Apitherapy for Parkinson s Disease: A Focus on the Effects...

Review ArticleApitherapy for Parkinson’s Disease: A Focus on the Effects ofPropolis and Royal Jelly

Amira Mohammed Ali 1,2 and Hiroshi Kunugi 1,3

1Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry,Tokyo, Japan2Department of Psychiatric Nursing and Mental Health, Faculty of Nursing, Alexandria University, Alexandria, Egypt3Department of Psychiatry, Teikyo University School of Medicine, Tokyo, Japan

Correspondence should be addressed to Amira Mohammed Ali; [email protected]

Received 3 July 2020; Revised 27 August 2020; Accepted 5 October 2020; Published 17 October 2020

Academic Editor: German Gil

Copyright © 2020 Amira Mohammed Ali and Hiroshi Kunugi. This is an open access article distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

The vast increase of world’s aging populations is associated with increased risk of age-related neurodegenerative diseases such asParkinson’s disease (PD). PD is a widespread disorder characterized by progressive loss of dopaminergic neurons in thesubstantia nigra, which encompasses a wide range of debilitating motor, emotional, cognitive, and physical symptoms. PDthreatens the quality of life of millions of patients and their families. Additionally, public welfare and healthcare systems areburdened with its high cost of care. Available treatments provide only a symptomatic relief and produce a trail of noxious sideeffects, which increase noncompliance. Hence, researchers have recently focused on the use of nutraceuticals as safe adjunctivetreatments of PD to limit its progress and associated damages in affected groups. Propolis is a common product of the beehive,which possesses a large number of therapeutic properties. Royal jelly (RJ) is a bee product that is fed to bee queens during theirentire life, and it contributes to their high physical fitness, fertility, and long lifespan. Evidence suggests that propolis and RJ canpromote health by preventing the occurrence of age-related debilitating diseases. Therefore, they have been used to treat variousserious disorders such as diabetes mellitus, cardiovascular diseases, and cancer. Some evolving studies used these bee products totreat PD in animal models. However, a clear understanding of the collective effect of propolis and RJ as well as their mechanismof action in PD is lacking. This review evaluates the available literature for the effects of propolis and RJ on PD. Wheneverpossible, it elaborates on the underlying mechanisms through which they function in this disorder and offers insights for fruitfuluse of bee products in future clinical trials.

1. Introduction

The numbers of aged population are exponentially expand-ing worldwide. Statistics predict that by 2050 the number ofolder adults over the age of 80 will grow from 11.5% toalmost the double (21.0%) [1, 2]. Aging is associated withprogressive functional decline, which results from chroni-cally increased production of free radicals and inflammatorymediators, which in turn promote long-term alterations incellular structure and function. Numerous physiological alter-ations contribute to cellular senescence such as mitochondrialdysfunction, telomere shortening, gene methylation, epige-netic alterations, protein misfolding and proteotoxicity, and

distorted nutrient sensing [3]. Thus, increased human survivalcomes at the cost of heightened vulnerability to various age-related pathologies.

Parkinson’s disease (PD) is an age-related neurologicaldisorder that affects more than 6.3 million people [4, 5]accounting for around 2% of the world’s population [6],which makes it the second most prevalent neurodegenerativedisease worldwide [7]. The key pathological hallmark of thedisease is chronic, progressive, and selective degeneration ofdopaminergic neurons in the substantia nigra pars compacta(SNC) that results from intraneuronal accumulation of mis-folded proteins, mainly the synaptic protein α-synuclein, amajor component of Lewy bodies [4, 6, 8].

HindawiOxidative Medicine and Cellular LongevityVolume 2020, Article ID 1727142, 18 pageshttps://doi.org/10.1155/2020/1727142

https://orcid.org/0000-0002-6448-8282https://orcid.org/0000-0002-7209-3790https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://doi.org/10.1155/2020/1727142

2. The Pathology UnderlyingParkinson’s Disease

PD is a multidimensional condition that results from variousfactors: heredity, lifestyle, nutritional, hormonal, physical,and psychosocial. Evolving knowledge indicates that PDpathology first occurs in the olfactory mucosa and the gutin response to alterations of gut microbiota as a result ofdirect exposure to ingested toxins or pathogens [6, 9]. α-Synuclein—a major contributor to neuronal death inPD—appears in enteric nerves and enteroendocrine cells ofPD patients, which is associated with the occurrence of gas-trointestinal (GI) symptoms in 70–80% of patients as earlyas a decade before motor and neurological signs appear.Experimentally, misfolded α-synuclein appears in entericnerves before it appears in the brain while injecting the intes-tinal wall with abnormal α-synuclein leads to its spread intothe vagus nerve. Given that vagotomy is associated with alow risk of PD development, the vagus nerve represents themain anatomically interconnected network through whichinitial seeds of α-synuclein get physically transmitted fromthe gut to neurons in the midbrain. Uptake of α-synucleinby vulnerable neurons induces pathological misfolding ofα-synuclein in recipient neurons, which is associated withfurther transmission to neighboring cells leading to sporadicspread of PD pathology and further progression of thedisease [9–11].

The activity of α-synuclein in PD brains is furtherexacerbated by oxidative stress, a principal contributor toneurodegeneration in PD. PD brains exhibit exceptionallyhigh levels of autoxidation and enzymatic oxidation ofdopamine resulting in high emission of reactive oxygenspecies (ROS). ROS stimulates mitochondrial dysfunctionof respiratory chain complex I in the SNC resulting inactivation of apoptotic signaling pathways, finally leadingto neuronal cell death [12, 13]. In addition, mitochondrialimpairment—caused by mutations in certain genes such asα-synuclein, parkin, protein deglycase (DJ-1), and PTEN-induced kinase 1 (PINK1)—leads to further ROS produc-tion in dopaminergic neurons of the SNC resulting in sev-eral brain changes such as higher metabolic stress,increased synaptic aberrations, and low expression of neu-roprotective factors, which all lead to a highly selectivenigrostriatal dopaminergic degeneration [12, 14–16].

ROS activate matrix metalloproteinases (MMPs), agroup of enzymes that are produced in an inert formand get activated by free radicals, hypoxia, infection,inflammation/immunological reactions, and enzymes thatfree the cysteine bond or cleave the propeptide region.Once activated, MMPs attack the extracellular matrix, basallamina, and tight junctions in endothelial cells of the blood-brain barrier resulting in increased permeability/leakage,vasogenic edema, increased extracellular space, hemorrhagictransformations, and acute neuroinflammation [17].Stromelysin-1 (MMP3) is the main MMPs involved in PDpathogenesis. Apoptotic dopaminergic neurons producelarge amounts of active MMP3, ROS, and inflammatorymediators. These molecules induce mutations in genesinvolved in lipid metabolism in the brain such as iPLA2-

VIA resulting in dysregulations in the metabolism of fattyacids through a mechanism that involves shortening ofacyl-chain in phospholipids, which interferes with mito-chondrial functioning, homeostasis, structure of synapticvesicles, and neurotransmission in the endoplasmic reticu-lum resulting in high loss of dopaminergic neurons. Inaddition, depletion of iPLA2-VIA is associated with lossof α-synuclein affinity for phospholipids with shorter fattyacyl chains evoking increases in α-synuclein accumulation,neuroinflammation, migration of reactive microglia intothe pathological region, barrier leakage, and reduction ofimmune cells infiltration into the SNC leading to increasedα-synuclein accumulation in neurons and further apopto-sis and cell death due to activation of apoptotic signalingcascade involving c-Jun N-terminal kinases and its down-stream effector, caspase-3 [4, 18].

Progressive deterioration of motor functions such as rest-ing tremor, rigidity, and bradykinesia is a key feature of PD,primarily associated with dopaminergic neurodegeneration.The Hoehn and Yahr scale is widely used to assess PDpatients according to five disease stages, which range fromonly unilateral involvement in stage I to being wheelchair-or bed-bound in stage V [19]. Nonetheless, the clinical pic-ture of the disease varies considerably among patients, evenwithin the same stage. This is because PD encompasses othermajor nondopaminergic alterations. Cumulative evidencedenotes that degeneration of dopaminergic neurons in theSNC of patients with PD occurs mainly at stage III, alongwith a concomitant loss of serotonergic neurons in the sero-tonergic raphe nuclei and cholinergic neurons in the nucleusbasalis of Meynert and in the perineuronal nets [20, 21].Thereby, PD entails a significant reduction of serotonergicand cholinergic markers, which is associated with decline ofcognitive functions, mood dysregulations, fatigue, insomnia,weight loss, autonomic dysfunction, olfactory abnormalities,and GI dysfunction such as constipation, nausea, bloating,drooling, delayed gastric emptying, and prolonged intestinaltransit time [10, 12, 19, 21, 22].

