A critical analysis on the concentrations of phenolic compounds tested using in vitro and in vivo Parkinson’s disease models

Abstract

Phenolic compounds (PCs) have neuroprotective effects with potential to prevent or slower the progression of Parkinson’s disease (PD). However, whether the PCs neuroprotective effects can be observed under their dietary concentrations remains unclear. Therefore, we searched for the most cited articles in density on PCs and PD in the Web of Science Core Collection and All-Database (WoS-CC/AD) and selected the articles based on our eligibility criteria. From these 81 articles selected, we extracted information on experimental design, compounds tested, concentration and/or dose administered, route of administration, and main results obtained. We compared the concentrations of PCs evaluated in vitro with the concentrations bioavailable in the human bloodstream. Further, after extrapolation to humans, we compared the doses administered to animals in vivo with the daily consumed amounts of PCs. Concentrations evaluated in 21 in vitro laboratory studies were higher than those bioavailable in the bloodstream. In the case of in vivo laboratory studies, only one study administered doses of PCs in normal daily amount. The results of the comparisons demonstrate that the neuroprotective effects of the selected articles are mainly associated with concentrations, amounts and routes of administration that do not correspond to the consumption of phenolic compounds through the diet.

Keywords:

• bioactive compounds
• natural antioxidants
• Parkinson’s disease

Introduction

Phenolic compounds (PCs) are secondary metabolites of plants responsible for protection against ultraviolet (UV) rays and pathogens (Cheynier et al. 2013). More than 10,000 PCs are known and can be classified as flavonoids, phenolic acids, lignans, and stilbenes (Tsimogiannis and Oreopoulou 2019). PCs can be found in foods and beverages of vegetable origin, such as fruits, wines, products derived from cacao, and olives (de Araújo et al. 2021).

The term bioavailability refers to the steps occurring after the consumption of these compounds, including their transport, biotransformation, and absorption, until they reach the target organ (Crozier, del Rio, and Clifford 2010; Stromsnes et al. 2021). Bioavailability is influenced by factors such as the chemical structure, food matrix, association with other foods, and microbiota composition (Duda-Chodak et al. 2015).

PCs have demonstrated neuroprotective effects in experimental models of Parkinson’s disease (PD), that have been associated to different mechanisms including antioxidant activity, regulation of mitochondrial dysfunction, anti-inflammatory activity, as well as inhibition and disaggregation of α-synuclein fibrils (Hussain et al. 2018; Reglodi et al. 2017; Magalingam, Radhakrishnan, and Haleagrahara 2015). However, the neuroprotective effects of PCs are related to the concentration and chemical structure of the evaluated compound, which is dependent on its bioavailability in the human body (Holst and Williamson 2008).

In a common oversight, research evaluating the bioactive potential of natural compounds is conducted using concentrations higher than those consumable through diet and those bioavailable after absorption (Bo’ et al. 2019; Stefania et al. 2021; Sang, Lambert, and Yang 2006; Mancuso, Siciliano, and Barone 2011) which leads to a false-positive results, emergence of false therapeutic candidates, or presumed activity against a wide panel of diseases (Ferreira, Martins, and Barros 2017).

The number of studies evaluating the neuroprotective potential of PCs against PD has increased after the demonstration of neuroprotective effects in vitro. However, whether PCs concentrations that demonstrate neuroprotection against PD can be achieved in humans through a natural diet, digestion, and absorption remains unclear.

To answer this question, we selected the most cited articles addressing the effects of PCs on PD from the Web of Science Core Collection (WoS-CC) and All-Database (WoS-AD) and identified articles that evaluated isolated compounds belonging to the main PCs classes (phenolic acids, flavonoids, stilbenes, and lignans) along with the experimental design used.

We also compared the concentrations of the compounds evaluated in vitro with the concentration normally found in human blood circulation, and in the case of in vivo experiments with rodents, after extrapolating the doses administered in animals to humans, we compared the concentrations of compounds belonging to the same subclass tested at the normal concentrations consumed.

Therefore, the main aim of this review is to evaluate whether the PCs concentrations presenting neuprotective effects in experimental models of PD can be achieved by consuming diets with foods rich in PCs.

Material and methods

Search strategy

The WoS-CC and WoS-AD was searched using the strategy described in Table 1.

Table 1. Search strategy.

Database	Section
Web of Science	Core Collection and All-database
	Search strategy
	TS = (“Phenolic compound” OR “phenolic acid” OR “benzoic acid” OR “hydroxycinnamic acid” OR flavonoid OR anthocyanin OR flavanol OR flavonol OR flavanone OR flavone OR isoflavone OR tannin OR coumarin OR lignan OR quinone OR stilbene OR curcuminoid OR Provinol OR Phenol OR polyphenol OR “polyphenolic antioxidant compound”) AND  TS = (“Lewy Body” OR Parkinson OR “Parkinson Disease” OR Parkinsonism OR “neurodegenerative disease” OR synuclein)

TS = Topic.

Articles published until December 2022 were searched without restrictions on language, year of publication, or methodology. The articles were organized in descending order according to the number of citations.

Eligibility criteria

The selection of articles was independently performed by two respondents. Articles were selected that contained some terms of the search strategy in the title, abstract or keywords and citation density (number of citations/time of publication) equal to or higher than ten, and included articles that evaluated pure compounds or extracts rich in natural PCS with defined concentrations and presented only model of PD. Disagreements were resolved using the agreement method. Conference papers were excluded.

Data extraction

The article title, citation count, publication year, pure compound(s) (up to nine) or extract (E), study design, concentration with neuroprotective effect tested, pathway administration (in case of in vivo laboratory studies), and neuroprotective mechanisms were recorded from the selected articles. The study designs were grouped as follows: clinic study (prospective cohort), laboratory studies (in vitro and in vivo) and literature review, (Cochrane Collaboration Glossary, 2019).

Extrapolation of doses administered in animals to humans

The doses administered in animals were extrapolated to humans using the body surface area (BSA) normalization method (Reagan‐Shaw, Nihal, and Ahmad 2008) from equation 1: [Eq. 1] $$\mathit{Human}\mathrm{ }\mathit{equivalent}\mathrm{ }\mathit{dose}\mathrm{ }\left(mg/kg\right)\mathrm{ }=\mathit{Animal}\mathrm{ }\mathit{dose}\mathrm{ }\left(mg/kg\right)\mathrm{ }\times \mathrm{ }\frac{\mathit{Animal}\mathrm{ }Km\mathrm{ }}{\mathit{Human}\mathrm{ }\mathrm{K}m}$$[Eq. 1] $$\text{Rats Km }=\mathrm{ }6;\text{ Human Km }=\mathrm{ }37$$

The Km factor, that is, body weight (kg) divided by BSA (m²), was used to convert the mg/kg dose used in the study to a mg/m² dose.

