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Nutrients 2017, 9(5), 477; https://doi.org/10.3390/nu9050477
Article
The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action
Department of Biotechnology, Human Nutrition and the Science of Food Commodities, University of Life Sciences in Lublin, Lublin 20704, Poland
*
Author to whom correspondence should be addressed.
Received: 23 March 2017 / Accepted: 4 May 2017 / Published: 10 May 2017
Abstract
:The neuroprotective role of phenolic acids from food has previously been reported by many authors. In this review, the role of phenolic acids in ameliorating depression, ischemia/reperfusion injury, neuroinflammation, apoptosis, glutamate-induced toxicity, epilepsy, imbalance after traumatic brain injury, hyperinsulinemia-induced memory impairment, hearing and vision disturbances, Parkinson’s disease, Huntington’s disease, anti-amyotrophic lateral sclerosis, Chagas disease and other less distributed diseases is discussed. This review covers the in vitro, ex vivo and in vivo studies concerning the prevention and treatment of neurological disorders (on the biochemical and gene expression levels) by phenolic acids.
Keywords:
cinnamic acids; benzoic acids; polyphenols; neuroprotection; neuroinflammation; central nervous system; neuron; glial cell; neurological disorder1. Introduction
Phenolic acids are one of the main classes of polyphenols. They are abundantly present in foods such as berries [1], nuts [2], coffee and tea [3] and whole grains [4]. Importantly, a recent meta-analysis showed that phenolic acid-rich foods decrease the risk of depression [5,6]. Figure 1 presents the chemical structures of phenolic acids discussed in this work. Previously, authors focused mainly on the antioxidant and antiradical activities of phenolic acids. However, in recent years, the interest in protecting neurons and glial cells by phenolic acids has considerably increased, and a great number of works elaborating the neuroprotective role of phenolic acids has been published. Changes in the central nervous system, as well as in the peripheral parts of the nervous system, including sense organs, affect the patient’s behavior and quality of life. Recently, we published a review paper on the anti-Alzheimer and cognition-enhancing role of phenolic acids originating from food [7]. In the following (Table 1), we present a review collating original papers concerning many other and previously omitted aspects of the neuroprotective role of phenolic acids originating from food. The presented review serves as assistance for quick access to the most prominent neuroprotective actions of phenolic acids.
2. Neuroprotective Activities of Phenolic Acids
3. Penetration of Brain by Phenolic Acids
Previously, it has been estimated that the daily consumption of phenolic acids is noticeable and totals ≈200 mg [111,112]. Moreover, the pharmacokinetic properties of phenolic acids are excellent. Bourne and Rice-Evans (1998) showed that the peak concentration of ferulic acid in plasma occurred 7–9 h after the consumption of tomatoes (360–640 g), with the recovery of the phenolic acid reaching 11–25% of the amount consumed [113]. Recently, a cross-sectional analysis of the consumption of polyphenols (involving 10 European countries and over half a million participants) revealed that the total amount of these secondary plant metabolites was high (744 mg/day in men and 584 mg/day in women in Greece to 1786 mg/day in men and 1626 mg/day in women in Denmark). Among polyphenols, phenolic acids represented the largest part (52.5–56.9% in women and men, respectively) in the diets of all groups, with the exception of men in the Mediterranean countries and “health-conscious” consumers in the United Kingdom (predominantly vegetarians). However, in the Mediterranean countries and in the “health-conscious” group in the U.K., phenolic acids were the second most distributed polyphenols (34–44%). Generally, hydroxycinnamic acids (ranging from 27% in women from the “health-conscious” group in the U.K. to 53% in men from non- Mediterranean