The available PD treatment is limited to a single drug,which functions by increasing dopamine levels in the brainto compensate for dopaminergic cell loss. It provides a symp-tomatic relief of motor symptoms during early stages of thedisease [10]. However, it turns to be less effective over time,and it exerts no effect on all nonmotor symptoms. Evenmore, some of them (e.g., GI symptoms) interfere with theaction of the drug and severely alter patients’ quality of life[6, 10]. Therefore, recent researches have focused on theuse of multifunctional, natural agents, and nutritional modi-fications as safe adjunctive treatments to impede diseaseprogress, alleviate its symptoms, and promote quality of lifein PD patients [6, 19]. Figure 1 briefly summarizes factorsassociated with PD and its underlying mechanism.

3. Apitherapy as a Possible ComplementaryTreatment for Parkinson’s Disease

The beehive produces a large number of products that areloaded with numerous bioactive ingredients such as propolis,bee pollen, honey, royal jelly (RJ), and bee venom [26]. Given

2 Oxidative Medicine and Cellular Longevity

the high nutrient content of most bee products, the last fewdecades have witnessed excessive use of bee products (e.g.,RJ, bee pollen, and propolis) as dietary supplements in manyparts of the world, especially in Japan [27–30]. In addition,bee products have been historically used as medicines inancient Egypt and China, and they are gaining research inter-est as drug targets nowadays [31–35]. Apitherapy is a type ofcomplementary medicine that involves the use of various beeproducts as therapeutic agents to prevent illnesses and mod-ify disease progression [33, 35].

Research documents antiaging effects of several bee prod-ucts including RJ and propolis [36, 37]. Accordingly, thisreview is aimed at investigating the effect of bee productson PD. To retrieve relevant studies, we searched PubMedand Google scholar using a combination of terminologies of“Parkinson’s disease” with “royal jelly, honey, bee pollen,propolis, bee venom, bee bread, bee wax, chrysin, apamin,caffeic acid phenethyl ester.” Manual hand-search was alsoconducted by checking reference lists of the obtained studies.

Literature search yielded a number of studies, which involvedthe use of RJ, bee venom, and propolis to target PD pathol-ogy. Given that an existing review has previously evaluatedthe effect of bee venom on PD [7], the current review focusedon examining the effect of other bee products (propolis andRJ) with further elaboration on their underlying molecularmechanism. This section describes active compounds inand biological properties of propolis and RJ in detail.

3.1. Composition and Biological Activities of Propolis. Propo-lis is a malleable, compact, resinous substance that foragingbees form by mixing resin, which they collect from differentplant tissues, with bee saliva, wax, and pollen [26]. Its phar-macological properties and color (e.g., green, red, brown, orblack) vary according to its botanical source [38]. The wordpropolis has two Greek parts “pro” and “polis,” which mean“defense” and “city or community.” This name is derivedfrom the function that this substance serves: repairing andsanitizing purposes in bee hives such as sealing holes and

Environmental factors(pathogens, toxins)

Physical factorse.g., hormones Heredity

Sedentarylifestyle

Psychosocial factorse.g., stress & loneliness

↓Antioxidant capacity / ↑oxidative stress

Cortical neuronal degeneration/↓ acetylcholine levels

SNC neuronal degeneration/↓ dopamine levels

↑ Mitochondrialrespiration

↑ Lipid metabolismalterations in the brain

↑ Expression of pathologicalgenes e.g., 𝛼-syn, parkin

Activation ofmicroglia/astrocytes

Altered microbiome& gut degeration

Formation of aninitial neuron 𝛼-synuclein seed

↑ 𝛼-Synuclein production,accumulation, & spreads

to contingent neurons

𝛼-Synuclein moves tothe CNS through the

vagus nerve

Gastrointestinalsymptoms of PD

Cognitive and psychiatricsymptoms of PD

Motor symptomsof PD

𝛼-Synuclein misfoldingin enteric neurons

↑ Formationof Lewy body

inside neurons

↓ Expression of genes involved inbiomembrane structure e.g., iPLA2-VIA

Chronic inflammation

Figure 1: Schematic summary of events contributing to the development of Parkinson’s disease. Multiple factors contribute to increasedproduction of free radicals in age people. Meanwhile, the antioxidant capacity decreases with aging, which is associated with chronicincrease of inflammatory markers [12, 14, 23, 24]. Inflammation along with free radicals induces morphological and functionalmitochondrial alterations resulting in impaired energy production and more emission of free radicals. Injuries of the gastrointestinal tractcaused by pathogens and ingested toxins stimulate the expression of the synaptic protein α-synuclein in enteric neurons. α-Synuclein thenmoves through the vagus nerve to be seeded in vulnerable neurons in the CNS [9–11]. In the meantime, the expression of genes involvedin the synthesis of phospholipids of the biomembrane such as iPLA2-VIA decreases whereas microglia and astrocytes get activated andmigrate in response to inflammation and auto-oxidation of dopamine, which trigger the expression of pathological genes such as α-synuclein and parkin [18]. As a result, α-synuclein pathology increases causing a widespread of initial seeds of α-synuclein to thevulnerable neighboring neurons. Consequently, continuous accumulation of α-synuclein results in the growth of intracellular tangles toform Lewy bodies inside dopaminergic neurons of the SNC contributing to neuronal dysfunction and death. α-Synuclein pathology movesfrom the SNC into the other brain regions such as the cortex leading to reduction of serotonergic and cholinergic markers such asserotonin and acetylcholine [11, 25]. Accordingly, PD patients undergo serious motor impairments, which decrease gait speed andincrease the risk of fall, in addition to a range of other debilitating cognitive, psychiatric, and gastrointestinal symptoms such as poorcognitive performance, mood dysregulation, depression, sleep disturbance, nausea, and chronic constipation—which altogether lowerquality of life and increase disability and mortality [20, 24]. ↑ denotes increase; ↓ denotes decrease; CNS: central nervous system; SNC:substantia nigra pars compacta; PD: Parkinson’s disease.

3Oxidative Medicine and Cellular Longevity

cracks, smoothing the inner surface, and maintaining tem-perature of the hive (e.g., narrowing the hive entrance duringcold weather), as well as mummifying and preventing decayof dead pests (e.g., mice) that get into the hives [26, 31].

Propolis has an unusual chemical structure (Figure 2)that involves more than 300 natural compounds [26, 28,39]. Its content of resins and vegetable balsam, wax, pollen,aromatic, and essential oils, in order, is 50%, 30%, 5%, and10% [31, 40]. In addition, 5% of propolis comprises differentlevels of vitamins (thiamin, riboflavin, pyridoxine, niacin, C,and E), amino acids, micronutrients, flavonoids and phenols,phenolic aldehydes, and terpenoids [26, 28, 31, 39, 40]. Thelimited solubility of crude propolis in water necessitates theuse of a suitable solvent (e.g., ethanol, which is the best sol-vent of propolis) in order to obtain extracts rich in bioactivecompounds [40, 41].

Some of the most therapeutic elements in propolisinclude caffeic acid phenethyl ester (CAPE), chrysin (5,7-dihydroxyflavone), and pinocembrin (PB). All these sub-stances are flavonoids that exist in multiple plants, and theypossess strong free radical scavenging potential, on top ofmany other biological activities, e.g., immunomodulatory,anti-inflammatory, antiviral, and ant-neoplastic [42–45].PB easily crosses the bloodbrain barrier and produces neuro-protective, antioxidant, and anti-inflammatory activities,which allowed its approval by China Food and Drug Admin-istration as a treatment for ischemic stroke [46].

Due to its total phenolic content (up to 300.36mg ofgallic acid equivalents (GAE)/g of dry weight) and flavo-noid content (up to 70mg of quercetin equivalents(QE)/g), propolis demonstrates a free radical-scavengingactivity of about 20 to 190μg/mL [31, 38]. In general, theexceptional antioxidant effect of propolis is as strong as thatof butylated hydroxytoluene, a synthetic antioxidant. How-ever, the antioxidant capacity of various types of propolisvaries considerably depending on the type of plant exudatesused for their production [31]. Because of its rich chemicalcomposition, propolis has a wide range of several othertherapeutic activities: antibacterial, antiviral, antifungal,anti-inflammatory, and anticarcinogenic anticholesterolproperties [29, 36, 38, 41, 47, 48]. Accordingly, propolisand its components have been used to promote woundhealing and to treat several diseased conditions such aspulp problems, oral candidiasis, genital herpes, and ische-mic stroke, to name a few [38, 39, 46, 48].

Propolis is also widely used as a preservative in severalfood products such as processed meat and wines [40].Despite the fact that daily consumption of 1.4mg/kg bodyweight/day of propolis is relatively safe for humans, individ-uals with atopy, bee venom allergy, and bronchial asthma candevelop a wide range of allergic reactions to this bee product.Hence, individuals with known allergies are advised tocompletely avoid the consumption of propolis and propoliscontaining products [49]. Given the enormous benefits ofpropolis, several methods have been developed to removeallergenic compounds in propolis such as benzyl cinnamateand benzyl salicylate [50, 51]. However, the safety profile ofpurified propolis extracts has not been evaluated in individ-uals allergic to propolis yet.