Obtaining data for average daily consumption and bioavailability of PCs

Data on daily intake and bioavailability of PC in human blood circulation were obtained from articles published up to December 2022 in the WoS-CC database. These were used as parameters for later comparison with the concentrations administered in the selected studies.

Comparison between concentrations

The concentrations of tested compounds were compared with those bioavailable in the human bloodstream and the doses administered to animals were compared with the quantities consumed through diet.

The concentrations of the compounds tested in studies with an in vitro laboratory experimental design (μM) and the concentration of the subclass bioavailable in the bloodstream (μM) were compared based on the ratio between the two concentrations.

The PCs doses utilized in vivo experimental models of PD, after extrapolation to humans, and the quantity of the compound subclass that was consumed daily (mg/kg) were also compared based on the ratio between the two concentrations.

Results

Using the search strategy described in Table 1, 2,594 articles were initially obtained. After classifying the citations in descending order, only 2,000 articles were evaluated by the eligibility criterion, since from the 2,000th article the number of citations is less than ten, so the density is also less than ten. From the 2,000 articles evaluated, 1,919 articles were excluded for not presenting citation density equal to or greater than ten and not exclusively addressing PD and CPs, resulting in 81 articles on PD and CPs with at least ten citations and citation density equal to or greater than ten. The articles selected were organized according to the experimental design in the following order: clinical study (prospective cohort), laboratory studies (in vivo), laboratory studies (in vitro), laboratory studies (in vivo and in vitro) and literature review (Table 2).

Table 2. Classification of articles selected from the experimental design.