countries) were the most important contributors to total polyphenols in the diet. The most important dietary source of phenolic acids in all studied European countries was coffee (58–75%), and the most distributed phenolic acids were caffeoylquinic acids (mainly 5-caffeoylquinic, 4-caffeoylquinic and 3-caffeoylquinic acid), followed by feruloylquinic, gallic, galloylquinic, 4-hydroxyphenylacetic, homovanillic, 3,4-dihydroxyphenylacetic and dihydro-p-coumaric acids [114]. Other major research papers have confirmed the high dietary intake of phenolic acids. Tresserra-Rimbau et al. (2013) calculated that the mean consumption of phenolic acids in a group of 7200 participants was 304 ± 156 mg/day (a parallel-group, aged 55–80 years; a validated one-year food frequency questionnaire in a multicenter, randomized, controlled five-year feeding trial). Phenolic acids were the main polyphenolics consumed (33% of all polyphenols), and 5-caffeoylquinic acid was the most abundant individual polyphenolic compound. Other phenolic acids broadly consumed were: 3-caffeoylquinic acid (49.75 ± 34.18 mg/day), 4-caffeoylquinic acid (42.60 ± 31.79 mg/day), ferulic acid (14.32 ± 14.35 mg/day), 5-feruloylquinic acid 7.24 ± 5.56 (mg/day), 4-feruloylquinic acid (6.17 ± 4.81 mg/day), syringic acid (4.82 ± 4.76 mg/day) and verbascoside (4.61 ± 7.00 mg/day) [115]. Grosso et al. (2014), in a study involving 10,477 persons aged 45–69 years (a validated 148-item food frequency questionnaire), estimated the daily intake of phenolic acids at 800 mg (521 mg/day as aglycone equivalents, 46% of total intake of polyphenols). The main phenolic acids were 5-caffeoylquinic and 4-caffeoylquinic acids (with average intake at 150 mg/day), followed by 3-caffeoylquinic acid (128.2 ± 111.6 mg/day), 5-O-galloylquinic acid (60.8 ± 45.4 mg/day), ferulic acid (43.9 ± 33.7 mg/day), stigmastanol ferulate (37.5 ± 22.6 mg/day), 5-feruloylquinic acid (27.9 ± 14.3 mg/day), gallic acid 25.0 ± 11.2 mg/day) and 4-feruloylquinic acid (20.4 ± 12 mg/day) [116].
The experimental data collated in Table 1 prove the positive role of phenolic acids in an indirect manner. The amount of phenolic acids administered to experimental animals in feed is known, but the authors did not study the content of phenolic acids in the brain. Therefore, the activity of phenolic acids in brains (on the biochemical and gene expression levels, amelioration of the enzyme activity changes) was discussed only by comparison with reference groups of animals fed with a standard diet. Although it is assumed that the transfer of polyphenols through the blood-brain barrier is limited, a considerable number of original papers confirm the presence of absorbed phenolic acid compounds in the brain. Phenolic acids can be accumulated in the brain at pharmacologically-relevant, nanomolar or micromolar concentrations, as described below. Gallic acid has been detected in trace amounts in brains (mouse model of Alzheimer’s disease) after repeated administration of grape seed polyphenolic extract for 10 days (intragastric gavage of 50, 100 and 150 mg/kg b.w.) [117]. Protocatechuic acid was detected in brain micro-dialysates (at maximal concentration of 0.09 ± 0.07 μg/mL, ≈0.58 ± 0.45 nmol/mL) 15 min–4 h after the administration of Danshen extract (Salvia miltiorrhiza, intragastrically, 40 mg/kg b.w.) to adult, male Sprague-Dawley rats [118]. 3-Hydroxybenzoic, benzoic and homovanillic acids were detected (at 0.43–1.06 nmol/g, 2.53–15.63 nmol/g and 1.84–2.39 nmol/g, respectively) in extracts of freeze-dried brain tissues of male Wistar rats orally fed with the grape seed proanthocyanidin extract (125, 250, 375, 1000 mg extract/kg b.w.). The levels of phenolic acids were dependent on the dose of the extract [119]. Benzoic acid was the main phenolic acid in brains of Sprague–Dawley rats that consumed wild blueberry for four and eight weeks. Other minor phenolic acids were also detected in brains, and the sum of all detected phenolic acids was 69.0 μg/g brain (which can be estimated for nanomolar concentrations, taking into consideration the molecular