Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities

Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are characterized by the progressive degeneration of neurons. Although the etiology and pathogenesis of neurodegenerative diseases have been studied intensively, the mechanism is still in its infancy. In general, most neurodegenerative diseases share common molecular mechanisms, and multiple risks interact and promote the pathologic process of neurogenerative diseases. At present, most of the approved drugs only alleviate the clinical symptoms but fail to cure neurodegenerative diseases. Numerous studies indicate that dietary plant polyphenols are safe and exhibit potent neuroprotective effects in various neurodegenerative diseases. However, low bioavailability is the biggest obstacle for polyphenol that largely limits its adoption from evidence into clinical practice. In this review, we summarized the widely recognized mechanisms associated with neurodegenerative diseases, such as misfolded proteins, mitochondrial dysfunction, oxidative damage, and neuroinflammatory responses. In addition, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols. Moreover, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability, such as poor stability and low permeability across the blood-brain barrier (BBB). In the future, the improvement of absorption and stability, modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. Lastly, we hope that the present review will encourage further researches on natural dietary polyphenols in the treatment of neurodegenerative diseases.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), are a group of incurable heterogeneous diseases. They are characterized by the gradual degeneration of the function and structure of neurons and overactivation of microglia in the central nervous system (CNS) [1]. To date, the accurate molecular mechanisms related to the pathogenesis and progression of neurodegenerative diseases are not well elucidated [2]. Although each neurodegenerative disease exhibits the respective pathological features, they also share some common molecular mechanisms, such as the aggregation of misfolded proteins, oxidative damage, mitochondrial dysfunction, DNA damage, neuroexcitotoxicity, biometal dyshomeostasis, neurotrophic impairment, and neuroinflammatory responses [3, 4]. Among them, the aggregated misfolded proteins have become the pathological hallmarks in many neurodegenerative diseases. For example, the extracellular deposition of amyloid-β (Aβ) fibrils and intracellular hyperphosphorylated Tau are found in the brain of AD. In addition, Lewy bodies containing α-synuclein, mutant huntingtin (mHtt), mutant superoxide dismutase 1 (SOD1), and TAR DNA-Binding Protein 43 (TDP-43) are closely associated with the pathogenesis of PD, HD, and ALS, respectively [5]. It is known to us that these misfolded proteins are increasingly accumulated with ageing and induce oxidative stress by generating excessive reactive oxygen species (ROS) and reactive nitrogen species (RNS), which is accompanied by mitochondrial dysfunction, DNA damage, neuroexcitotoxicity, and ultimately neuronal death [6]. In addition, neuroinflammation plays a critical role in the early onset and late-stage of neurodegenerative diseases [7]. Microglia known as the resident macrophage cells in the brain are chronically activated by the Pathogen-Associated Molecular Patterns or Danger-Associated Molecular Patterns (PAMPs/DAMPs), such as misfolded protein aggregates, bacteria, viruses, lipopolysaccharides (LPS), and many environmental toxins. Then, the sustained activated microglia subsequently release several cytokines and induce proinflammatory responses [8]. Therefore, neuronal death and microglial overactivation are two major indicators for the pathological development and process of neurodegenerative diseases. Emerging evidence indicates that the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are two important processes that facilitate the clearance of misfolded proteins and damaged or unnecessary organelles, such as mitochondria [9]. At the early onset of neurodegenerative diseases, ALP and UPS acting as collaborators play protective roles in the degradation of toxin misfolded proteins, resistance to oxidative stress, and suppression of neuroinflammation [10, 11]. However, the normal function of ALP and UPS is impaired with ageing by the increasingly accumulated misfolded proteins and toxins [12, 13]. In this review, we summarized the current well-studied molecular mechanisms closely associated with the development of neurodegenerative diseases, including the aggregation of misfolded proteins, oxidative damage, mitochondrial dysfunction, DNA damage, excitotoxicity, biometal dyshomeostasis, and neuroinflammatory responses. However, the molecular mechanism of neurodegenerative diseases is still in its infancy and requires further in-depth investigations.