Reference	numerical representation	Citation number	Citation Density	Compound or Extract (E)	Concentration (µM) or amount (mg/kg/day)	Pathway	Results
Clinic Study (Cohort prospective)
(Gao et al. 2012)	[17]	187	19	E			Men with high consumption of foods rich in flavonoids, mainly anthocyanins, were found less likely to develop PD during 20–22 years of follow-up
Laboratory studies (in vivo)
(Levites et al. 2001)	[18]	448	21	EGCG	1.6	O	Prevention of the loss TH-positive neurons in the SNc, and increase in SOD and CAT activity
(Zbarsky et al. 2005)	[19]	326	19	Curcumin Naringenin Quercetin Fisetin	8 8 3.2 3.2	O	Curcumin and naringenin prevented the reduction of TH-positive cell levels and DA
(Khan et al. 2010)	[20]	185	15	Resveratrol	3.2	I.P.	Increase in antioxidant status, attenuation of DA depletion and attenuation in the increased levels of TBARS as well as the activity of PCsa and PLA2
(Karuppagounder et al. 2013)	[21]	138	15	Quercetin	24	I.P.	Attenuation of unilateral rotations, the loss of striatal DA content and reduced GSH
(Patil et al. 2014)	[22]	131	16	Apigenin Luteolin	3.2 3.2	O	Neuroprotective effects probably by reducing oxidative damage, neuroinflammation, and microglial activation
(Anusha, Sumathi, and Joseph 2017)	[23]	98	20	Apigenin	3.2	I.P.	Attenuated upregulation of NF-κB gene expression; inhibited the release of TNF-α, IL-6, and iNOS-1; prevented the reduction of BDNF and GDNF mRNA expression; downregulated α-syn aggregation; and upregulated TH protein expression
(Brunetti et al. 2020)	[24]	85	43	Hydroxytirosol Oleuropein	c	c	Increased survival after heat stress, but only hydroxytirosol increased lifespan in unstressed conditions
(Cui, Li, and Zhu 2016)	[25]	84	14	Curcumin	32	O	Alleviated motor dysfunction, increased TH activity and GSH levels, reduced ROS and MDA content, restored the expression levels of HMOX1 and NQO1
(Xu et al. 2017)	[26]	75	15	EGCG	4	O	Rescued neurotoxicity by increasing rotational latency; improved DA levels and substantia nigra ferroportin expression
(Chen et al. 2015)	[27]	74	11	Piceid	22	O	Attenuated motor defects; prevented changes induced in the levels of GSH, thioredoxin, ATP, MDA, and SOD in the striatum; rescued DN neurodegeneration
(Goes et al. 2018)	[28]	70	18	Chrysin	1.6	O	Prevented motor and cognitive impairments; increased the levels of TNF-α, IFN-γ, IL-1β, IL-2, IL-6, and NF-ĸB; decreased the levels of IL-10, DA, DOPAC, HVA, TH, and TRAP
(Ren et al. 2016)	[29]	64	11	Dihydromyricetin	1.6	I.P.	Attenuated motor impairments and dopaminergic neurons loss, cell injury, and ROS production as well as increased GSK-3β phosphorylation
(Baluchnejadmojarad et al. 2017)	[30]	60	12	Ellagic acid	8	O	Reduced striatal MDA, ROS, and DNA fragmentation, and improved MAO-B, Nrf2, and HO-1. Prevented loss of TH-positive neurons
(El-Horany et al. 2016)	[31]	60	10	Quercetin	8	I.P.	Attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress-induced apoptosis with attenuated oxidative stress
(di Rosa et al. 2020)	[32]	54	27	Hidroxytyrosol E	c	c	the E led to much stronger beneficial locomotion effects in wild-type worms compared to HT at the same concentration
(Abolaji et al. 2018)	[33]	49	12	Resveratrol	D	D	Ameliorated MPTP-triggered cell death, histological alterations, behavioral deficits and accumulation of nitric oxide and hydrogen peroxide levels
(Rui et al. 2020)	[34]	46	23	Baicalein	86.4	O	Inhibited NLRP3 and caspase-1 activation and suppressed gasdermin D-dependent pyroptosis
(Zhou, Zhu, and Liang 2018)	[35]	43	11	EGCG	8	O	Reduced expression of inflammatory factors tumor necrosis factor-α and interleukin-6 in serum
(Ho et al. 2019)	[36]	35	12	E			Different E-derived microbial phenolic acid metabolites with different bioavailability and interfere with α-syn misfolding or inflammation
(Zhang et al. 2020)	[37]	29	15	E			Reversed the loss of dopaminergic neurons and neural vasculature, as well as reduced the number of apoptotic cells in the zebrafish brain
(Kumar et al. 2020)	[38]	22	11	Fisetin	3.2	O	SNEDDS improved the oral bioavailability which further helped in improving its neuroprotective activity in rat model of PD
(Xiong et al. 2020)	[39]	21	11	Resveratrol	0.8	O	Improved behavior and elevated striatal dopamine levels
(Zhao et al. 2021)	[40]	15	15	Baicalein	48	O	Alleviated depression-like behavior and protected synaptic plasticity and activated the BDNF/TrkB/CREB pathway
(Antunes et al. 2021)	[41]	11	11	Hesperidin	8	O	Attenuated the degeneration of dopaminergic neurons, prevented mitochondrial dysfunction, and modulated apoptotic, thereby improving behavioral changes
Laboratory studies (in vitro)
(Zhu et al. 2004)	[42]	360	20	Baicalein	50		Inhibited the formation and induced disaggregation of α-syn fibrils
(Levites, Youdim, et al. 2002)	[43]	328	16	EGCG	1		Decreased cell death through PKC stimulation and gene modulation
(Levites, Youdim, et al. 2002)	[44]	250	13	E			Inhibited both NF-ĸB nuclear translocation and binding activity
(Bureau, Longpré, and Martinoli 2008)	[45]	216	15	Resveratrol Quercetin	0.1		Both reduced inflammation-mediated apoptosis
(Caruana et al. 2011)	[46]	197	18	14 PCs	10		Baicalein, EGCG, Myricetin could be classified as being the best-combined inhibitors and disaggregates of α-syn fibrils
(Mercer et al. 2005)	[47]	183	11	Catechin Quercetin Chrysin Puerarin Naringenin Genistein	40		All of these protected midbrain cultures from MPP^+ injury. Catechin also reduced the damage induced by hydrogen peroxide, 4-hydroxynonenal, rotenone, and 6-hydroxydopamine
(Uversky et al. 2010)	[48]	168	14	48 flavonoids	50		Eriodictiol, gossypetin, baicalein, and 5,6,7,4'-tetrahydroxyflavone bound and stabilized α-syn in the natively unfolded conformation
(Pandey et al. 2008)	[49]	167	12	Curcumin	1		Inhibited α-syn fibril aggregation, disaggregated preforms and increased the solubility of α-syn fibrils in cells
(Okawara et al. 2007)	[50]	156	10	Resveratrol	100		Prevented ROS accumulation and GSH depletion; decreased DN; and increased absorption of propidium iodide
(Wruck et al. 2007)	[51]	151	10	Luteolin	5		Conferred neuroprotection against oxidative stress via Nrf-2
(Bournival, Quessy, and Martinoli 2009)	[52]	142	11	Resveratrol Quercetin	0.1		Both decreased dopaminergic neurodegeneration by acting on the expression of pro- and anti-apoptotic genes, Bax and BCL2
(Lorenzen et al. 2014)	[53]	130	16	EGCG	1		Inhibited α-syn fibril toxicity, moderately reduced membrane binding, and immobilized the C-terminal tail of the oligomer
(Zhang et al. 2012)	[54]	129	13	Baicalein	200		Increased transcriptional Nrf2/HO-1 expression and decreased Keap1, thus attenuating apoptosis
(Zhang et al. 2010)	[55]	124	10	Resveratrol	60		Inhibited microglial activation and subsequently reduced pro-inflammatory factor release
(Strathearn et al. 2014)	[56]	119	15	E			Extracts rich in anthocyanins and proanthocyanidins exhibited greater neuroprotective activity than that of extracts rich in other PCs
(Tamilselvam et al. 2013)	[57]	103	11	Hesperidin	20		Attenuated loss of mitochondrial membrane potential, ROS generation, and depletion of GSH; enhanced the activities of CAT, SOD, and GPx; upregulated Bax, cyt C, and caspases 3 and 9; and downregulated Bcl-2
(Ardah et al. 2014)	[58]	83	10	Gallic acid	40		Bound to soluble oligomers without β-sheet content and stabilized its structure
(Xu et al. 2016)	[59]	61	10	EGCG	0.25		Inhibited α-syn fibril aggregation through unstable hydrophobic bonds
(Palazzi et al. 2018)	[60]	42	11	Oleuropein	700		Interacted and stabilized α-syn monomers, thus hindering the growth of oligomers in the pathway
(Chandrasekhar et al. 2018)	[61]	41	10	Gallic Acid	5		Attenuated mitochondrial membrane potential disruption, reduced the proportion of pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2
(Mohammad-Beigi et al. 2019)	[62]	30	10	E			The variety with the most effective antioxidant and aggregation activities was Koroneiki
(Elmazoglu et al. 2020)	[63]	24	12	Luteolin	20		Protected microglia through favorable effects in regulating oxidative stress response, PD-associated genes, and inflammatory pathways
(Limboonreung, Tuchinda, and Chongthammakun 2020)	[64]	21	11	Chrysoeriol	20		reversed the decrease in cell viability and increase in apoptosis and mitigated increases in levels of the prosurvial signaling proteins
(Cirmi et al. 2021)	[65]	16	16	E			Inhibited cell death by blocking caspase 3 and modulation of p53, Bax and Bcl-2 genes
(Trapani et al. 2021)	[66]	13	13	E			Co-administration of E/DA nanoparticle resulted in an increase in SH-SY5Y cell viability
(Sergi et al. 2021)	[67]	10	10	Viniferin Resveratrol			Protected agains 6-OHDA-induce dopaminergic cells lost, cytotoxicity and apoptosis
Laboratory studies (in vitro and in vivo)
(Lou et al. 2014)	[68]	141	18	Naringenin	20 11.2	O	Increased Nrf-2 protein levels and activated ARE pathway genes
(Mu et al. 2009)	[69]	133	10	Baicalein	185 32	O	Prevented apoptosis and promoted neurite outgrowth; attenuated muscle tremors and increased the number of TH-positive neurons
(Zhang et al. 2015)	[70]	108	15	Protocatechuic acid Chrysin	1000 and 12 1000 and 16	O	Increased neuroprotective effects through a combination of mechanisms including antioxidant and anti-inflammatory cytoprotection
(Ay et al. 2017)	[71]	88	18	Quercetin	30 28	O	Induced activation of PKD1 and Akt, increased mitochondrial biogenesis, improved motor deficits, increased the levels of TH-positive cells and DA
(Cao et al. 2017)	[72]	74	15	Amentoflavone	75 8	O	Rescued DN loss, increased PI3K and Akt activation as well as the Bcl 2/Bax ratio, alleviated gliosis and the gene expression of IL 1β and iNOS
(Zhang et al. 2017)	[73]	61	12	Baicalein	- 32	O	Attenuated behavioral impairments and depletion of dopaminergic neurons in addition to restoring mitochondrial functions and improving mitobiogenesis
(Zhang et al. 2018)	[74]	50	13	Resveratrol	350 1.6	O	Inhibited α-synuclein aggregation and cytotoxicity, decreasing total protein and oligomer levels
(Hu, Li, and Wang 2018)	[75]	47	12	Vitexin	40 8	O	protected dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through activation of the PI3K/Akt signaling pathway
(Xia, Sui, and Zhang 2019)	[76]	42	14	Resveratrol	5 x 10^4 8	O	Increased the number of TH-positive cells and the expression of miR-129, while decreased the expression of MALAT1 and SNCA
(Yang et al. 2019)	[77]	41	14	Calycosin	- 4.8	I.P.	Attenuated PD symptoms through TLR/NF-κB and MAPK in mice and cell lines
(Pan et al. 2020)	[78]	20	10	Kaempferol	50 3.2		Increased monoamine levels in the striatum and SN region of the brain, inhibited apoptosis, inhibited ROS and apoptosis by more than 50%
(Bai et al. 2020)	[79]	20	10	Piceid	50 D	D	Attenuated rot-induced decreases in cell viability, mitochondrial membrane potential and Sirt 1 expression, ROS and DJ1 expression
(Wang et al. 2021)	[80]	17	17	Quercetin	20 4.8	O	Reduced oxidative stress, increased levels of mitophagy markers PINK1 and Parkin, decreased α-syn protein expression, alleviated motor behaviors impairments
(Kesh, Kannan, and Balakrishnan 2021)	[81]	13	13	Naringenin	25 Z	Z	Reduced CAT, GSH, SOD, and ROS levels, rescued mitochondrial membrane potential, and improved locomotion
(Han et al. 2021)	[82]	12	12	Kaempferol	30 8	I.P.	Protected against TH-positive neuronal loss and behavioral deficits, accompanied by reduced lipid oxidative stress in the SNc
Literature Review
(Mythri and Bharath 2012)	[83]	208	21	Curcumin			Acts on oxidative/nitrosative stress, mitochondrial dysfunction, and protein aggregation
(Aquilano et al. 2008)	[84]	180	13				Antioxidant and anti-inflammatory agents based on PCs, could be proposed for treating PD
(Magalingam, Radhakrishnan, and Haleagrahara 2015)	[85]	87	12				Some flavonoids such Quercetin, rutin, isoquercitrin, and catechin increased the levels of the natural antioxidant enzymes, inhibited the MAPK signaling pathways and activated of the ERK5, JNK, and p38 pathways. EGCG modulated expression of proapoptotic genes like Bax, Bad, and Mdm2 whilst genistein induced changes in the expression of the Bcl-2 gene, thereby increasing survival of cells.
(Singh, Tripathi, et al. 2020)	[86]	62	31				The therapeutic roles of polyphenols in NF-kappa B-mediated neuroinflammation in PD
(Wang et al. 2017)	[87]	50	10	Curcumin			Curcumin: anti-inflammatory effect in the PD animal models; Protection in substantia nigra neurons and improved striatal dopamine levels; Effective in reducing neuronal apoptosis and improving functional outcome in animal models of PD. No beneficial effects against Mn-induced disruption of hippocampal metal and neurotransmitter homeostasis.
(Jung and Kim 2018)	[88]	47	12				The flavonoids regulate a important physiological responses which may contribute to neuroprotective effects in PD
(Angelopoulou, Pyrgelis, and Piperi 2020)	[89]	44	20	Chrysin			The antioxidant effects of chrysin are mainly mediated via NRF2 activation so that it can assign the effect neuroprotective role against PD
(Ullah and Khan 2018)	[90]	43	11	Silymarin			Silymarin is responsible for neuroprotection through antioxidant mechanisms
(Kim et al. 2020)	[91]	37	19				Chrysin has the ability to act as an MAO-B inhibitor, increase dopamine levels in the brain and potentially neuroprotective
(Singh, Tripathi, et al. 2020)	[92]	22	11				Summarizes: major natural polyphenols (Epigallocatechin, quercetin, baicalein, resveratrol, luteolin, curcumin, puerarin, genistein, hyperoside naringin) for effective action against dopaminergic neuronal death, the major disease mechanisms (oxidative stress and mitochondrial dysfunction) and limitations and strategies for the clinical utilization of polyphenols.
(Malar et al. 2020)	[93]	21	11				Green tea consumption as protection against free-radicals, neuroinflammation and neuro-damages in PD
(Aryal et al. 2020)	[94]	20	10				Summarizes the effects of intake of dietary polyphenols in PD: decrease the symptoms and increase quality of life in PD patients. Also, Polyphenols have a positive effect on the gut microbiome, decreasing inflammation that contributes to inhibit neurodegeneration and the progression of PD.
(Kung et al. 2021)	[95]	19	19	Resveratrol			Resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways
(Su et al. 2021)	[96]	17	17	Resveratrol			Experimental studies have shown that resveratrol has significant neuroprotective effects in different PD models quantified using qualitative and quantitative methods
(Giuliano, Cerri, and Blandini 2021)	[96]	13	13				Action of polyphenols promoting the restoration of oxidative homeostasis, the reduction of the neuroinflammatory process and the increase of α-syn clearance.

