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

Figures & data

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.

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.

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)

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

and in vivo oral administration

.

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

and in vivo oral administration

and intraperitoneal administration.

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

and in vivo oral intraperitoneal administration.

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

and in vivo oral administration

.

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

and in vivo oral administration

and intraperitoneal administration.

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

and in vivo oral administration

.

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

oral administration.

Zheng, J., H. Xiong, Q. Li, L. He, H. Weng, W. Ling, and D. Wang. 2019. Protocatechuic acid from chicory is bioavailable and undergoes partial glucuronidation and sulfation in healthy humans. Food Science & Nutrition 7 (9):3071–80. doi: 10.1002/fsn3.1168.

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Jeong, S. H., J. H. Jang, H. Y. Cho, I. J. Oh, and Y. B. Lee. 2020. A sensitive UPLC–ESI–MS/MS method for the quantification of cinnamic acid in vivo and in vitro: Application to pharmacokinetic and protein binding study in human plasma. Journal of Pharmaceutical Investigation 50 (2):159–72. doi: 10.1007/s40005-019-00444-0.

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Wu, H., G. Oliveira, and M. A. Lila. 2022. Protein-binding approaches for improving bioaccessibility and bioavailability of anthocyanins. Comprehensive Reviews in Food Science and Food Safety (1):333–354. doi: 10.1111/1541-4337.13070

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DeRango-Adem, E. F., and J. Blay. 2021. Does oral apigenin have real potential for a therapeutic effect in the context of human gastrointestinal and other cancers? Frontiers in Pharmacology: (12).

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Soyata, A., A. N. Hasanah, and T. Rusdiana. 2021. Isoflavones in soybean as a daily nutrient: The mechanisms of action and how they alter the pharmacokinetics of drugs. Turkish Journal of Pharmaceutical Sciences 18 (6):799–810. doi: 10.4274/tjps.galenos.2020.79106.

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Joshi, R., Y. A. Kulkarni, and S. Wairkar. 2018. Pharmacokinetic, pharmacodynamic and formulations aspects of naringenin: An update. Life Sciences 215:43–56. doi: 10.1016/j.lfs.2018.10.066.

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Dabeek, W. M., and M. V. Marra. 2019. Dietary quercetin and kaempferol: Bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients 11:(10).

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Cai, Z. Y., X. M. Li, J. P. Liang, L. P. Xiang, K. R. Wang, Y. L. Shi, R. Yang, M. Shi, J. H. Ye, J. L. Lu, et al. 2018. Bioavailability of tea catechins and its improvement. Molecules 23:(9).

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Calvo-Castro, L. A., C. Schiborr, F. David, H. Ehrt, J. Voggel, N. Sus, D. Behnam, A. Bosy-Westphal, and J. Frank. 2018. The oral bioavailability of trans-resveratrol from a grapevine-shoot extract in healthy humans is significantly increased by micellar solubilization. Molecular Nutrition & Food Research 62 (9):1701057. doi: 10.1002/mnfr.201701057.

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Kim, S. J., H. Shin, S. M. Cheon, S. M. Ko, S. H. Ham, Y. D. Kwon, Y. B. Lee, and H. Y. Cho. 2017. A sensitive UHPLC–MS/MS method for the simultaneous quantification of three lignans in human plasma and its application to a pharmacokinetic study. Journal of Separation Science 40 (17):3430–9. doi: 10.1002/jssc.201700588.

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Alemán-Jiménez, C., R. Domínguez-Perles, S. Medina, I. Prgomet, I. López-González, A. Simonelli-Muñoz, M. Campillo-Cano, D. Auñón, F. Ferreres, and Á. Gil-Izquierdo. 2021. Pharmacokinetics and bioavailability of hydroxytyrosol are dependent on the food matrix in humans. European Journal of Nutrition 60 (2):905–15. doi: 10.1007/s00394-020-02295-0.

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Jude, S., A. Amalraj, A. B. Kunnumakkara, C. Divya, B. M. Löffler, and S. Gopi. 2018. Development of validated methods and quantification of curcuminoids and curcumin metabolites and their pharmacokinetic study of oral administration of complete natural turmeric formulation (CureitTM) in human plasma via UPLC/ESI-Q-TOF-MS spectrometry. Molecules 23(10). doi: 10.3390/molecules23102415.

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Data availability statement

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