3.2. Composition and Biological Activities of Royal Jelly.Royal jelly is an acidic, pungent smelling, yellow-whitish,creamy substance excreted from the pharyngeal gland ofyoung Apis mellifera bee workers [13, 52, 53]. RJ is a com-plex material (Figure 2). In its fresh state, RJ consistslargely of water (50%–60%) [54]. Proteins are the largestfraction in RJ (18%), and they represent around 50% ofits dry weight [54]. Proteins in RJ are one of its mostactive components, especially a group of 9 nonwater-soluble proteins of molecular weights that range between49 and 87 kDa, known as major RJ proteins (MRJPs1-9).MRJPs account for around 80% of the protein fractionof RJ, and MRJPs1-5 constitute 82-90% of MRJPs. MRJP1is the most abundant among all MRJPs [37, 55, 56]. Dueto their high content of amino acids (up to 578), MRJPsare reported to prevent senescence of human cellsin vitro [57] as they promote cell proliferation, cell adhe-sion, cell growth, and immunity [58, 59]. The rest of theprotein fraction of RJ comprises antioxidative peptides,free amino acids (including at least eight essential aminoacids) [55], and small amounts of royalisin, jelleines, andaspimin—proteins, which express strong antimicrobialand bactericidal activities even against drug resistant bac-teria [31, 32].

Carbohydrates constitute 15% of RJ content, and theyconsist mainly of glucose and fructose [54]. Sugars of RJare thought to contribute to larval development intoqueens through stimulation of the activities of the nutrientsensing mammalian target of rapamycin pathway andinsulin/insulin-like signaling, which stimulate food con-sumption and increase of body size [60]. Fats represent3%–6% of RJ content [54], and they largely consist of agroup of rare short hydroxyl fatty acids or dicarboxylicacids with 8–12 carbon atoms in the chain such astrans-10-hydroxy-2-decenoic acid (10-HDA, also knownas queen bee acid or RJ acid) and sebacic acid. 10-HDAis one of the most common bioactive ingredients in RJ,and it is used as an indicator of its freshness [31, 61].Furthermore, RJ is rich in phenols, vitamins (especiallyniacin and B complex), minerals, and trace elements. Italso contains small amounts of nucleotides (e.g., adeno-sine, guanosine, and adenosine monophosphate), severalbioactive substances (e.g., acetylcholine), volatile organiccompounds (e.g., acetic acid, esters, and aldehydes),ketones, alcohol, and other compounds that have not beenidentified yet [37, 54, 55]. The percentages of compoundsin RJ are relative, and they vary considerably accordingto several factors including bee species, geographical loca-tion, season, botanical origin, and sugar suplementation tonurse bees [37, 62].

Existing knowledge denotes that RJ is promising as anantiaging compound that is capable of enhancing healthspan through the promotion of reviving cellular processessuch as cellular metabolism, protein translation, ribosomalbiogenesis, and autophagy [37]. Owing to its antioxidant,anti-inflammatory, neuroprotective, cardioprotective, anti-proliferative, antimicrobial, antilipidemic, antidiabetogenic,antiadipogenic, and antifatigue properties, RJ is used as anadjuvant modality for the treatment of various clinical


conditions such as cancer, hypertension, hyperlipidemia,diabetes, and neurodegenerative diseases such as Alzhei-mer’s disease and Parkinson’s disease [37, 58, 63–71].

RJ is heat sensitive, and it should be kept frozen in orderto keep its bioactive ingredients and pharmacological effects.This is because the storage of RJ at a temperature of 5°C orabove promotes enzymatic degradation leading to loss of itscontent of soluble nitrogen and free amino acids [53].Despite the fact that RJ has the potential to suppress hista-mine H1 receptor resulting in several antiallergic activities[30, 72], the occurrence of allergic reactions to RJ in peoplewith a history of bronchial asthma and atopy has beenreported in a number of case studies [73, 74]. Research dem-onstrates that some proteins in RJ are allergenic such asmajor royal jelly proteins 8 and 9 [37] and water-soluble pro-teins 1 and 2 (molecular weight: 55 and 47 kDa) [75]. Treat-ing RJ with bacterial alkaline proteases removes allergenicproteins by breaking them into small peptides and aminoacids without affecting RJ freshness or content of 10-HDAand vitamins [75, 76]. Administering proteases-treated RJ(pRJ) to individuals allergic to RJ did not cause allergic reac-tions in vivo and in vitro [76].

4. Animal Models of Parkinson’s Disease

Experimental models of PD are distinguished into 3 mainclasses: genetic, pharmacological, and environmental(Figure 3). Various models express PD characteristics onlypartially, i.e., there is no typical model that perfectly exhibitsthe typical progressive, behavioral, neurologic, and patholog-ical features of the disease, which may represent a challengefor PD research [6]. Many transgenic PD mice models havebeen recently generated by inducing mutations in genesinvolved in PD pathology such as A53Tα-Syn, Thy-α-Syn,and aggregates of α-Syn preformed fibrils (PFF). These muta-tions accelerate intraneuronal accumulation of α-synuclein

in a fashion similar to the naturally occurring ones [6, 77].For instance, A53Tα-Syn model develops mid- to late-onsetneurodegeneration with aggregation of filamentous α-synu-clein cytoplasmic inclusions all over the neuroaxis [77]. Somegenetic models may demonstrate behavioral dysfunctionwithout neurodegeneration (e.g., parkin, PINK1, and DJ-1)or demonstrate impaired dopaminergic transmission withno clear motor dysfunction (e.g., Leucine-rich repeat kinase2 (LRRK2)). On the other hand, mice with mutations in vac-uolar protein sorting-associated protein (VPS) 35 demon-strate aggregation of α-synuclein accumulation along withlow striatal dopamine level and motor dysfunction. Mitoparkmodels progressively develop motor deficits of PD due tomitochondrial insult in dopaminergic neurons resultingfrom knock out of the gene coding for mitochondrial tran-scription factor A [6].

Pharmacological treatments such as haloperidol blockdopamine activity without inducing dopaminergic neurode-generation in the SNC. Thus, they do not cause PD, but theyinduce transient behavioral alterations similar to thoseoccurring in PD, known as PD akinetic deficit/akinesia orcatalepsy [78]. Environmental models of PD are producedby treating animals with neurotoxins (e.g., rotenone), whichselectively induce degeneration in dopaminergic neurons inthe SNC via various mechanisms that embroil activation ofsignaling pathways involved in inflammation, oxidativestress, and apoptosis [79–81].

According to Table 1, PD models in studies includedin this review were induced by treating laboratory animalsand cell lines with 3 neurotoxins. Rotenone was used inone study to induce PD in rodents via inhibition of mito-chondrial complex I of the mitochondrial respiratorychain, which was associated with high emission of mito-chondrial ROS and induction of apoptosis via activationof caspase-3 [44]. 6-Hydroxydopamine (6-OHDA) hasbeen used both in vivo and in vitro in 6 studies to induce

Proteins 18%

Carbohydrates 15%

Lipids 3-6%

Water 50-60%Resins andbalsam 50%

Wax 30%

Essential oils 10%

Pollen 5%

Minerals, vitamins,micronutritents, etc.Propolis

Flavonoids and phenols

Royal jelly

Minerals, trace elements,vitamins, nucleotides, etc.

Therapeutic properties

Antioxidant, anti-inflammatory, anitcarcinogenic,anti-cholesterol, antiobsity, neuroprotective, cardioprotective,antidiabetic, antiaging, antibacterial, antiviral, antifungal, etc.

Figure 2: Components of propolis and royal jelly along with their pharmacological activities. Propolis and royal jelly are rich in numerousbioactive elements. Therefore, they express a range of beneficial activities. The key action through which these bee products promotehealth span stems mainly from their phenolic and flavonoid fractions, which contribute to their strong antioxidant activities. Scavengingfree radicals (which activate destructive molecules such matrix metalloproteinases) and enhancing the expression of antioxidant genespromote the suppression of inflammatory responses, thus protecting against cancer, obesity, diabetes, heart disease, neurodegenerationand neurotoxicity, rheumatoid arthritis, and the like.


PD [13, 42, 45, 79, 82, 83]. It selectively provokes apopto-sis of dopaminergic neurons via mechanisms that involveincreasing the production of ROS, accelerating lipid peroxida-tion (production of malondialdehyde (MDA)), and evokingan imbalance between the antiapoptotic B cell lymphoma2 (bcl-2) and the proapoptotic bcl-2-associated X protein(bax) [79].

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)and its metabolite 1-methyl-4-phenylpyridinium (MPP)were used in 3 studies to induce in vivo and in vitro modelsof PD [84–86]. Inside the body, MPTP changes into MPP,which activates key inflammatory signaling pathways suchas nuclear factor kappa B (NF-κB), interleukin-1, and induc-ible nitric oxide synthase (iNOS) resulting in SNC microglialactivation, cytokine production, and secondary dopaminer-gic neuron damage [84, 85, 87]. In addition, MPTP movesinto and accumulates inside nigrostriatal neurons through

the activity of dopamine transporter while the membranepotential facilitates its transport into the mitochondria [85].Accordingly, it alters mitochondrial enzymes resulting inincreased mitochondrial production of ROS, collapse ofmitochondrial membrane proteins, and mitochondrial mem-brane permeability. Mitochondrial membrane permeabilitypromotes the leak of mitochondrial proteins (e.g., cyto-chrome c) into the cytoplasm, which is associated with acti-vation of caspase-3, a downstream executive of apoptosisand cell death [84–86].