E = extract, O = orally, I.P. = intraperitoneally, c = C. elegans, D = D. melanogaster, z = zebra-fisher.

The quantities consumed daily and bioavailable in human blood circulation for each subclass of PCs extracted from the Phenol Explorer and Integrity databases are shown in Table 3. Notably, the quantity consumed daily and their bioavailability are not available for some subclasses.

Table 3. Concentration consumed daily and max concentration of PCs found in plasma.

Class Subclass	Quantity consumed daily (mg/kg)	Cmax Plasma (μmol/L)	Reference
Phenolic Acids
Benzoic Acids	0.3	0.003	(Zheng et al. 2019)
Cinnamic Acids	12.6	0.1	(Jeong et al. 2020)
Flavonoids
Anthocyanins	0.4	0.06	(Wu, Oliveira, and Lila 2022)
Flavones	0.2	5	(DeRango-Adem and Blay 2021)
Isoflavone	0.2	2.19	(Soyata, Hasanah, and Rusdiana 2021)
Flavanones	0.4	0,07	(Joshi, Kulkarni, and Wairkar 2018)
Flavonols	0.8	0.3	(Dabeek and Marra 2019)
Flavanols	3	1.6	(Cai et al. 2018)
Stilbenes	0.04	0,02	(Calvo-Castro et al. 2018)
Lignans	0.5	0.03	(Kim et al. 2017)
Tyrosols	Not found	0.02	(Alemán-Jiménez et al. 2021)
Curcuminoids	Not found	0.2	(Jude et al. 2018)

Phenolic acid

Benzoic acids

Three studies evaluated benzoic acids in in vitro experimental design. The compounds evaluated were protocatechuic acid (Zhang et al. 2015) and gallic acid (Ardah et al. 2014; Chandrasekhar et al. 2018) (Figure 1).

Figure 1. Articles that evaluated benzoic acids in experimental models of PD in vitro

and in vivo oral administration

.