At present, there are currently many drugs developed and approved for the improvement of the symptoms of patients with neurodegenerative diseases in the clinical, but few of them can cure these diseases. More seriously, there might have side effects that appeared owing to the long-term use. In addition, many drugs, such as bapineuzumab, gantenerumab, and solanezumab, were recently declared failures during the clinical trial [14, 15]. Therefore, the accurate molecular mechanism and discovery of targeted drugs for the treatment of neurodegenerative diseases are still urgent and attract more and more attention [16]. In this review, we summarized the main current therapies and their mechanisms of action, neuroprotective effects, and limitations in various neurodegenerative diseases (Table 1). In view of the diversity of pathogenic mechanisms, the combinational therapies or the discovery and development of drugs with multitargets bring new hope for the treatment of neurodegenerative diseases. Therefore, more and more attentions are paid to natural medicine such as traditional Chinese medicines (TCMs) with multicompounds, multitargets, and multieffect properties. TCMs originating from natural products have a 2000-year history of treating diseases in China and have been proved to be safe and effective. To date, various kinds of bioactive compounds, including alkaloids, polyphenols, and saponins, are isolated and identified from natural plants. Among them, polyphenols, an important type of natural product, are mainly widely distributed in natural dietary plants. They are commonly divided into flavonoids and nonflavonoids which are subclassified into phenolic acids, stilbenes, lignans, curcuminoids, and coumarins. The modern pharmacological studies demonstrate that these polyphenols exhibit potential neuroprotective effects including the inhibition of neuronal death and the attenuation of neuroinflammatory responses in vitro and in vivo [17]. In this review, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols in various cellular and animal models of neurodegenerative diseases. In addition, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability. In the future, we hope that the improvement of absorption and stability, the modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. The present review will aid the researchers to know the research advances of polyphenols in neurodegenerative diseases. Lastly, we hope further researches will be encouraged for natural dietary polyphenols in the treatment of neurodegenerative diseases.

Table 1

The main current therapies and their mechanisms, effects, and limitations for neurodegenerative diseases.

Drugs	Mechanisms	Main effects	Main limitations	Diseases
Donepezil, Ralantamine, Rivastigmine	Inhibiting acetylcholinesterase	Increasing levels of synaptic acetylcholine	Increasing cognitive impairment; low CNS selectivity; gastrointestinal toxicity (nausea, vomiting, and diarrhea)	AD [18–24]
Memantine	Antagonizing N-methyl-D-aspartate-receptor (NMDAR)	Blocking glutamate from accessing NMDA receptors	Inability to slow down the progression of the disease
Aducanumab	Human, immunoglobulin gamma 1 (IgG1) monoclonal antibody	Reducing aggregated soluble and insoluble forms of Aβ	High cost and failure to show definite effect in clinical trials
Levodopa+Carbidopa	Inhibiting DA precursor and DOPA decarboxylase	Increasing DA levels in SNc	Wearing and movement disorders; dizziness and gastrointestinal upset	PD [25–28]
Pramipexole and Apomorphine	Agitating DA	Activating DA receptors	Less effective than levodopa; worsen dyskinesia
Selegiline, Rasagiline, and Safinamide	Inhibiting monoamine oxidase B (MAO-B)	Preventing DA metabolism	Mild efficacy in monotherapy
Gocovri (Amantadine)	Antivirus	Reducing levodopa-induced dyskinesia	Several side effects including psychosis, edema, constipation, and livedo reticularis
Trihexyphenidyl	Antagonizing muscarinic acetylcholine receptor	Reducing tremor	Serious side effects including memory impairment, confusion, and hallucinations
Levodopa+Carbidopa+Istradefylline	Inhibiting DA precursor, DOPA decarboxylase, and antagonizing A2A receptor	Reducing the “off” episodes	Higher incidence of treatment-emergent adverse events (TEAEs) and dyskinesia
Levodopa+Carbidopa+Opicapone	Inhibiting DA precursor, DOPA decarboxylase, and catechol-o-methyl transferase (COMT)	Reducing the “off” episodes	Higher incidence of TEAEs and worsen dyskinesia than istradefylline
Tetrabenazine (TBZ; Xenazine™) and deutetrabenazine (AUSTEDO™)	Inhibiting vesicular monoamine transporter type 2 (VMAT2)	Treating chorea associated with HD and tardive dyskinesia	Inability to slow down the progression of the disease	HD [29]
Riluzole	Blocking the presynaptic release of glutamate	Inhibiting the excitotoxicity	High cost and modest efficacy	ALS [30–33]
Edaravone (RADICAVATM)	Antioxidant	Protecting neuronal cells from oxidative stress, ameliorating motor dysfunction	Limited patient population