5. Evidence from Preclinical Studies

The effects of both propolis and its flavonoids and RJ and itslipids on PD were examined both in vivo and in vitro. Thefindings indicate that these bee products can induce bothstructural and symptomatic improvements and reduce the

Models of Parkinson’sdisease

NeurotoxinsEnvironmental

Pharmacological

Genetic

Dopamineblockers

Genemutations

Example: rotenone, 6-OHDA, and MPTP

Example: haloperidol

Example: A53T𝛼-Syn,parkin, and Mitopark

Trigger selectivedopaminergic

neuron loss

Evoke behavioraldeficits without

neuron loss

Knock out genesinvolved in PD

pathology

↑ 𝛼-Synuclein accumulation, ↑mitochondrial insult, ↓ dopamineneurotransmission with no motordeficit, ↑ motor symptom with no

neuron loss.

↑ Microgalia activation, ↑ cytokinerelease, ↑ ROS production, ↑

mitochondrial injury, ↑ caspase-3.

↓ Dopamine neurotransmissionresulting in a reversable cataleptic state.

Figure 3: Various experimental models of Parkinson’s disease. Multiple experimental models of PD have been developed. They aredistinguished into 3 classes. Environmental models of PD are produced by numerous neurotoxins, which selectively induce dopaminergicneurodegeneration via mechanisms that involve induction of neurodegeneration through increased production of free radicals,inflammation, and mitochondrial dysfunction. Pharmacological models produce clinical manifestations of PD, e.g., catalepsy anddyskinesia without alterations in neuron structure or function—they block dopamine activity. Genetic models are miscellaneous, and theyare produced through induction of gene mutations related to dopamine neurotransmission, mitochondrial function, and proteinmisfolding (α-synuclein). ↑ denotes increase; ↓ denotes decrease; PD: Parkinson’s disease; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA: 6-hydroxydopamine; ROS: reactive oxygen species; caspase-3: cysteine-aspartic acid protease 3.

Table 1: Neurotoxins used to induce Parkinson’s disease in animal models and cell lines in included studies.

Neurotoxin Treatment Mechanism of neurotoxicity Reference

Rotenone In vivo.↓ Mitochondrial complex I.

↑ ROS and caspase-3.[44]

MPTP and MPP In vivo and in vitro. ↑ ROS, production of cytokines, and caspase-3. [84–86]

6-OHDA In vivo and in vitro.↑ ROS, MDA, caspase-3, bax.

↓ Bcl-2 and SOD.[13, 42, 45, 79, 82, 83]

MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP: 1-methyl-4-phenylpyridinium; 6-OHDA: 6-hydroxydopamine; bcl-2: B cell lymphoma 2; bax:bcl-2-associated X protein; ROS: reactive oxygen species; MDA: malondialdehyde; SOD: super oxide dismutase; caspase-3: cysteine-aspartic acid protease 3.


behavioral and histomorphometrical dysfunctions that arecaused by PD in rodents. In this regard, a water extract ofpropolis (200mg/kg/d/40 days) reduced dopaminergic neu-rodegeneration and striatal fiber degeneration induced by6-OHDA along with maintenance of body weight andimprovement of cardiac and autonomic functions [83].CAPE (10mg/kg) significantly decreased stepping ratio,improved coordination, shortened the latency to orientdownwards on pole test, prolonged the permanence time,and increased the activity index and rears in rotenone-challenged mice [44]. This effect is a read out for reducedneurotoxicity demonstrated by CAPE in mice treated withMPTP and rotenone as depicted by increased percentage ofviable dopaminergic neurons in the SNC by 73% and 92%,respectively [44, 84]. Chrysin treatment for 28 days protectedmice against behavioral deficits triggered by interstriatalinjection of 6-OHDA 36 days after lesion induction asreported by decreasing the number of rotations and latencyfor the first fall elicited by 6-OHDA. This report speaks forthe molecular actions of chrysin, which contribute to neuro-nal survival such as increased production of neurotrophinsand endogenous antioxidants reactivity and reduced levelsof cytokines [42]. Moreover, treating 6-OHDA-PD ratmodels with RJ (100 or 200mg/kg), 4 weeks after lesioninduction, resulted in a significant decrease in the numberof rotations in ipsilateral and contralateral to striatal lesioninduced by apomorphine subcutaneous injection (0.2mg/kg)in the 7th week after lesion induction compared withuntreated PD rats [82]. The reported improvements of motorperformance occurred for the reason that RJ restored thebrain structure in 6-OHDA-treated rats by preventing neu-ron death in the SNC and in the caudate putamen unit(CPU) as well as by increasing the thickness of gray andwhite matter of the cerebral cortex and cerebellum comparedwith the untreated controls [82]. Pinocembrin (PB) was usedonly in vivo to evoke cellular and molecular effects, which areaddressed in detail in Section 6 [79, 85, 86]. Table 2 presentsmore details on propolis and RJ treatments and key findingsof the relevant studies.

6. Mechanisms of Action of Propolis and RoyalJelly in Parkinson’s Disease

Relatively few studies have explored the mechanism throughwhich propolis and RJ may be beneficial for PD. Figure 4shows that propolis and RJ operate through a range of inter-related mechanisms, which are detailed in this section.

6.1. Bee Products Protect Neurons against Oxidative Stress.Antioxidants protect neurons against neurotoxins by inhi-biting the generation of free radicals. Several lines of evi-dence denote that flavonoids in propolis and derivativesof RJ lipids demonstrate neuroprotective effects in dopa-minergic neurons, to a great extent, through modulationof oxidative stress. CAPE blocked the production of O2−and peroxynitrite in the brain of MPTP-intoxicated miceand inhibited the activity of the prooxidant iNOS inrotenone-induced mouse model of PD [44, 84]. In vitroinvestigations show that CAPE also protected cerebellar

granule neurons (CGNs) and rostral mesencephalic neu-rons (RMNs) against free radicals induced by 6-OHDA[45, 88]. PB conferred protection against cytotoxicityinduced by MPP+ and 6-OHDA in vitro through upregu-lation of the expression of heme oxygenase-1 (HO-1) [85,86], superoxide dismutase (SOD), and γ-glutamylcysteinesynthetase (γ-GCS) [79]. An in vitro study involvingapplication of 6-OHDA to human neuroblastoma SH-SY5Y cells to induce cell death as a model of PD showedthat treatment with a derivative of RJ lipids known as 4-hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE)markedly stimulated the expression of antioxidant genessuch as HO-1, γ-glutamylcysteine ligase (γ-GCL), andNAD(P)H quinone dehydrogenase 1 (NQO1) [13].

Antioxidants such as HO-1, which act as stress-rela-ted/phase II detoxification enzymes, are thought to havea role in PD pathology. This suggestion is derived fromthe fact that HO-1 is upregulated in the cytoplasm ofdopaminergic neurons in the SNC of PD brains whilethe saliva of PD patients expresses a moderate increasein HO-1 protein levels compared with normal cross-matched control individuals. In addition, Lewy bodiesexhibit a strong immunoreactivity to HO-1 [89, 90]. Onthe other hand, injecting adenovirus containing humanHO-1 gene (Ad-HO-1) locally into the SNC of rats intox-icated with MPP+ significantly accelerated the survival rateof dopaminergic neurons—an effect that was associatedwith upregulation of brain-derived neurotrophic factor(BDNF) and glial cell line-derived neurotrophic factor(GDNF), downregulation of tumor necrosis factor-α(TNF-α) and interleukin-1β (IL-1β), and restoration ofdopamine levels in the SNC. Ad-HO-1 counteractedapomorphine-induced rotation following MPP+ treatment.Hence, increased levels of HO-1 in PD brains represent adefense attempt against neuronal insult [91]. In thisregard, Wang et al. [86] reported that treating mice withMPP+ induced HO-1 in a dose-dependent fashion.Cotreatment with PB further accelerated the expressionof HO-1, which was associated with significant reductionsin MPP+-induced neurotoxicity, ROS production, cleavageof caspase-3, and the rate of apoptosis and cell death in adose-dependent manner [79, 85, 86]. Inhibition of HO-1by zinc protoporphyrin-IX attenuated the neuroprotectiveeffects of PB [86].

Western blot analysis shows that the antioxidant effectsof PB and HPO-DAEE in SH-SY5Y cells result from activa-tion of 2 main signaling pathways: nuclear factor erythroid2- (NRF2-) antioxidant response element (ARE), which is amain regulator of antioxidative responses, and eukaryoticinitiation factor 2α (eIF2α), an upstream effector of theactivating transcription factor-4 (ATF4), which cooperateswith NRF2 to modulate the expression of antioxidant genes[13, 86]. Interestingly, the mechanism through which HPO-DAEE exerts its antioxidant effect involves slight emissionof ROS upon HPO-DAEE treatment, which represents asublethal stress that causes preconditioning of SH-SY5Ycells against subsequent severer oxidative stress inducedby 6-OHDA. The authors noticed that ROS deactivatedKeap1, the cytoplasmic protein that degrades NRF2, which


allowed NRF2 phosphorylation and translocation into thenucleus. In the nucleus, NRF2 binds to the small Maf pro-teins to form heterodimers, which further phosphorylateARE in the 5′-regulatory region of antioxidant enzymes

and phase II detoxifying enzymes—which result in theexpression of antioxidant genes. In the same manner,HPO-DAEE activated the phosphorylation of eIF2α, whichresulted in aggregation of ATF4 in the nucleus, and

Table 2: Characteristics of included preclinical experiments involving administration of propolis, royal jelly, and their constituents in animaland cell culture models of Parkinson’s disease (number of included studies = 11).