masses of the various phenolic acids) [120]. In another work, 3-hydroxybenzoic and 3-(3′-hydroxyphenyl) propionic acids were accumulated at μmol concentrations in perfused brain tissues of rats fed for 11 days with grape seed polyphenol extract. Both phenolic acids were shown to accumulate in brains in a dose-dependent manner. Treatment with 250 mg extract/kg b.w./day increased brain contents of 3-hydroxybenzoic and 3-hydroxyphenylpropionic acid 3.2-fold and 7.7-fold, respectively (in comparison to controls). Furthermore, hydroxybenzoic, 4-hydroxybenzoic, 3-hydroxyphenylacetic, 3,4-dihydroxyphenylacetic and 3-hydroxyphenylpropionic acids were detected in brains, but no detectable changes in the content of these phenolic acids were observed after the treatment with various doses of the extract [121]. Ferulic acid was detected in brains (2.6 μg/g of tissue, ≈13.39 nmol/mL) after the oral administration to rats (521 μmol acid/kg b.w.), and the concentration of this acid in brains was decreased only by 50% 60 min after the consumption [122]. Other works confirm the penetration of brain by ferulic acid [123], caffeic acid and caffeic acid phenethyl ester [124] and rosmarinic acid [125]. Ferulic, caffeic, rosmarinic acids and caffeic acid phenethyl ester can also protect blood-brain barrier and brain structures [126,127,128,129]. Chlorogenic acid was detected in the cerebrospinal fluid of rats that were fed with chlorogenic acid-enriched Eucommia ulmoides bark extract (200 and 400 mg extract/kg b.w./day, for seven days). The levels of phenolic acid were ≈0.42–0.56 ng/mL (≈0.0011–0.0015 nmol/mL) (1 h and 1.5 h after consumption, respectively) [42]. Moreover, degradation of absorbed, more complex polyphenols from foods yielding simple phenolic acids can be observed, thus increasing the levels of bioavailable phenolic acids in the brain. For example, cyanidin 3-O-glucopyranoside is degraded in vivo in SH-SY5Y bone marrow neuroblastoma cells, yielding protocatechuic acid [130]. Taking the above results into consideration, it can be claimed that phenolic acids can effectively accumulate in brain achieving the levels required for the pharmacological effect.
A very interesting aspect of the neuroprotective activity of phenolic acids in biological systems is the activity rather at low and not at high concentrations, as was explicitly stated by some authors. Caffeic acid dimethyl ether, when used at lower concentrations (15–50 µmol/L), was more efficient than applied at a higher dose (at 50–100 µmol/L) for the elevation of the expression of heme oxygenase-1 in cultivated astrocytes, leading to the increased concentrations of reduced glutathione in cultured cells [131]. Similarly, ferulic acid ethyl ester effectively induced heme oxygenase-1 protein expression in cultivated astrocytes at low (5 µmol/L), but not at high concentrations (15 µmol/L), along with the maximal expression of mRNA coding for heme oxygenase-1 [132].
4. Concluding Remarks
This review was designed as a compact, comprehensive, content-rich compendium of the latest reports on the role of phenolic acids in improving neurological dysfunctions by direct positive influence on neural and glial cells. Especially, the years 2014–2016 were very fruitful in terms of the very in-depth knowledge about biochemical parameters, new specific markers and gene expression modifications caused by phenolic acids, involved in the proper functioning of neural and glial cells.
In summary, it can be stated that due to a wide distribution in natural sources, a considerable daily intake, relatively high stability in foods, as well as high intestinal absorption (in comparison to more complex polyphenols) and efficient brain absorption, phenolic acids may be considered as promising compounds for the future combination therapy of neurological disorders.
Acknowledgments
This scientific work was supported by the Ministry of Science and Higher Education of the Republic of Poland (Scientific Grant No. 2339/B/P01/2010/38) and the University of Life Sciences in Lublin, which is financed by the Polish Government.
