Oxidative damage, mitochondrial dysfunction, and neuroinflammation are strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD), and a substantial portion of elderly population at risk of these diseases requires nutritional intervention to benefit health due to lack of clinically relevant drugs. To this end, anti-inflammatory mechanisms of several phytochemicals such as curcumin, resveratrol, propolis, polyunsaturated fatty acids (PUFAs), and ginsenosides have been extensively studied. However, correlation of the phytochemicals with neuroinflammation or brain nutrition is not fully considered, especially in their therapeutic mechanism for neuronal damage or dysfunction. In this article, we review the advance in antioxidative and anti-inflammatory effects of phytochemicals and discuss the potential communication with brain microenvironment by improved gastrointestinal function, enhanced systemic immunity, and neuroprotective outcomes. These data show that phytochemicals may modulate and suppress neuroinflammation of the brain by several approaches: (1) reducing systemic inflammation and infiltration via the blood-brain barrier (BBB), (2) direct permeation into the brain parenchyma leading to neuroprotection, (3) enhancing integrity of disrupted BBB, and (4) vagal reflex-mediated nutrition and protection by gastrointestinal function signaling to the brain. Therefore, many phytochemicals have multiple potential neuroprotective approaches contributing to therapeutic benefit for pathogenesis of neurodegenerative diseases, and development of strategies for preventing these diseases represents a considerable public health concern and socioeconomic burden.
With rapid population aging, advanced age is a major risk factor leading to an increased prevalence of neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and multiple sclerosis (MS). The common characteristic of these diseases is progressive neuronal loss and impaired neuronal function, and one of their critical backstage manipulators is extracellular neurotoxic microenvironment linked to oxidative stress, chronic inflammation, and mitochondrial dysfunctions [
Traditionally, parenchymal cells (i.e., neurons, astrocytes, microglia, and oligodendrocytes) of the CNS are separated from the rest of body by BBB to form an immune-privileged organ, and peripheral immune cells and nutrients such as resveratrol and curcumin are restricted into the brain. However, in recent years, substantial evidence shows that the brain itself is fully immune competent due to the participation of microglia and astrocytes in immune response [
In this article, based on the availability in daily life and reported evidence, we chose five phytochemicals, i.e., curcumin, resveratrol, propolis, polyunsaturated fatty acids (PUFAs), and ginsenosides, as representatives of various phytochemicals and discuss their neuroprotective mechanism and therapeutic implication for neurodegenerative diseases, including their anti-inflammatory and antioxidative effects on gastrointestinal dysfunction, peripheral immune system, and brain innate immunity, as well as potential communication of their nutritional signals between the brain and the periphery. The data about phytochemicals curcumin, resveratrol, propolis, PUFAs, and ginsenosides are collected from PubMed database and addressed in terms of antioxidative or anti-inflammatory mechanism and nutritional or protective effects on the gastrointestinal tract, systemic immunity, and neuroimmunity.
Oxidative stress associated with mitochondrial dysfunction and neuroinflammation is a common characteristic of neurodegenerative diseases, mainly due to metabolic features of the CNS: high oxygen consumption even under basal conditions and high production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from specific neurochemical reactions, as well as increased metabolites such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) with aging [
Correlation between oxidative stress, mitochondrial dysfunction, and neuroinflammation. Various aging factors and environmental factors stimulate glial cells to induce inflammatory response, oxidative stress, and mitochondrial dysfunction, which orchestrate to impact on neuronal apoptotic mechanism and glial inflammatory mechanism, leading to neuronal dysfunction or loss in neurodegenerative diseases.
Oxidative stress is defined as an imbalance between production of oxidants such as ROS and ability to detoxify reactive oxygen intermediates, causing cellular damage by free radicals. Normally, the brain function is highly sensitive to oxygen metabolic activity or production of ROS such as hydrogen peroxide (H2O2), hydroxyl free radical (∙OH), superoxide anion (O2−∙), and peroxynitrite (ONO2−), and approximately 98% of ROS is formed in mitochondria as by-products of cellular respiration [
Chronic inflammation, another aging contributor, plays a critical role in neurodegenerative pathogenesis from initiation and progression to outcome of diseases, as a consequence of persistent stimuli of chronic stress antigens such as PAMPs, DAMPs, and senescence-associated secretory phenotype (SASP) [
Mitochondrial dysfunction is a major source of ROS due to high energy demand and high dependence of brain activities on efficient mitochondria. It is readily affected by various environmental factors to occur early as a primary event in the aging process (e.g., mitochondrial DNA damage) and then is potentiated by microglia-mediated oxidative stress and neuroinflammation to fuel the pathogenesis of neurodegenerative disorders [
Gastrointestinal function acts on gut microbiota, mucus integrity, gut immunity, and intramural neural plexus, and these functional components are readily influenced or damaged by gut inflammation and oxidative stress linked to various adverse factors. Especially, the gut damage, as a peripheral inflammatory stimulation signal, can be sensed by the brain through vagal reflex and exacerbate brain inflammatory response in the onset and progression of neurodegenerative diseases [
Inflammatory reflex or vagal reflex, a bidirectional neuroimmune communication pathway between the gut and brain, also called gut-brain axis, consists of an afferent arm that senses peripheral inflammation and an efferent arm that sends out the signals integrated in the brain to inhibit gut inflammation and innate immune response. In detail, afferent signals in the vagal nerve, while reaching the solitary tract nucleus and brainstem, activate central neurons that project to the hypothalamus and other CNS nuclei responsible for inflammatory response control [