2. The Common Molecular Mechanisms of Neurodegenerative Diseases

2.1. Aggregation of Misfolded Proteins

The aggregation of misfolded proteins is recognized to be the common pathological feature of neurodegenerative diseases, such as Aβ and hyperphosphorylated Tau in AD, mutant α-synuclein in PD, and mHtt in HD, as well as SOD1 and TDP-43 in ALS [5, 34, 35] (Figure 1). It is known to us that ALP and UPS are two major intracellular elimination pathways for the clearance of these neurotoxic proteins in neurons and other cells in the brain [9, 36–38]. In the early onset of neurodegenerative disease, these toxic misfolded proteins are degraded via ALP and UPS pathways or effectively engulfed by microglia and astrocytes under normal physiological conditions. However, there is a growing body of studies showing that these misfolded protein aggregates are increasingly accumulated with ageing, accompanied by dysregulated or impaired ALP and UPS, which is implicated in the late stage of various neurodegenerative diseases [39]. Lastly, the normal function of neurons is becoming lost, and the microglia are overactivated, which ultimately results in neuronal death and proinflammatory responses [40] (Figure 1). For example, many accumulated autophagosomes and autophagic vesicles in the brain of AD patients are observed at the late stage of autophagy flux under immunoelectron microscopy [41]. In addition, autophagy is activated in the brain cells of AD patients and APP/PS1 mice. However, autophagy is impaired with ageing as revealed by the accumulation of Aβ-containing autophagic vesicles [42]. Therefore, autophagy plays a protective mechanism that fights against toxic protein-induced neuronal death and neuroinflammation at the early stage of AD, while the normal function of autophagy is impaired by the overgenerated toxic misfolded proteins (e.g., Aβ and Tau). In PD, emerging evidence indicates that the accumulation of mutant genes, including α-synuclein, Parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL-1), is closely associated with the dysfunction of ALP and UPS [43]. At the early stage of PD, autophagy participates in the clearance of misfolded proteins, damaged mitochondria, and generated ROS. However, autophagy is impaired in the brain of PD toxin-induced animals or transgenic mice with PD. For instance, the mRNA level of ubiquitinated α-synuclein is significantly increased in the brain of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced mice [44]. In addition, the impaired lysosome is accompanied by the accumulation of α-synuclein in mice which are chronically injected with probenecid and MPTP [45]. There is a growing body of evidence showing that UPS plays an important role in the degradation of soluble mHtt, but almost 90% of long-lived or large aggregated proteins such as mHtt can only be degraded via ALP [46]. For example, rapamycin, a potent autophagy inducer, significantly accelerates the autophagic degradation of mHtt, while autophagy inhibitors including 3-methyladenine (3-MA) and bafilomycin A1 attenuate the effect of rapamycin [47, 48]. Taken together, the aggregation of misfolded proteins is the pathological hallmarks of neurodegenerative diseases, while ALP and UPS act as a protective mechanism that timely clears the misfolded protein aggregates to maintain cellular homeostasis at the early stage of neurodegenerative diseases. However, misfolded proteins are increasingly accumulated with ageing, which dysregulates the normal functions of ALP and UPS [49]. Therefore, the discovery of ALP or UPS enhancers that target the clearance of misfolded proteins and damaged organelles is recognized to be a promising therapeutic strategy for neurodegenerative diseases.