Protocatechuic acid was evaluated in concentration of 1000 μM (Zhang et al. 2015). Considering 0.003 μM as the concentration of benzoic acid subclass bioavailable in human blood circulation (Table 3) that amount of protocatechuic acid evaluated is 33,300 times higher than the concentration of benzoic acid bioavailable in human blood. Likewise, gallic acid was evaluated at a concentration of 5 μM (Chandrasekhar et al. 2018) and 40 μM (Ardah et al. 2014) which is 1,666 times and 13,000 times higher than the reported bioavailable concentration of benzoic acids in human blood circulation, respectively.

Among the included studies, only two studies evaluated benzoic acids in vivo experimental design. The compounds evaluated were ellagic acid (Baluchnejadmojarad et al. 2017) and protocatechuic acid (Zhang et al. 2015). The dose administered to animals when extrapolated to humans was equal to 8 and 12 mg/kg/day, respectively, which was 26.6 and 40 times higher than the amount of benzoic acid subclass (0.3 mg/kg) consumed daily (Table 1).

Flavonoids

Flavones

In total, 13 articles were identified to evaluate flavones in an in vitro experimental design. The compounds evaluated included amentoflavone, apigenin, baicalein, chrysin, chrysoeriol, luteolin and vitexin (Figure 2).

Figure 2. Articles that evaluated flavones in experimental models of PD in vitro

and in vivo oral administration

and intraperitoneal administration.

Baicalein was evaluated in six studies (Zhu et al. 2004; Caruana et al. 2011; Uversky et al. 2010; Zhang et al. 2012; Mu et al. 2009; Zhang et al. 2017). The lowest evaluated concentration of baicalein was 10 μM. Considering 5 μM as the concentration range of flavones bioavailable in human blood circulation (Table 3), the baicalein concentrations evaluated in these nine articles were 2–40 times above the concentration range bioavailable in human blood circulation.

Chrysin was evaluated in two studies (Mercer et al. 2005; Zhang et al. 2015). The lowest evaluated concentration of chrysin was 40 μM. Thus, the chrysin concentrations evaluated in these two articles were 8–200 times higher than the bioavailable range of flavones found in human blood circulation (5 μM).

Luteolin was evaluated in two studies (Wruck et al. 2007; Elmazoglu et al. 2020). The lowest evaluated concentration of luteolin was 5 μM, which can be found bioavailable in the human bloodstream. While the concentration tested in study 63 was 20 μM, which is 4 times higher than the flavone concentration that can be found bioavailable in the bloodstream (5 μM).

The compounds amentoflavone, chrysoeriol and vitexin were evaluated in each study. The concentrations evaluated were 75, 20 and 40 respectively, which are in the range of 4 - 15 times higher than the flavone concentration found bioavailable in human bloodstream.

Ten articles that evaluated flavones using an in vivo experimental laboratory design were identified. The evaluated compounds were amentoflavone, apigenin, baicalein, chrysin, luteolin and vitexin (Figure 2).

Apigenin, and luteolin were evaluated by oral administration at a concentration of 3.2 mg/kg/day (Patil et al. 2014). Apigenin was also evaluated by intraperitoneal administration at a concentration of 3.2 mg/kg/day (Anusha, Sumathi, and Joseph 2017). Considering that the daily consumed quantity of flavones is 0.2 mg/kg (Table 3), the evaluated concentrations were 16 times higher than the daily amount consumed.

Baicalein was evaluated in four studies (Rui et al. 2020; Zhao et al. 2021; Mu et al. 2009; Zhang et al. 2017). The lowest evaluated concentration of the compound was 32 mg/kg/day, administered orally (Mu et al. 2009; Zhang et al. 2017). Thus, the evaluated concentration is 160 times higher than the daily quantity consumed (0.2 mg/kg/day). Baicalein was also orally administered to animals at a concentration of 48 and 86.4 mg/kg/day in two other studies (40andRui et al., 2020). which are in the range of 240–432 times higher than the daily quantity consumed (0.2 mg/kg/day).

Chrysin was evaluated in 2 articles (Goes et al. 2018; Zhang et al. 2015), and the lowest concentration of the compound, administered orally, was 1.6 mg/kg/day (Goes et al. 2018). Considering that the daily quantity of flavones consumed is 0.2 mg/kg (Table 3), the evaluated concentration was 8 times higher. Chrysin was also administered orally at 16 mg/kg/day (Zhang et al. 2015), which was 80 times higher than the daily quantity consumed.

The compounds amentoflavone and vitexin were administered in amounts 8 mg/kg/day orally in two studies (Cao et al. 2017; Hu, Li, and Wang 2018). The amount is 40 times higher than the daily consumed amount of flavone (0.2 mg/kg/day).

Isoflavones

Three studies evaluating isoflavones were identified. The compounds evaluated were puerarin, genistein, and calycosin (Figure 3).

Figure 3. Articles that evaluated isoflavones in experimental models of PD in vitro

and in vivo oral intraperitoneal administration.

Puerarin and genistein compounds were evaluated at a concentration of 40 μM (Mercer et al. 2005). Compared with the concentration of isoflavone bioavailable in human blood circulation 2.19 μM, the evaluated concentration was 18 times higher.

Calycosin was evaluated in one study (Yang et al. 2019), but the concentration was not expressed and it was not possible to make comparisons with the concentration of isoflavone found bioavailable in human blood circulation.

Among the selected studied, only one study evaluated isoflavone in vivo (Yang et al. 2019). The compound evaluated, calycosin, was administered intraperitoneally at a concentration of 4.8 mg/kg/day. Compared with the daily quantity of isoflavonoids consumed (0.2 mg/kg, Table 3), the evaluated concentration was 24 times higher (Figure 3).

Flavanones

Among the articles included in this study, five evaluated flavanones using an in vitro experimental design (Figure 4).

Figure 4. Articles that evaluated flavanones in experimental models of PD in vitro

and in vivo oral administration

.

Naringenin was evaluated in three studies (Mercer et al. 2005; Lou et al. 2014; Kesh, Kannan, and Balakrishnan 2021). The lowest evaluated concentration of naringenin was 20 μM. Compared with the bioavailable concentration of flavanones in human blood circulation (0.07 μM), the evaluated concentrations of naringenin in these studies were 200 - 500 times higher.

Hesperidin was evaluated at 20 μM (Tamilselvam et al. 2013), which is 280 times higher than the bioavailable concentration of flavanones in human blood circulation and eriodictyol, was evaluated at 50 μM (Uversky et al. 2010), which is 700 times higher than the bioavailable concentration of flavone in human blood circulation.

Four articles evaluated flavanones in an in vivo experimental design using rats and zebrafish model. The evaluated compounds were naringenin and hesperidin (Figure 4).