Animal/cell line model Treatment Summary of effects and mechanism Reference

6-OHDA-induced rat model of PDPropolis gavage (200mg/kg/d/40

days)

↑ TH+ neurons↓ Striatal fiber degeneration

Propolis restored body weight and reverted6-OHDA-induced reductions in HR and HRV

[83]

Rotenone-induced mouse modelof PD

CAPE (2.5-10mg/kg/p.o./everyother d/17 days)

↓ Motor deficits, microglia activation (CD11b+),TNF-α and IL-1β, COX-2, iNOS, and NF-κB

↑ Striatal dopamine and TH+ neurons[44]

MPTP-induced mouse model ofPDMPTP-treated CGNs and RMNsas cellular models of PD

CAPE (2-10mg/kg/p.o./d/7 days)

↑ Neuronal viability, striatal dopamine, TH+ neurons↓ iNOS, caspase-1, cytochrome c, AIF, MPP-inducedformation of free radicals and peroxynitrite, and

neurotoxicity

[84]

6-OHDA-treated CGNs andhepatic cells as a cellular model ofPD and oxidative stress

CAPE (10 μM/4 h) followed by atreatment with 6-OHDA

(70 μM for 6 h)

↑ Neuronal viability↓ Cytochrome c, caspase-3, and H2O2-induced

neurotoxicity

[45]

6-OHDA-treated CGNs andRMNs as a cellular model of PD

CAPE (10 μM) for 2 h↑ Neuronal viability

↓ Formation of O2− and peroxynitrite andH2O2-induced neurotoxicity

[88]

MPP+-treated SH-SY5Y cells as acellular model of PD

PB (1, 10, 20 μM) for 24 h↑ Neuronal viability, mitochondrial membrane

potential, and bcl-2/bax ratio↓ ROS, caspase-3, apoptotic rate, and cytochrome c

[85]

MPP+-treated SH-SY5Y cells as acellular model of PD

PB (20 μM) for 24 h↓ Neurotoxicity

↑ ERK/MAPK and HO-1[86]

6-OHDA-treated SH-SY5Y cells asa cellular model of PD

PB (25 μM) for 4 h↓ Neurotoxicity, ROS, MDA, and apoptotic rate

↑ Nrf2/ARE, SOD, HO-1, γ-GCS, bcl-2/bax ratio, andmitochondrial membrane potential

[79]

6-OHDA-induced rat model of PDChrysin orally (10mg/kg/twice a

d/28 days)

↓ TNF-α, INF-γ, IL-1β, IL-6, IL-10, NF-κB, TRAP, andS100B

↑ Dopamine, DOPAC, HVA, BDNF, NGF,GDNF, TAR, and TH+ neurons

[42]

6-OHDA-induced mouse modelof PD

Dietary RJ 100 or 200mg(3 weeks)

↑ Neuronal survival (the number of Nissl-stainedneurons in the SNC and CPU) and the thickness of grayand white matter of the cerebral cortex and cerebellum↓ Motor deficits and contralateral to striatal lesion

induced by apomorphine injection

[82]

6-OHDA-treated SH-SY5Y cells asa cellular model of PD

RJ fatty acids: 10-HDA, 10H2DA,SA, their derivatives DAEE and

HPO-DAEE (4 h)

Only HPO-DAEE ↑ cell viability, NRF2-ARE signaling,HO-1, γ-GCL, and NQO1

↓ ROS emission[13]

↑ denotes increase; ↓ denotes decrease; RJ: royal jelly; d: day; h: hour; PD: Parkinson’s disease; 6-OHDA: 6-hydroxydopamine; HR: heart rate; HRV: heart ratevariability; SNC: substantia nigra pars compacta; CPU: caudate putamen unit; 10-HDA: 10-hydroxy-decanoic acid; 10H2DA: 10-hydroxy-2-decenoic acid; SA:sebacic acid; DAEE: 2-decenoic acid ethyl ester; HPO-DAEE: 4-hydroperoxy-2-decenoic acid ethyl ester; HO-1: heme oxygenase 1; γ-GCL: γ-glutamylcysteineligase; NQO1: NAD(P)H quinone dehydrogenase 1; ROS: reactive oxygen species; NRF2-ARE: nuclear factor erythroid 2-antioxidant response element; eIF2α-ATF4: eukaryotic initiation factor 2, an upstream effector of the activating transcription factor-4; CAPE: caffeic acid phenethyl ester, genes encoding CD11b (amicroglia surface antigen); COX-2: cyclooxygenase-2; iNOS: inducible nitric oxide synthase; NF-κB: nuclear factor-κB; TH: tyrosine hydroxylase; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CGNs: cerebellar granule neurons; RMNs: rostral mesencephalic neurons; p.o.: oral gavage; AIF: apoptosisinducing factor; MPP: 1-methyl-4-phenylpyridinium; caspase-3: cysteine-aspartic acid protease 3; H2O2: hydrogen peroxide; PB: pinocembrin; bcl-2: B celllymphoma 2; bax: bcl-2-associated X protein; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; γ-GCS: γ-glutamylcysteine synthetase; MDA: malondialdehyde; SOD: super oxide dismutase; DOPAC: 3,4-dihydroxyphenylacetic acid; HVA: homovanillic acid;BDNF: brain-derived neurotrophic factor; NGF: nerve growth factor; GDNF: glial cell line-derived neurotrophic factor; TNF-α: tumor necrosis factor-α;INF-γ: interferon-gamma; IL-1β: interleukin-1β; IL-2: interleukin-2; IL-6: interleukin-6; IL-10: interleukin-10; NF-κB: nuclear factor-kappa B; S100B:calcium-binding protein B; TRAP: total reactive antioxidant potential; TAR: total antioxidant reactivity.


subsequent augmentation of NRF2-induced activation ofthe HO-1 expression, which eventually protected cellsagainst 6-OHDA toxicity [13]. The mechanism involvedin NRF2 activation by PB is a bit different.

In vitro investigations revealed that PB induced the phos-phorylation of extracellular signal-regulated kinase (ERK) 1and 2/mitogen-activated protein kinase (MAPK) in SH-SY5Y cells treated with neurotoxins [86] resulting in deacti-vation of Keap1 and phosphorylation of NRF2 [86] andARE [79], which caused a significant increase in the produc-tion of antioxidant enzymes [79, 85, 86]. Suppression ofERK/MAPK signaling by PD98059, an ERK inhibitor, orsuppression of HO-1 by zinc protoporphyrin abolished theneuroprotective effects of PB [86]. Similarly, knockdown ofthe NRF2 expression by transfecting SH-SY5Y with scram-bled NRF2 or NRF2-specific small interfering RNA (siRNA)

inhibited the antioxidant effect of PB: these maneuvers inhib-ited the expression of NRF2 and its target genes (HO-1 andγ-GCS), which accelerated 6-OHDA-induced cell death[79]. Altogether, these findings confirm that the PB activatesERK/MAPK/NRF2/ARE cascade resulting in the productionof endogenous antioxidants, which in turn suppress neuro-toxicity and apoptosis [79, 85, 86].

6.2. Bee Products Protect Neurons againstNeuroinflammation. Research shows that both central andlocal inflammation, which involves CD4 T cell infiltrationand activation of CD11b+microglia/macrophages, play akey role in neuron loss in PD. Chronic activation of thesecells is associated with morphological and functional alter-ations that promote excessive production of ROS [44, 87].According to Table 2, treating a rotenone-induced mouse

↑ERK/MAPK

↑ NRF2/ARE

↑ Antioxidantse.g., HO-1

↑ Scavenging offree radicals

↓ NF-𝜅B, andinflammatory cytokines

e.g., TNF-𝛼

↑ Estrogen receptors

↑ Neurotrophinse.g., GDNF

↑ Tyrosinehydroxylase

↑ Survival anddifferentiation of

dopaminergic neurons

↑ Neuronal affinityfor dopamine

uptake↓ Apoptosis (caspase-3 andbax) and neurodegenerations

↓ Motor, cognitive, and mood symptoms of PD

↓ Mitochondrial respiration(cytochrome c and AIF)