Author Contributions
All authors contributed to the gathering of source articles and writing of this paper.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
3NP | 3-Nitropropionic acid |
6-OHDA | 6-Hydroxydopamine |
BAD | Bcl-2-associated death promoter |
Bax | Bcl-2-like protein 4 |
BCL | B-cell lymphoma |
BCL-2 | B-cell lymphoma 2 |
Bcr-Abl | fusion between break point cluster (Bcr) gene and the Abelson (Abl) tyrosine kinase gene |
BDNF | Brain-derived neurotrophic factor |
b.w. | Body weight |
Casp-3 | Caspase-3 |
Casp-8 | Caspase-8 |
Casp-9 | Caspase-9 |
CAT | Catalase |
CCI | Chronic constriction injury |
CD40 | Cluster of differentiation 40 |
COX-2 | Cyclooxygenase-2 |
CREB | cAMP response element-binding protein |
CUMS | Chronic unexpected mild stress |
EPO | Erythropoietin |
ERK | Extracellular signal-regulated kinase, protein-serine/threonine kinase |
ERK1 | Extracellular signal-regulated kinase 1, protein-serine/threonine kinase 1 |
ERK2 | Extracellular signal-regulated kinase 2 protein-serine/threonine kinase 2 |
FST | Forced swimming test |
GFAP | Glial fibrillary acidic protein |
GPx | Glutathione peroxidase |
i.p. | Intraperitoneally |
IL-1β | Interleukin 1β |
IL-4 | Interleukin 4 |
IL-5 | Interleukin 5 |
IL-6 | Interleukin 6 |
IL-13 | Interleukin 13 |
iNOS | Inducible nitric oxide synthase |
JNK | c-Jun N-terminal kinase |
LDH | Lactate dehydrogenase |
LPS | Lipopolysaccharide |
MAO | Monoamine oxidase |
MDA | Malondialdehyde |
MEK | Mitogen-activated protein kinase |
MHX | major histocompatibility complex II molecules |
NF-κB | Nuclear factor-κB |
NO | Nitric oxide |
NRF1 | Nuclear respiratory factor 1 |
Nrf2 | Nuclear factor (erythroid-derived 2)-like 2 |
Nrf2/HO-1 | Nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 |
p38 | MAP Kinase (MAPK), CSBP Cytokinin-Specific Binding Protein or RK |
p90RSK | MAPK-activated protein kinase-1 (MAPKAP-K1) |
pCREB | phosphorylated cAMP response element-binding protein |
PD | Parkinson disease |
PGE2 | Prostaglandin E2 |
p.o. | Orally |
p-p38 | phosphorylated p38 |
PTZ | Pentylenetetrazol |
ROS | Reactive oxygen species |
SOD | Superoxide dismutase |
TBI | Traumatic brain injury |
Th1 | T helper type 1 (Th1) cells |
Th2 | T helper type 2 (Th2) cells |
TNF-α | Tumor necrosis factor-α |
TST | Tail suspension test |
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Figure 1.
Chemical structures of phenolic acids discussed in this work.

Table 1.
Summary of the neuroprotective activities of phenolic acids.
Ferulic Acid | Antidepressant-like Effect:
|
Caffeic Acid | Inflammation:
|
Caffeic Acid Phenethyl Ester | Antioxidant Activity:
|
Chlorogenic Acid | Reversing of the Glutamate-induced Toxicity:
|
Chlorogenic Acid and Its Metabolites | Reversing of the Glutamate-induced Toxicity:
|
Rosmarinic Acid | Antioxidant Activity:
|
P-Coumaric Acid | Protection from Ischemia/ Reperfusion Injury:
|
Sinapic Acid | PD:
|
Cinnamic Aldehyde | Inflammation and Cognition:
|
Salicylic Acid | Antioxidant Activity:
|
Acetylsalicylic Acid | Inflammation and Antioxidant Activity:
|
Protocatechuic Acid | Antioxidant Activity:
|
Gallic Acid | Antioxidant Activity:
|
Tannic Acid | Antioxidant Activity:
|
Homovanillic Acid | Antidepressant Effect:
|
Syringic Acid | Protection from Ischemia/reperfusion Injury:
|
Ellagic Acid | Anticancer Activity:
|
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