Naringenin was evaluated on zebrafish (Kesh, Kannan, and Balakrishnan 2021) and after oral administration on rats (Levites et al. 2001; Lou et al. 2014). The lowest evaluated concentration of naringenin was 3.2 mg/kg/day. The evaluated concentrations were in the range of 3.2 − 11.2 mg/kg/day. Compared with the daily quantity of flavonones consumed (0.4 mg/kg, Table 3), the evaluated concentrations were 8 – 28 times higher (Figure 4).

Hesperidin was evaluated in vivo using oral administration in an animal model at 8 mg/kg/day (Antunes et al. 2021), which was 20 times higher than the daily quantity of flavonones consumed (Figure 4).

Flavonols

We found 8 articles that evaluated flavonols using an in vitro experimental design. The evaluated compounds were gossypetin, kaempferol, myricetin and quercetin (Figure 5).

Figure 5. Articles that evaluated flavonols in experimental models of PD in vitro

and in vivo oral administration

and intraperitoneal administration.

Quercetin was evaluated in five studies, and (Bureau, Longpré, and Martinoli 2008; Mercer et al. 2005; Bournival, Quessy, and Martinoli 2009; Ay et al. 2017; Wang et al. 2021) its lowest evaluated concentration was 0.1 μM (Bureau, Longpré, and Martinoli 2008; Bournival, Quessy, and Martinoli 2009). The concentration of flavonols that is bioavailable in human blood circulation is 0.3 μM. Thus, the quercetin concentrations evaluated in the two studies can be found bioavailable in human blood circulation. However, the concentrations of quercetin evaluated in other studies were 60 – 130 times higher than the bioavailable concentration in human blood circulation.

Myricetin was evaluated in one study at a concentration of 10 μM (Caruana et al. 2011) which is 30 times higher than the concentration of flavonol that can be found in human blood circulation. The compounds gossypetin and kaempferol were evaluated at a concentration of 50 μM (Uversky et al. 2010; Pan et al. 2020) which is greater than 100 times the concentration of flavonol found in blood.

Eight articles evaluated flavonols in an in vivo experimental design using rodents. The evaluated compounds were dihydromyricetin, fisetin, kaempferol and quercetin (Figure 5).

Fisetin and quercetin were orally administered at concentrations of 3.2 mg/kg/day (Zbarsky et al. 2005; Kumar et al. 2020). Considering that the daily quantity of flavonols consumed is 0.8 mg/kg (Table 3), the evaluated concentrations were four times higher.

Quercetin was also evaluated in four other articles (Karuppagounder et al. 2013; El-Horany et al. 2016; Ay et al. 2017; Wang et al. 2021), by intraperitoneal administration at 8 - 24 mg/kg/day (Karuppagounder et al. 2013; El-Horany et al. 2016). Additionally, quercetin was administered orally at a concentration range of 4.8–28 mg/kg/day. Compared with the daily quantity of flavonols consumed (0.8 mg/kg, Table 3), the evaluated concentrations were 6–35 times higher.

Dihydromyricetin and kaempferol were evaluated by intraperitoneal and orally administration at 1.6 and 3.2 mg/kg/day, respectively (Ren et al. 2016; Hu, Li, and Wang 2018). Compared with the daily quantity of flavonols consumed (0.8 mg/kg, Table 3), the evaluated concentrations were in 2–4 times higher.

Flavanols

We identified 5 studies that evaluated flavanols. The compounds evaluated included catechin and epigallocatechin gallate (Figure 6).

Figure 6. Articles that evaluated flavanols in experimental models of PD in vitro

and in vivo oral administration

.

Catechin was evaluated in a study at a concentration of 40 µM (Mercer et al. 2005). Compared to the bioavailable concentration of flavanols in human blood circulation at 1.6 μM (Table 3), the concentrations evaluated in this study were 25 times higher.

Epigallocatechin gallate (EGCG) was evaluated in four studies (Levites, Youdim, et al. 2002; Caruana et al. 2011; Lorenzen et al. 2014; Xu et al. 2016). The lowest evaluated concentration of EGCG was 0.2 μM (Xu et al. 2016), and the concentrations evaluated in two studies (Levites, Youdim, et al. 2002; Lorenzen et al. 2014) and the concentrations evaluated in two studies (Levites, Youdim, et al. 2002; Lorenzen et al. 2014), can be found bioavailable in human blood circulation. The concentration evaluated in the other study was 6 times higher than the bioavailable flavanol concentration in human bloodstream.

Three studies evaluated EGCG in vivo using rats by oral administration (Levites et al. 2001; Xu et al. 2017; Zhou, Zhu, and Liang 2018), at 1.6 – 8 mg/kg/day (Figure 5). Compared with the daily quantity of flavanols consumed, (3 mg/kg, Table 3), the amounts evaluated in one article (Levites et al. 2001) were less than the amount of flavanols consumed daily, whereas the amount evaluated in other two (Xu et al. 2017; Zhou, Zhu, and Liang 2018) was 1–3 times higher than the daily consumed amount of flavanols.

Stilbenes

Seven studies evaluated stilbenes in vitro experimental design. The compounds evaluated were viniferin (Sergi et al. 2021), piceid (Bai et al. 2020) and resveratrol (Okawara et al. 2007; Bournival, Quessy, and Martinoli 2009; Zhang et al. 2010; Sergi et al. 2021; Zhang et al. 2018; Xia, Sui, and Zhang 2019). Viniferin was not evaluated in clear concentration in μM preventing comparisons between tested values and the amount consumed. On the other hand, piceid was evaluated at a concentration of 50 μM. Considering 0.02 μM as the concentration of stilbenes subclass bioavailable in human blood circulation (Table 3), that amount of piceid is 2,500 times higher than the reported bioavailable concentration of stilbenes in human blood circulation.

Resveratrol was extensively evaluated, in concentrations of 0.1 (Bournival, Quessy, and Martinoli 2009), 60 (Zhang et al. 2010), 100 (Okawara et al. 2007), 350 (Zhang et al. 2018) and 50,000 μM (Xia, Sui, and Zhang 2019). These concentrations of resveratrol evaluated are, respectively 5, 3,000, 5,000, 17,500 2,5.10⁶ times higher than the concentration of stilbenes bioavailable in human blood.

Among the included studies, seven studies evaluated stilbenes in vivo experimental design. The compounds evaluated were piceid (Chen et al. 2015; Bai et al. 2020) and resveratrol (Khan et al. 2010; Abolaji et al. 2018; Abolaji et al. 2018; Zhang et al. 2018; Xia, Sui, and Zhang 2019; Bai et al. 2020). The piceid was evaluated in clear concentrations only in one study (Chen et al. 2015), with 22 mg/kg/day. Considering 0.04 mg/kg/day as the concentration of stilbenes subclass consumed in the human diet (Table 3), that amount of piceid is 550 times higher than the reported consumed amount of stilbenes consumed daily.