[figure omitted; refer to PDF]

Polyphenols are complex plant secondary metabolites, which are mainly from dietary plants and exhibit a variety of pharmacological activities, such as antioxidant, anti-inflammatory, anticancer, liver protection, and neuroprotection [140, 449, 450]. Although most of the polyphenols are demonstrated to exhibit neuroprotective effects in various cellular and animal models, there are still very limited polyphenols or plant extracts that are developed into new drugs for the treatment of neurodegenerative diseases. In this respect, only 18 polyphenols are reported to have clinical studies by the US National Institute of Health (NIH). In addition to the poor stability, the literatures indicate that poor absorption, rapid metabolism and systemic elimination, inefficient delivery systems, and selective permeability across the BBB are also serious issues, which largely limit the bioavailability and neuroprotective effects of polyphenols in neurodegenerative diseases [451]. With the development of pharmaceutics, nanoencapsulation of polymeric nanoparticles or liposomes was employed to increase the permeability across BBB and improve the bioavailability of polyphenols. For example, an in silico validation along with the synthesis of CGA-loaded polymeric nanoparticles (CGA-NPs) by ionic gelation method is developed to overcome its pharmacological limitations and improve its stability in targeting neurodegenerative diseases [452]. In addition, liposomal resveratrol exhibits a more pronounced antioxidative effect as evidenced by the radical scavenging ability and reduction in ROS production when compared to resveratrol alone [453]. In LPS-stimulated HMC3 cells and murine acute brain slices, the liposomal curcumin shows a better effect in attenuated neuroinflammatory and reactive astrogliosis reactions than free curcumin [454]. Furthermore, the combinational use of polyphenols with other known compounds with neuroprotective effects is a promising strategy for improving their neuroprotective effects. It is reported that quercetin can function as an effective adjuvant to levodopa therapy might through its COMT/MAO inhibition property in the treatment of PD [455]. With the development of medical chemistry, increasing derivates are synthesized based on the polyphenols with the best neuroprotective effect. According to the structure of resveratrol, a series of compounds are designed and synthesized for the treatment of AD. Among them, compound 5d can be across the BBB and exhibit low toxicity in mice at doses of up to 2000 mg/kg [456]. Therefore, with the evidence suggesting the potential neuroprotective effect of polyphenols and dietary plants in various neurodegenerative diseases (Figure 7), more technologies and strategies on how to improve the absorption and stability, the modification of structure and formulation, and combination therapy are developing, which provide more opportunities from the laboratory into the clinic for polyphenols in the treatment of neurodegenerative diseases.

Authors’ Contributions

Da-Lian Qin, Xiao-Gang Zhou, and An-Guo Wu conceived the paper. Lu Yan, Min-Song Guo, and Wei Ai wrote the original manuscript. Yue Zhang, Feng-Dan Zhu, Yong Tang, Hua Li, and Mao Li collected the data in the tables. An-Guo Wu and Chong-Lin Yu drew the figures. Lu Yu, Qi Chen, and Jian-Ming Wu checked all the references and manuscript. All authors approved the final version of the manuscript. Lu Yan, Min-Song Guo, and Yue Zhang contributed equally to this work.

Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (Grant Nos. 81903829 and 81801398), the Science and Technology Planning Project of Sichuan Province, China (Grant Nos. 22GJHZ0008, 2021YJ0180, and 2020YJ0494), the Macao Science and Technology Development Fund of Macao SAR (Project Nos.: SKL-QRCM(MUST)-2020-2022 and MUST-SKL-2021-005), the Southwest Medical University (Grant Nos. 2021ZKZD015, 2021ZKZD018, and 2021ZKMS046), and the Joint project of Luzhou Municipal People’s Government and Southwest Medical University, China (Grant No. 2020LZXNYDJ37).

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