Nrf2 pathway and thus counterbalances the redox status through the Nrf2‐HO‐1 pathway.61 In fact, Morroni et al.61 postulated that the effects on Nrf2‐HO‐1 signaling by CAPE are primary modulated by GSK3β activation. We hypothesize that all CAPE molecular signaling targets described above display synergistic effects that result in positive effects on cognition.
Pinocembrin has also been postulated as a beneficial bioactive compound with regard to cognitive processes in animal models of cerebral damage (i.e., ischemia, diabetic encephalopathy, and neurodegenerative disease).
The exact mechanism of neurodegenerative/neuroinflammatory/ischemic‐induced cognitive impairment recovery by pinocembrin requires further investigation; however, reduced mitochondrial dysfunction, oxidative stress, and astrogliosis have been reported.63,65 In addition, reduced astrocyte activation diminishes the overproduction of pro‐inflammatory mediators (i.e., NF‐κB and TNF‐α) that prevents neuronal loss, a phenomenon that might explain one pathway that is activated by pinocembrin (Figure 5).65,66
In a neurodegenerative model, pinocembrin inhibits advanced glycation end products (RAGE) upregulation, phosphorylation of p38, stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK), and the subsequent pro‐inflammatory cascades (for a review, see Shen et al.67). Finally, the ERK–CREB–BDNF pathway is improved, an effect that triggers cholinergic neurotransmission on cognitive regions of the CNS by pinocembrin may play a central role on its mnemonic effects.46
We believe that the synergistic effects of both CAPE and pinocembrin might reinforce the robust cognitive activities have been observed in propolis‐related research (Figure 5).

3.2| Psychiatric disorders
3.2.1| Anxiety
The anxiolytic effects of propolis have rarely been explored. Due to pharmacological activities of several of propolis components, preliminary efforts have been made to investigate its action on anxiety‐like behavior. In 2011, a study demonstrated that propolis essential oil—primarily composed of aromatic carboxylic acids and terpenoids—displays anxiolytic activity by reducing hypothalamic‐pituitary‐adrenal (HPA) axis hyperactivity and oxidative stress.68 Thereafter, our group demonstrated that both the oil and hydroalcoholic extract of propolis elicits anxiolytic effects on an arena and elevated plus‐maze paradigm.13,20 In the studies described above, CAPE and pinocembrin were absent in the propolis constituents; however, other phenolic hydroxyl group, including CA and its correlates, which have reported anxiolytic effects, were sometimes present.13,68,69
Although the effects of CAPE on anxiety‐like disorders have not yet been investigated, we hypothesize that the CAPE‐mediated improvement in BDNF signaling in limbic areas, as reported by Nanaware et al.,54 might promote an anxiolytic response. Considering the neurotrophic hypothesis for anxiety, we believe that the increased BDNF expression induced by CAPE might promote neurogenesis and neural plasticity and modulate the hippocampal‐amygdala‐prefrontal circuitry (fear pathway). This effect could subsequently abrogate the anxiety‐ related profile (for a review, see Dincheva et al.70; Figure 6).71
Like CAPE, pinocembrin has not yet been adequately examined with regard to its anxiolytic activity. Given that pinocembrin modulates the ERK–CREB–BDNF pathway in the amygdala and hippocampus, this action might play a pivotal role in anxiety‐related behavior (Figure 6).46,72,73 Overall, the present work highlights the lack of the studies related to CAPE as well as pinocembrin on anxiety‐like behavior, despite the suggestive evidence.

3.2.2| Depression
The antidepressant property of propolis has also been poorly explored. In 2013, the antidepressant effects were addressed in a study that utilized a Korean propolis. In that report, the antidepressant activity was associated with upregulation of glucocorticoid receptor (GR) and the CREB downstream pathway, actions that restore the HPA axis homeostasis.74 Subsequently, our group examined the antidepressant effects of an oil and ethanolic extract of Brazilian propolis. These findings reinforce the potential of propolis for the treatment of depression.13,20 In the above studies, the presence of CAPE and pinocembrin were not proven, although phenolic acids were found.13
Researchers have speculated about several mechanisms that might underlie the propolis‐induced anti- depressant properties. Monoamine oxidase (MAO) inhibition, which is one mechanism used by antidepressant drugs, has been attributed to some bioactive constituents of propolis.75,76 In addition, the neurotrophic hypothesis of depression is focused on BDNF–MAPK kinase–ERK, BDNF–PI3K–AKT, and BDNF/NF‐kB signaling, all of which regulate neurogenesis in key CNS regions and promote axonal and dendritic growth, synaptic plasticity, neuro- transmitter homeostasis, and mood improvement.77,78 Considering that propolis increases BDNF levels in the CNS, we speculate that this natural product presents potential effects for depression‐like disorders (Figure 6).54 Interestingly, NF‐κB also contributes to mood homeostasis. In contrast to NF‐κB overexpression, NF‐κB basal levels promote neurogenesis, neurite outgrowth, synaptic transmission, neuroprotection, and mood improvement (for a review, see Caviedes et al.78). In this sense, the BDNF‐NF‐κB interactions through multiple pathways might elicit novel targets for depression disorders.78
Consistent with this hypothesis, CAPE was tested as a potential bioactive antidepressant compound in a gold standard antidepressant paradigm (i.e., forced swim test). In this unique study, 21‐day CAPE treatment promoted antidepressant‐like effects through positive modulation of GR function. This effect occurred via p38 mitogen‐ activated protein kinase (p38MAPK).79 We hypothesize that there are other antidepressant mechanisms mediated by CAPE that might occur and remain to be elucidated, since ERK–CREB–BDNF and NF‐κB pathways are affected by this bioactive compound (Figure 6).59
Although the effects of pinocembrin on signaling that modulates depression pathophysiology mechanisms are well outlined (i.e., BDNF regulation), the antidepressant activity for this compound has not yet been explored.46 We believe that pinocembrin has potential as an antidepressant‐like agent, and this factor deserves further investigation.
All experimental models cited here are detailed below (Table 3).

4| CONCLUSION
Although several drugs are available for neurological disorder therapies, there is a lack of new compounds that exhibit optimal tolerability and efficacy. In this context, propolis is a potential nutraceutical that might ameliorate CNS disorders. In addition, numerous studies have proposed that two propolis components—CAPE and pinocembrin—are valuables tools for the treatment of CNS disorders. In this sense, further research is necessary to fully elucidate the therapeutic effects for propolis and its constituents, mainly on neurological and psychiatric disorders, as well as the exact mechanisms that are modulated by CAPE and pinocembrin.

ACKNOWLEDGMENTS
This study is supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES‐FINANCE CODE 001). Manoela Domingues Martins, Cristiane Maia, Marta Monteiro, and Rui Prediger are research fellows funded by the Brazilian National Council for Scientific and Technological Development (CNPq).

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.

ORCID
Cinthia C. S. Menezes da Silveira https://orcid.org/0000-0003-0438-0525 Diandra A. Luz https://orcid.org/0000-0002-9703-2062
Rui D. S. Prediger https://orcid.org/0000-0002-7547-6463
Manoela D. Martins https://orcid.org/0000-0001-8662-5965
Marco A. T. Martins https://orcid.org/0000-0001-7834-3319
Enéas A. Fontes‐Júnior https://orcid.org/0000-0002-6186-9581
Cristiane S. F. Maia https://orcid.org/0000-0003-4493-7375

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