Resveratrol was extensively evaluated in five articles with dose administered to animals extrapolated to humans equal to 0.8, 1.6, 3.2, 9.6 and 22 mg/kg/day, respectively. These amounts are 20 - 550 times higher than the amount of stilbenes subclass consumed daily.

Tyrosols

Only one study evaluated a tyrosol in vitro experimental design. The compound evaluated was oleuropein (Palazzi et al. 2018) at a concentration of 700 μM. Considering 0.02 μM as the concentration of tyrosols subclass bioavailable in human blood circulation (Table 3), that amount tested of oleuropein is 35,000 times higher than the reported bioavailable concentration of tyrosols in human blood circulation.

Among the included studies, two studies evaluated tyrosols in vivo experimental design. The compounds evaluated were hydroxytyrosol and oleuropein (Brunetti et al. 2020; di Rosa et al. 2020). However, the amounts tested are not clearly described by the authors. In addition, the daily amounts consumed of tyrosols in the human diet are not found in the literature, preventing comparisons between tested values and the amount consumed.

Curcuminoids

Only one study evaluated a curcuminoids in vitro experimental design. The compound evaluated was curcumin (Pandey et al. 2008) at a concentration of 1 μM. Considering 0.2 μM as the concentration of curcuminoid bioavailable in human blood circulation (Table 3), that amount tested of curcumin is 5 times higher than the reported bioavailable concentration of curcuminoids in human blood circulation.

Among the included studies, two studies evaluated curcuminoids in vivo experimental design. The compound evaluated was only curcumin (Zbarsky et al. 2005; Cui, Li, and Zhu 2016) at concentrations 8 and 32 mg/kg/day, respectively. On the other hand, the daily amounts consumed of curcuminoids in the human diet is not consolidated in the literature, preventing comparisons between tested amounts in the studies and the reference amount consumed (Figure 7).

Figure 7. Articles that evaluated flavanols in experimental models of PD

oral administration.

Discussion

Based on experimental designs, the 100 most-cited articles on PD and PCs included one prospective cohort study, 24 in vivo studies, 26 in vitro laboratory studies, 15 studies using both in vivo and in vitro assays and 15 literature reviews.

After extrapolation to human doses, only one group were found to be administered PCs at concentrations below the amounts daily consumed. Only five articles with in vitro assays were found to have evaluated PCs at concentrations below the bioavailable range in human blood circulation.

Therefore, approximately 96% of the studies with an experimental laboratory design evaluated PCs at higher concentrations than those normally found in the blood circulation and/or concentrations consumed in human diet.

In the 1970s and 1980s, David Sackett, David Eddy, and Archie Cochrane through evidence-based medicine (MBE), highlighted the need to strengthen the empirical practice of medicine and proposed the initial rules of evidence to guide clinical decisions (Djulbegovic and Guyatt 2017).

MBE suggests a pyramid of evidence focused on design and clinical studies to determine the reliability of results related to the effects of evaluated treatments. The evidence pyramid shows laboratory studies (in vitro and in vivo) and case series at the bottom, followed by case-control and cohort studies in the middle, followed by randomized controlled trials, systematic reviews, and meta-analyses at the top (Murad et al. 2016).

The neuroprotective potential of PCs in PD has been demonstrated in several studies; however, the scientific evidence remains limited because the results are derived from in vitro and in vivo experimental designs using PD models, which do not reproduce completely the complexity of the human disease.

In vitro experimental designs for PD are necessary to initially evaluate the off-target pharmacology, cytotoxicity, genetic toxicity, and neuroprotection of PCs, as well as for controlling the concentration and time of cellular exposure to neurotoxins. It is also possible to identify the role of pathological pathways in neurodegeneration (Dexter and Jenner 2013).

The selected articles that used an in vitro design demonstrated the neuroprotective effect of the tested PCs; however, these results should be considered with caution, because the in vitro models are not representative of the susceptibility of DN affected by PD in humans and because neuroprotection varies according to the bioavailability of each PCs (Ferreira, Martins, and Barros 2017; Dexter and Jenner 2013).

Upon oral consumption, PCs undergoes metabolic reactions and conjugations along the gastrointestinal tract and is then transported through the blood-brain barrier. Structural alterations caused by enzymes, which exist particularly at the blood-brain interfaces, where they influence the cerebral availability of toxic compounds, leading to the formation of metabolites, mainly glutathione and glucuronic acid derivatives, which localize in brain tissues nonspecifically at levels below of 1 nmol/g of tissue (Ferreira, Martins, and Barros 2017). Further, articles that used the in vitro experimental design tested pure compounds considering that they reached the DN without undergoing any structural changes.

Furthermore, the concentration of metabolites that crosses the blood-brain barrier and reaches the brain is higher than that of the parent compounds (Clancy 2002). In several cases, the concentrations of the tested pure compounds were 100 times higher than the bioavailable concentrations found in plasma.

After crossing the BBB, PCs can act to increase the expression of endogenous antioxidant enzymes, inhibit the expression of inflammatory cytokines, increase the activity of the mitochondrial complex and interact with the α-syn protein through covalent and non-covalent bonds, forming soluble oligomers that prevent aggregation and formation as described in Table 2.

The ideal experimental design for PD should include degeneration of dopaminergic and non-dopaminergic neurons, the central and peripheral nervous systems, and motor and non-motor symptoms; however, none of the currently available experimental models fulfill these characteristics.

The second most common experimental design among the articles involved in vivo animal models using rats, zebra-fish, and flies. In vivo experimental designs mimic the actual conditions of the organism, facilitating evaluation of the efficiency, efficacy, safety, and therapeutic dose of the phenolic matrix studied (Clancy 2002). Further, in vivo experimental models of PD contribute significantly to enhance the understanding of disease progression and identification of potential target therapeutics.

In vivo experimental PD models can be classified as either genetic or neurotoxic (Tieu 2011). Genetic models are created using known mechanisms causing the disease but without significant neurodegeneration and phenotypes. The limitations of these models can be complemented using neurotoxic models, which use different molecules to cause damage to the nigrostriatal pathway (Tieu 2011). Among the articles on WoS-CC and WoS-AD the neurotoxin models included 6-OHDA, MPTP, LSH and rotenone.

Another point to be reviewed in the experimental laboratory design in vivo is the route of PCs administration. The speed and amounts of compounds reaching the target organ (determinants of treatment effectiveness) depend on the route of administration. The routes of administration can be classified as enteral (oral, sublingual, rectal), parenteral (intravascular, intramuscular, subcutaneous, and inhalation), or topical (skin or mucus membranes). Each route has a specific purpose, advantage, and disadvantage (Mignani et al. 2013).