↓ Oxidative stress ↓ Neuroinflammation

Maintain brain structure: intact SNCand cerebral cortex

Proper levels of dopamineand acetylcholine

↓ Keap1

Propolis and royal jelly

Release electron fromphenolic group

Figure 4: Probable mechanisms through which propolis and royal jelly (RJ) alleviate symptoms of Parkinson’s disease. Propolis, RJ, and theircompounds alleviate oxidative damage directly by scavenging free radicals through the release of an electron from their phenolic group andindirectly through activation of ERK/MAPK signaling, which deactivates Keap1, the molecule that degrades NRF2 resulting in NRF2translocation into the nucleus to activate ARE, which stimulates the expression of antioxidant genes such as HO-1. On the other hand,NRF2 and HO-1 prevent the transcription of inflammatory pathways such as NF-κB resulting in less production of inflammatorycytokines. Mitigation of oxidative stress and neuroinflammation is associated with less mitochondrial respiration and less production ofapoptotic molecules such as caspase-3 and bax, eventually leading to less neurodegeneration. On the other side, chrysin increased theexpression of various neurotrophic factors possibly through its contribution to HO-1 production; however, the detailed mechanism is notclearly understood. RJ also stimulates the expression of cerebral and hippocampal GDNF, possibly through activation of estrogenreceptors. GDNF is associated with neuroprotective effects: enhancing the survival and morphological differentiation of midbraindopaminergic neurons and fostering their affinity for dopamine. All these events prevent neuronal degeneration, maintain intact brainstructure, keep proper levels of dopamine and acetylcholine, and eventually improve motor and cognitive symptoms of PD. ↑ denotesincrease; ↓ denotes decrease; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; NRF2: nuclear factorerythroid 2; ARE: antioxidant response element; HO-1: heme oxygenease-1; NF-κB: nuclear factor kappa B; TNF-α: tumor necrosis factoralpha; GDNF: glial cell line-derived neurotrophic factor; AIF: apoptosis inducing factor; caspase-3: cysteine-aspartic acid protease 3; bax:bcl-2-associated X protein; SNC: substantia nigra pars compacta; PD: Parkinson’s disease.


model of PD with CAPE (2.5-10mg/kg/every other d/17days) inhibited microglial activation (CD11b+); downregu-lated the activity of NF-κB, iNOS, and cyclooxygenase-2(COX-2); and reduced the production of TNF-α and IL-1β. Amelioration of rotenone-induced inflammatoryresponse was associated with increased dopaminergic neu-ronal survival and decreased motor deficits [44]. Likewise,oral treatment of rats intoxicated by 6-OHDA with chry-sin (10mg/kg/twice a day) inhibited NF-κB signaling,which was accompanied by downregulation of inflamma-tory markers (e.g., TNF-α, INF-γ, IL-1β, IL-6, IL-10) andrelated destructive molecules such as total reactive antiox-idant potential (TRAP) and calcium-binding protein B(S100B) [42].

Research shows that bee products such as RJ displayimmunomodulatory and anti-inflammatory functions underconditions of neuroinflammation via activation of NRF2[13]. In addition to being a master pathway that stimulatesthe release of antioxidants, NRF2 plays a central role in thesuppression of inflammatory responses directly throughdownregulation of the transcription of proinflammatorycytokines such as IL-6 and IL-1β [92]. Moreover, redox con-trol (expression of antioxidant genes such as HO-1) isanother mechanism through which RJ might silence neuro-inflammation [13]. HO-1 is a main cytoprotective agent notonly against oxidative stress but also against inflammation.It exerts its anti-inflammatory effect by catalyzing the enzy-matic degradation of nonprotein bound free heme, whichdemonstrates cytotoxic and proinflammatory properties.Heme degradation induced by HO-1 results in three maincatabolites: [1] carbon monoxide, which expresses numerousanti-inflammatory and antiapoptotic effects, [2] ferritin,which chelates free iron, and [3] biliverdin, which is reducedby biliverdin reductase into bilirubin, a potent antioxidant[93]. Activation of HO-1 gene in H2O2-challenged humanneuroblastoma cells SH-SY5Y treated by Carvacrol (anessential oil found in Labiatae) is associated with downregu-lation of NF-κB, low lipid peroxidation, and less carbonyla-tion and nitration of proteins of the mitochondrialmembrane [94].

6.3. Inhibiting Apoptosis of Dopaminergic Neurons. Cell via-bility assays [13, 45, 79, 84–86, 88] and tyrosine hydroxy-lase (TH) immunohistochemistry analysis were used inmany studies to examine dopaminergic neurons loss inthe SNC [42, 44, 81, 84]. These investigations showed thatrelatively high doses of CAPE (5 or 10mg/kg) decreasedneurotoxicity induced by MPTP and rotenone as demon-strated by the increased percentage of TH-immunostainedneurons in the SNC by 73% and 92%, respectively [44,84]. Four-week treatment of 6-OHDA-induced rat modelsof PD with chrysin resulted in a significant increase in thenumber of TH+ neurons in the SNC compared withuntreated animals [42]. The neuroprotective effects ofCAPE [45, 84, 88], PB [79, 85, 86], and HPO-DAEE [13]were vividly expressed in CGNs, RMNs, and SH-SY5Y cellsthat were challenged with neurotoxins.

Loss of dopaminergic neurons in PD is attributed, atleast in part, to activation of various signaling pathways

(e.g., Jun N-terminal kinase), which induce apoptosis asa programmed form of morphological cell death in PD.Neurotoxins such as MPTP induce PD via activation ofJun N-terminal kinase [95, 96]. Therefore, the neuropro-tective effects of phenolic compounds in propolis as wellas RJ and its derivatives, which were observed in differentmodels of PD (Table 2), might be due to modulation ofcell survival and apoptotic pathways.

Active flavonoids in propolis inhibited dopaminergicneuronal apoptosis by affecting the signaling of mitochon-drial apoptotic pathway. PB remarkably inhibited thecleavage of caspase-3 and decreased the rate of apoptosisby blocking MPP+-induced mitochondrial alterations,e.g., mitochondrial release of cytochrome c and reductionof membrane potential, thus preventing the transfer ofMPP+ into mitochondria; thus, inhibiting ROS productionand mitochondrial membrane permeability, which evokeapoptotic pathways [85]. In the same way, CAPE increasedthe survival of 6-OHDA-treated CGNs via a mechanismthat involved stabilizing mitochondrial functioning. It mit-igated apoptosis by deactivating caspase-3 and inhibitingmitochondrial release of cytochrome c under treatmentwith Ca2+ [45].The antiapoptotic effects of CAPE are pos-sibly related to amelioration of oxidative stress. In vivo,CAPE inhibited the activity of iNOS and caspase-1 inthe brain of mice treated with MPTP [84]. To explorethe detailed mechanism, the authors isolated brain mito-chondria and treated them with MPP, which is knownto stimulate ROS production. MPP increased the produc-tion of ROS, cytochrome c, and apoptosis inducing factor(AIF), which mediate MPP neurotoxicity. CAPE inhibitedmitochondrial release of cytochrome c and AIF [84].Whereas neurotoxins such as MPTP trigger cell death sig-naling via increasing bax and inhibiting bcl-2, the effect ofbee products and their derivatives (e.g., PB) on dopami-nergic cell viability is mediated by regulating the expres-sion of bax and bcl-2 in an antiapoptotic mechanism [85].

6.4. Maintaining Brain Levels of Dopamine. Dopamine isthe main neuroactive substance involved in PD [31]. Cur-rent PD treatments are based on dopamine replacement[44]. Active compounds in propolis increased dopaminelevels in the SNC of experimental models of PD. In thisregard, treatment of rats intoxicated by 6-OHDA withchrysin (10mg/kg/twice a day) increased the levels ofdopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), andhomovanillic acid (HVA) [42]. DOPAC and HVA portraydopamine turnover in dopaminergic nerve terminals [35].In the same way, high-performance liquid chromatographyshowed that CAPE (10mg/kg) increased striatal levels ofdopamine in MPTT-PD mice [44, 84]. CAPE did not altermono amino oxidase activity and brain levels of MPPdenoting that its neuroprotective activity does not involvedecreasing the metabolism of MPTP to MPP+ [84]. There-fore, enhanced dopamine production following treatmentwith chrysin [42] and CAPE [44, 84] speaks for the neuro-protective effects of these compounds—as noted by viabilityassays and neurohistochemistry analyses, which revealedimproved neuronal viability and increased numbers of TH+


neurons in animals challenged with neurotoxins followingtreatment with RJ, HPO-DAEE, and flavonoids of propolis(Table 2).