The oral route of administration has several advantages over other routes, including a low total dose, reduced gastrointestinal side effects, improved efficacy/safety ratio, and good patient acceptance and compliance; however, compounds administered via this route are not always fully absorbed (Mignani et al. 2013; Lambkin and Pinilla 2002).

Generally, absorption is affected by the structure of phenolic compounds. Before absorption, PCs with simpler structures are deglycosylated in the upper fraction of the gut, and those with more complex structures reach the colon, where they are transformed by the microbiota into low-molecular-weight metabolites for absorption (de Araújo et al. 2021).

Once absorbed, PCs undergo conjugation with enzymes in the liver. Hepatic metabolites (methylated, sulfated, or glucuronidated conjugates) can then be transported by the circulatory system to organs or be excreted, as these processes increase water solubility (Chen, Cao, and Xiao 2018).

Intraperitoneal administration is a type of parenteral administration, which results in rapid initial action on the target organ along with predictable and high bioavailability, suggesting that the administered amount of compounds is completely absorbed; however, this route presents risks of adverse effects owing to the rapid accumulation of high amounts of the administered compound and a risk of infection at the injection site (Chen, Cao, and Xiao 2018).

If the objective of studies is to evaluate the neuroprotective effects of PCs and their inclusion in the diet for the prevention of PD, the oral route of administration in in vivo experimental designs would be the most appropriate, as it would demonstrate neuroprotective effects based on the bioavailability of PCs from the diet.

In fact, the oral route was more used for the administration of PCs than other routes such as intraperitoneal (25, 7 studies, respectively). However, the results obtained in these studies should be considered with caution, as the extrapolation of the doses used in animals to humans revealed that the amount administered in 99% of the studies was higher than the daily amount consumed in CPs ingested through the diet. This suggests that the aim of the articles is focused on identifying therapies that could be administered orally as high-dose drugs.

Inappropriate translation of doses evaluated in animals to humans is one of the main causes of drug inefficacy in clinical studies. Extrapolation of the tested dose in animals to humans should use the most appropriate normalization based on body surface area (Reagan‐Shaw, Nihal, and Ahmad 2008).

The neuroprotective effects of PCs in humans from the diet depend on the amount ingested, which is estimated from the PCs concentration in food and their bioavailability PCs. The amount of PCs ingested PCS varies with individual food culture, sex, age, and other factors (Pinto and Santos 2017).

Consumption of PCs by the general population in Brazil is approximately 460.2 mg/day. This amount is lower than PCs consumed by the general population in the USA (900 mg/day), France (1,193.0 mg/day), and Japan (1,500 mg/day) (Bo’ et al. 2019). The doses evaluated in the experimental laboratory designs in vivo, when extrapolated to humans were 2 – 400 times higher than the daily amounts consumed.

Conclusion

The findings of the articles reviewed in this study indicate the neuroprotective potential of PCs on PD. The experimental designs of the studies evaluated in 80% are laboratory studies that suggest the neuroprotective effects of PCs not through the diet, but from the development of drugs with a high concentration of PCs for oral therapeutic use. However, it is necessary to validate the results obtained with the most promising PCs through highly controlled clinical studies, so that a diet enriched with these new products can be designed.

Abbreviations
5-HT	=	Serotonin
6-OHDA	=	6-Hydroxydopamine
α-syn	=	α-Synuclein
AChE	=	Acetylcholinesterase
Akb	=	Protein kinase B
ARE	=	Antioxidant response elements
Bax	=	BCL2 associated X
BBB	=	Blood-brain barrier
BCL2	=	BCL2 apoptosis regulator
BDNF	=	Brain-derived neurotrophic factor
BTE	=	Black tea extract
CaMKII	=	Ca2+/calmodulin-dependent protein kinase II
CAT	=	Catalase
C-Jun	=	Protein encoded by the JUN gene
COMT	=	Catechol O-methyltransferase
Cyt c	=	Cytochrome c
DA	=	Dopamine
DARPP-32	=	Dopamine- and cAMP-regulated phosphoprotein-32
DN	=	Dopamine neurons
EGCG	=	Epigallocatechin gallate
ERK 1/2	=	Extracellular signal-regulated kinases
GDNF	=	Glial cell-derived neurotrophic factor
GPx	=	Glutathione peroxidase
GSH	=	Glutathione
GSK-3β	=	Glycogen synthase kinase-3β
GTP	=	Green tea polyphenols
HMOX1	=	Heme oxygenase-1
HVA	=	Homovanillic acid
IFN-γ	=	Interferon-gamma
IL	=	Interleukin
iNOS	=	Nitric oxide synthase
I.P.	=	Intraperitonial
JNK 1/2	=	c-Jun N-terminal kinase
Keap1	=	Kelch-like ECH-associated protein 1
LDH	=	Lactate dehydrogenase
MAO-Bis	=	monoamine oxidase type B inhibitors
MDA	=	Malondialdehyde
MMP	=	Mitochondrial membrane potential
MPP	=	1-methyl-4-phenylpyridinium mRNA = Messenger ribonucleic acid
NDGA	=	Nordihydroguaiaretic acid
NF-ĸB	=	Nuclear factor-kappa B
NO	=	Nitric oxide
NQO1	=	NAD(P)H:quinone oxidoreductase
Nrf-2	=	Erythroid nuclear factor-2 related to factor 2
O	=	orally
P38	=	p38 mitogen-activated protein kinases
PCa	=	Carbonyl protein
PC	=	Phenolic compounds
PD	=	Parkinson’s disease
PIK-3	=	Phosphoinositide 3-kinase
PKC	=	Protein kinase C
PLA2	=	Phospholipase A2
ROS	=	Reactive oxygen species
SMAC	=	Second mitochondria-derived activator of caspase
SOD	=	Superoxide dismutase
TBARS	=	Thiobarbituric acid reactive substances
TCM	=	Traditional Chinese Medicine
TH	=	Tyrosine hydroxylase
TH-ir	=	TH-immunoreactive
TNF-α	=	Tumor necrosis factor alpha
TRAP	=	Total reactive antioxidant potential
TS	=	Topic
VOSviewer	=	Visualization of Similarities Viewer
WoS-CC	=	Web of Science Core Collection

Acknowledgements

José Messias Perdigão and Bruno José Brito Texeira and Vinicius Carvalho-da-Silva performed experiments, analyzed, interpreted the data and drafted the manuscript. Rui Daniel Prediger, Rafael Rodrigues Lima and Hervé Rogez formulated the study concept, designed the study, and made critical revisions of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This study was supported by the European Union in French Guiana (Interregion Program of Amazon Cooperation), CAPES Fundation and National Council for Scientific and Technological Development (CNPq)(grants) and PROPESP-UFPA (publication charges).