The contribution of RJ, CAPE, and chrysin to mainte-nance of the dopaminergic system in PD is probablylinked to their antioxidant activity and the associatedanti-inflammatory and antiapoptotic effects [31, 42, 44,45, 79, 85, 86, 88]. Dopamine is a monoamine derivedfrom tyrosine. Environmental factors, including the con-sumption of food rich in tyrosine, can boost the produc-tion of dopamine [82]. RJ contains tyrosine in additionto numerous free amino acids, e.g., valine, glutamic acid,serine, glycine, cysteine, threonine, alanine, tyrosine, phe-nylalanine, hydroxyproline, leucine-isoleucine, and gluta-mine. Some of these amino acids can be converted intotyrosine [31, 97]. Thus, RJ may promote the biosynthesisof dopamine [31]. Queen bees exhibit higher brain levelsof dopamine and its metabolites (e.g., N-acetyl-dopamineand norepinephrine) than workers [98]. Meanwhile, treatingworkers with RJ stimulated the gene expression of severaltypes of receptors of dopamine and tyramine [98]. Evidenceindicates that the consumption of both RJ and tyrosine signif-icantly improves brain levels of dopamine, tyramine, and theirmetabolites in emerging bee workers (4-8 days old) and in 8days old males compared with control bees. The author indi-cated a relationship between age and the dopaminergic effectof RJ [97, 98]. In line, oral supplementation of RJ to micetreated with tartrazine—an azo dye derived from coal tar thathas a DNA-damaging effect—was associated with reduction ofapoptotic cell markers and restoration of different brain neu-rotransmitters, including dopamine [99]. RJ contains excep-tionally high concentrations of acetylcholine (4–8mM),which resists degradation due to the acidic pH (4.0) of RJ.Hence, the well-conserved acetylcholine of RJ [100] mightpositively contribute to neuromodulation in the dopamine-acetylcholine circuit of PD. Evidence denotes that agonismof α7 nicotinic acetylcholine receptors in the CNS providesmaximal beneficial responses with minimal adverse effectssince it prevents neuronal cell loss in the SNC and reduceslevodopa-induced dyskinesias [101]. Further in-depth investi-gations of the molecular events involved in dopamine increasefollowing treatment with bee products are needed.

6.5. Enhancement of the Production of Neurotrophins inthe Brain. Neuronal adversities such as chronic oxidativestress, neuroinflammation, and excitotoxicity are key con-tributors to progressive neurotoxicity and neurodegenera-tion. Neurotrophins are compounds that are essential forthe survival of specific neurochemical phenotype classesof neurons [42]. As illustrated in Table 2, only one studyexamined the effect of bee products on the production ofneurotrophins. Chrysin increased the expression of BDNF,nerve growth factor (NGF), and GDNF in 6-OHDA-PDmice [42]. Given that induction of HO-1 in MPP+ modelsvia Ad-HO-1 is associated with increased production ofBDNF and GDNF in the SNC [91], it is possible thatthe neurotrophic effects of chrysin are triggered by itsantioxidant action. However, the definite underlyingmolecular events are not clear.

GDNF, one of the main neurotrophic factors of thebrain, is a distantly related member of the transforminggrowth factor-beta superfamily [102]. Research signifies arole of GDNF in the treatment of PD: it maintains thesurvival and morphological differentiation of cultured mid-brain dopaminergic neurons and enhances their dopamineuptake [103]. Meanwhile, injecting external GDNF intothe SNC or striatum of aged mice experiencing a partial6-OHDA-induced lesion increases levels of tyrosinehydroxylase mRNA in lesioned dopaminergic neurons,which is associated with less degeneration of nigrostriataldopaminergic neurons and increased affinity of bindingof the dopaminergic transporter ligand [(125)I]IPCIT inthe lesioned striatum [104]. In another study, oral con-sumption of RJ by adult mice stimulated the expressionof GDNF [102], which implies that the neuroprotectiveeffect of RJ in dopaminergic neurons could be attributedto enhancing GDNF levels. RJ and its fatty acids demon-strate an estrogenic activity as they bind estrogen receptorsβ and α to stimulate the release of BDNF, GDNF, andNGF. These neurotrophins modulate cell proliferationand regulate the expression of various genes that counter-act inflammation and oxidative stress in the brain neurons[61, 66, 105–107].

6.6. Restoration of Normal Brain Structure. PD involves mor-phological alterations in different parts of the brain, includ-ing reduced volumes of the caudate nucleus, thalamus, andwhite matter, as well as atrophy of the basal ganglia, contrac-tion in the left cerebellum, decreased gray matter in the rightquadrangular lobe, reduced fractional anisotropy, neurome-lanin pigmentation, neuronal loss within the SNC, andincreased mean and radial diffusivity within the SNC andglobus pallidus [108]. Experimental models indicate that RJinduces structural and symptomatic improvements in PDmice by protecting against the histomorphometrical dysfunc-tions caused by the disease. In this context, one study exam-ined the effect of oral RJ treatment (100 or 200mg/kg/day/3weeks) on the brain structure of male mice receiving unilat-eral injection of 6-OHDA in the CPU. Histomorphometryrevealed that compared with untreated PD mice, the num-bers of Nissl-stained neurons in the SNC and CPU were sig-nificantly higher in the RJ (100 or 200mg) treated groups.Both doses of RJ significantly increased the thickness of grayand white matter of the cerebral cortex and cerebellum [82].Similarly, light microscopical examination of the cerebralcortex structure in mice treated with tartrazine revealed lessdamages in animals receiving RJ compared with controls asindicated by fewer cells with pyknotic nuclei as well as lessssDNA positive cells [99]. The effect of RJ on the integrityof brain structure is attributed to its antioxidant, anti-inflam-matory, and antiapoptotic effects, which all lower the loss ofdopaminergic and cholinergic neurons [99, 109]. The effectof propolis on brain structure was evaluated in 6-OHDA-challenged rats. Compared with the sham and placebo(water) groups, propolis significantly reduced striatal fiberdegeneration [83]. However, the effect of active compoundsin propolis on anatomical structures in the brain needs tobe explored in future studies.


7. Discussion

Few preclinical studies have evaluated the effect of propolisflavonoids, RJ, and RJ lipids on PD. Whole RJ [82], CAPE[44], and chrysin [42] improved motor behavioral alterationsin PD animals. The protective effects of these compounds arelikely attributed to their ability to reduce the production offree radicals [13, 42, 44, 45, 79, 84, 86], proinflammatorycytokines [42, 44], and mitochondrial proteins [45, 84]involved in cell death as well as their downstream effectorssuch as caspase-3 [85] and bax [79]. Immunochemistry andcell viability analyses revealed higher survival of dopaminer-gic neurons treated with these compounds both in vivo [42,44, 84] and in vitro [13, 45, 79, 84, 86]. These results indicatethat bee products such as propolis and RJ can be a potentiallysafe adjunctive treatment for PD.

Investment in animal studies provides valuable knowl-edge, which sometimes cannot be derived from human trialsdue to ethical, technical, and logistic complexities. To ourknowledge, the effect of propolis and RJ on PD in humanshas not been examined till now. Yet, considering the reportedanti-Parkinson effects of these products in laboratory ani-mals, similar effects might be expected to occur in humans.Therefore, the anti-Parkinson effects of propolis and RJdeserve to be evaluated in soundly designed RCTs.

From a theoretical point of view, propolis and RJ may bebeneficial not only for the main motor symptoms of PD butalso for other nonmotor symptoms such as cardiac, auto-nomic, GI, depressive, and cognitive symptoms [19, 83,110]. In connection with this standpoint, propolis(200mg/kg/40 days) increased the survival of dopaminergicneurons and maintained striatal structure in a PD rat modelinduced by bilateral injection of 6-OHDA in the striatum.Along with such neurological improvements, propolis alsorestored body weight and reverted the cardiological andautonomic alterations caused by 6-OHDA treatment asdetected by increased heart rate and heart rate variabilitycompared with the placebo treatment [83]. Existing knowl-edge emphasizes an association between PD and cardiac dis-orders as they share common pathologies such asinflammation, cellular stress, and impaired metabolism oflipids and glucose. Meanwhile, coffee consumption andphysical activity seem to be protective against both condi-tions [111]. Common autonomic symptoms in PD patients(e.g., orthostatic hypotension) interfere with activities ofdaily living, limit physical activity, and heighten the risk offalls, hospitalization, and mortality [112]. Evidence denotesthat autonomic failure in PD patients is significantly linkedto striatal serotonergic and dopaminergic degenerationexpressed by lower [123I]FP-CIT binding ratios in the rightcaudate nucleus. These symptoms are mostly driven by GIand cardiovascular dysfunctions [113].

RJ may relieve GI discomfort commonly experienced bymost PD patients. Evidence indicates that RJ alleviates GIsymptoms such as anorexia in cancer patients [114] and con-stipation [115]—its acetylcholine content exerts a directeffect on the muscarinic receptors of the intestinal smoothmuscle resulting in intestinal contractions. However, thiseffect does not stem from a single oral dose [115]. From

another perspective, evidence indicates that early develop-ment of dopaminergic lesions in a 6-OHDA rat model ofPD is associated with reduction of BDNF and occurrence ofdepressive-like behaviors, which could be relieved by antide-pressant treatment [116]. More, PD is known as manifestLewy body dementia because severe cognitive alterationsdevelop, especially during late stages of the disease [19].Research shows that propolis and RJ possess a capacity toimprove cognitive performance [71] and alleviate depressivesymptoms through mitigation of oxidative stress [117] andactivation of signaling pathways that promote the productionof various neurotrophic factors such as BDNF [118], GDNF[102], and NGF [119, 120]. Altogether, according to thesescenarios, propolis and RJ may represent a multidimensionaltreatment, which may promote the quality of life among PDpatients.

It is now well-known that altered gut microbiome is amajor contributor to the initiation and development of PDpathology [10, 11, 121]. Evolving knowledge implies that die-tary interventions such as fatty acids (phospholipid mem-brane precursors), amino acids, and microbiota-directedtherapy (e.g., probiotics, prebiotics, and postbiotics) may cor-rect gut alterations, treat GI symptom, and promote CNSfunctioning in PD [10, 18, 121, 122]. Propolis and RJ are richin amino acids, fatty acids, and phospholipids [28, 37, 41, 55].In addition, they are abundant in beneficial bacteria such aslactic acid bacteria, which is commonly used as probioticsto improve health and enhance growth and reproductive per-formance—43 species of these bacteria have been identifiedin bees and bee products such as RJ with 20 of them havinginhibitory effects against 28 species of human and animalpathogens, some of which are antibiotic-resistant [123].Propolis possesses strong antimicrobial properties, and it isused by bee workers as a disinfecting agent to keep integrityof the beehive [40]. Meanwhile, RJ contributes to the diver-sity and vitality of gut microbiome in queen bees. For exam-ple, Lactobacillus apis and Bifidobacterium are abundant inthe gut of queen bees, and they produce metabolites that pre-vent the expression of oxidative stress genes and contributeto the excellent physical and reproductive traits of queenbees. On the other hand, these bacteria are deficient in beeworkers, which feast mainly on honey and pollens [124].The literature denotes that both propolis and RJ contributeto the maintenance of GI function. In this respect, supple-menting rats on high fat diet with 0.2% dietary green propolissignificantly altered the structure of gut microbiome. Thiseffect was associated with less intestinal permeability, lowerlevels of lipopolysaccharide in the systemic circulation, anddownregulation of activity of toll-like receptor 4 and cytokineexpression in skeletal muscle [125]. Propolis was alsoreported to protect rats against gastric mucosal lesionsinduced by stress [126]. RJ has been shown to enhance thegrowth of beneficial gut bacteria such as Bacteroides fragillisand Bacteroides thetaiotaomicron, which colonize in the dis-tal end of the gut to ferment and degrade indigestible pro-teins and carbohydrates; they also play a role in theactivation of the regulatory T cells. In addition, RJ also dem-onstrates protective effects on the intestinal wall by contrib-uting to the viability of the human epithelial colorectal cell


line Caco-2 [127]. Thus, we suggest that propolis and RJ maypositively affect the gut-brain axis in PD patients by modulat-ing microbiota composition. Future studies exploring theeffect of bee products on microbiota in PD and its associationwith the molecular and cellular adversities associated withPD will provide insightful information. It might be helpfulto compare the effect of combining propolis and RJ withother conventional treatments such as dietary modificationsand exercise since these interventions express their effects,in part, through the modulation of gut microflora [128].

Identification of target subjects for RCTs using beeproducts to prevent pathologies underlying PD is of crucialimportance. Since GI symptoms, especially constipation,occur in 80% of PD patients a long time before appearanceof motor symptoms, early treatment of people with chronicconstipation may represent a preventive modality of PDthat worth investigation in future RCTs [10]. Various typesof genetic variation may affect response to treatment withapi-materials, which may be challenging if we are to identifycandidates for pathology prevention in humans. For instance,Asian PD patients, not Caucasians, exhibit mutations incoiled-coil-helix-coiled-coil-helix domain containing 2, amitochondrial protein that decreases oxygen consumptionand ATP production, increases ROS production and mito-chondrial cristae dilation resulting in heightened apoptoticdegeneration in skeletal muscle. Immunosignals of thisprotein are most profuse in dopaminergic neurons of theSNC, cortical and hippocampal pyramidal neurons, andmotor neurons in the anterior horn of the spinal cord [129].In addition to race, possible other characteristics that mightaffect muscular functions should also be addressed such asgender, general health status, activity level, psychosocialstresses, nutrition, and levels of testosterone.

Both propolis and RJ comprise a large number of compo-nents. As shown in Table 2, CAPE, chrysin, and PB, whichare key flavonoids in propolis, could modulate oxidative,inflammatory, and apoptotic events that underly the patho-genesis of PD. On the other hand, the literature is short ofinformation on the most beneficial specific ingredients forPD in RJ [31, 130]. Yet, according to the current knowledge,RJ lipid component might be the most probablecandidate—HPO-DAEE ameliorated oxidative stress in neu-rons treated with 6-OHDA [13]. On the other hand, MRJPs,peptides, and amino acids contribute, in a great part, to themultiple biological properties of RJ [58, 59]. Still, their rolein PD has not been adequately explored. Similarly, the effectof RJ contents of tyrosine (a dopamine precursor) and acetyl-choline (which function as a neurotransmitter) has not beenexamined in PD models. In addition, adenosine monopho-sphate N1 oxide (AMP N1-oxide) is another ingredient thatmerits further investigation given that it stimulates neuronaldifferentiation [131].

It is worth noting that natural products such as propolisand RJ can be affected by several factors such as season, geo-graphical location, botanical source, bee species, environ-mental conditions (e.g., storage temperature), harvestingtime (e.g., RJ harvested within 24 hours from larvae is higherin its phenols content than that harvested 72 hours or later),and methods of handling (e.g., pRJ contains more bioactive

ingredients than crude RJ such as short peptides and aminoacids) [31, 37, 130]. All such factors can affect the potencyand quality of bioactive ingredients in these products. Hence,researchers should consider the relevant evidence concerningthe quality of the used api-materials and their ingredients inintended RCTs. In the reviewed experimental studies, propo-lis extracts and RJ were administered orally; however, it is notclear if this route has the best effect. This is because, MRJPs,except for MRJP2, get rapidly degraded in the stomach andsmall intestine [132]. Therefore, attention should be paid tothe route of administration, e.g., the absorption of capsulatedRJ might be better than direct oral consumption.

8. Conclusion

All animal studies discussed above indicate that wholepropolis, CAPE, PB, chrysin, whole RJ, and its lipid deriv-ative (HPO-DAEE) might counteract oxidative stress, neu-roinflammation, and mitochondrial dysfunction resultingin mitigation of neuronal damage and improvement ofmotor symptoms of PD. However, more studies areneeded to examine the specific cellular and molecularmechanisms of whole propolis and RJ, as well as maincompounds in RJ (MRJPs, peptides, phenols, bioactive sub-stances) in PD. To identify the most effective compounds inpropolis and RJ, it might be important to compare the effectof various active ingredients in these products either alone orin combination with other PD treatments. Future RCTs thatinvestigate the effect of bee products on PD should considerindividual variations (e.g., race, gender, general health, activ-ity level, and diet) and accompany subjective outcomemeasures with sound predictive biomarkers.

Abbreviations

6-OHDA: 6-Hydroxydopamine10H2DA: 10-Hydroxy-2-decenoic acid10-HDA: Trans-10-hydroxy-2-decenoic acidγ-GCL: γ-Glutamylcysteine ligaseγ-GCS: γ-Glutamylcysteine synthetaseAIF: Apoptosis inducing factorARE: Antioxidant response elementATF4: Activating transcription factor-4Bax: Bcl-2-associated X proteinBcl-2: B cell lymphoma 2BDNF: Brain-derived neurotrophic factorCAPE: Caffeic acid phenethyl esterCaspase-3: Cysteine-aspartic acid protease 3CGNs: Cerebellar granule neuronsCNS: Central nervous systemCOX-2: Cyclooxygenase-2CPU: Caudate putamen unitDOPAC: 3,4-dihydroxyphenylacetic acidDAEE: 2-Decenoic acid ethyl estereIF2α: Eukaryotic translation initiation factorERK: Extracellular signal-regulated kinaseGDNF: Glial cell line-derived neurotrophic factorGI: GastrointestinalHO-1: Heme oxygenase 1


HPO-DAEE: 4-Hydroperoxy-2-decenoic acid ethyl esterHVA: Homovanillic acidINF-γ: Interferon-gammaiNOS: Inducible nitric oxide synthaseIL: InterleukinMAPK: Mitogen-activated protein kinaseMDA: MalondialdehydeMPP: 1-Methyl-4-phenylpyridiniumMMPs: Matrix metalloproteinasesMRJPs: Major royal jelly proteinsMPTP: 1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridineNF-κB: Nuclear factor kappa-BNGF: Nerve growth factorNQO1: NAD(P)H quinone dehydrogenase 1NRF2: Nuclear factor erythroid 2PB: Pinocembrinp.o.: Oral gavagePD: Parkinson’s diseasepRJ: Protease-treated RJRCT: Randomized control trialRMNs: Rostral mesencephalic neuronsRJ: Royal jellyROS: Reactive oxygen speciesS100B: Calcium-binding protein BSNC: Substantia nigra pars compactaSOD: Super oxide dismutaseTH: Tyrosine hydroxylaseTNF: Tumor necrosis factorTAR: Total antioxidant reactivityTRAP: Total reactive antioxidant potential.

Conflicts of Interest

The authors declare that there is no conflict of interestregarding the publication of this article.

Acknowledgments

This study was supported by the Strategic Research Pro-gram for Brain Sciences from Japan Agency for MedicalResearch and development, AMED, Japan (Grant No.18dm0107100h0003).

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