Curcumin is an oil-soluble polyphenolic phytochemical from
Resveratrol, a nonflavonoid plant polyphenol mainly found in red grapes and wine, possesses an anti-inflammatory effect to benefit gut health as evidenced in various inflammation models. In H2O2-induced Caco-2 cells, resveratrol increases epithelial expression of occludin and zonula occluden to protect gut barrier function and reduces intracellular ROS accumulation, along with increased expression of superoxide dismutase (SOD) and HO-1, to prevent oxidative damage [
Propolis or bee glue is a resinous substance that bees collect from various living plants for construction and adaptation of their nests, consisting of three major components: flavonoids, phenolic compounds, and caffeic acid phenethyl ester (CAPE). As a functional food, it has a range of biological activities such as anti-inflammatory, antibiotic, antioxidative, anticancer, antifungal, anesthetic, and cytostatic effects [
PUFAs, a group of unsaturated fatty acids enriched in vegetable and fish oil, functionally act as important signaling molecules regulating diverse physiological processes. They are divided into two families: omega- (
Ginsenosides or panaxosides, a class of natural steroid glycosides and triterpene saponins in the plant
Taken together, the phytochemicals can counteract inflammatory and oxidative stresses by their intrinsic ability to scavenge free radicals and maintain homeostasis of gut microbiota, gut barrier integrity, and immune barrier function. The improved gastrointestinal function can activate vagal neural reflex or gut-brain axis or microbiome-gut-brain axis by gut nutritional signals to change brain neurochemistry and behavior and to reverse neuroinflammatory pathogenesis in the brain [
Immunosenescence or age-based immunity decline is a gradual deterioration of the immune system with natural age advancement, involving decline in production of new naive lymphocytes and functional competence of memory cell populations. This phenomenon entails increased risk and severity of diseases such as infections, chronic inflammation, autoimmunity, and cancer, especially obscure presentation of nonspecific signs and symptoms, leading to increase in prevalence of neurodegenerative diseases [
Curcumin, an antioxidative and anti-inflammatory agent, can enhance systemic immunity by influencing expression or release of proinflammatory cytokines, ROS/RNS, TLRs,
Resveratrol, a well-known anti-inflammatory, antioxidant, immunomodulatory, and anticarcinogenic agent, can promote immune surveillance and reduce immunosenescence in rodents and humans. Evidence shows that resveratrol modulates transcription factors AP-1, NF-
Propolis has a wide spectrum of pharmacological activities such as anti-inflammation and antioxidation in systemic immunity, which are principally attributed to presence of flavonoids, phenolic compounds, and CAPE [
PUFAs, a group of immunomodulatory agents, function differently based on their families and cell contexts. In
Ginsenosides play a critical role in regulating immune responses in inflammatory and immune-related diseases. In LPS-stimulated macrophages, ginsenoside Rg1 and its metabolites inhibit NF-
Taken together, better understanding of immune enhancement mechanisms of phytochemicals and their relevant communication routes between the periphery and the brain, is essential to develop preventive strategies to counteract impact of systemic inflammation on brain activities in older adults, especially those with preclinical neurodegenerative diseases. The phytochemicals have a direct beneficial effect on the peripheral immune system, and so their dietary administration is an optimal choice to ameliorate systemic inflammation and then reverse pathogenesis of neurodegenerative diseases [
Neurodegenerative diseases are characterized by progressive neuronal loss and impaired neuronal function, along with activation of microglia and astrocytes and increased release of a range of proinflammatory cytokines such as TNF-
Curcumin, as a food additive with antioxidative and anti-inflammatory properties, has a neuroprotective effect in neurodegenerative diseases. Accumulated evidence shows that curcumin can prevent
Resveratrol, as a neuroprotective agent, can suppress overexpression of inflammatory mediators in activated microglia and astrocytes. In LPS-induced cortical neurotoxicity, resveratrol significantly protects cortical neurons against neuroinflammation by inhibiting microglia activation and subsequent production of proinflammatory and cytotoxic factors such as TNF-
Propolis has been confirmed to have neuroprotective effects. In the microglia treated by hypoxia, propolis significantly inhibits expression of proinflammatory cytokines such as IL-1
PUFAs, the structural component of cellular membrane in the brain, are a source of bioactive lipid mediators enzymatically derived from DHA of
Ginsenosides, the major bioactive components of ginseng, possess multiple immunoregulatory effects, involving inhibition of neuroinflammation and oxidative stress, maintenance of neurotransmitter balance, and antiapoptosis and mitochondrial stabilization in the brain. In mice with LPS-induced depression, ginsenoside Rg3 significantly reduces plasma levels of IL-6 and TNF-
Collectively, neuroinflammation, oxidative stress, and mitochondrial dysfunction are three major situations in pathogenesis of neurodegenerative diseases (Figure
Anti-inflammatory or antioxidative mechanisms of several phytochemicals in gastrointestinal health, systemic immunity, and neuroimmunity.
Phytochemicals | Approaches | Action mechanisms | Major outcomes | References |
---|---|---|---|---|
Curcumin | Gastrointestinal health | BiP ↓ and IL-8 ↓, in IECs | Anti-inflammation ↑ and ER stress ↓ | [ |
Serotonin ↓, BDNF ↓, and pCREB ↓, in gut | Gut function ↑ | |||
Mesenteric afferent nerve response by colorectal distension or capsaicin ↓ | Gut nociception ↓ | |||
NO ↓, lipid peroxides ↓, neutrophils infiltration ↓, and cell apoptosis ↓, in TNF- |
Antioxidation ↑ | |||
Naïve CD4(+) T cells differentiation ↑, Treg ↑, and IL-10-producing Tr1 cells ↑, in intestine | Intestinal lamina propria immunity ↑ | |||
Systemic immunity | Circulating IL-6 ↓, DC maturation ↓, proinflammatory cytokine ↓, and allospecific T cell response ↓ | Systemic inflammation ↓ | [ | |
Monocyte phagocytosis of A |
Systemic immunity ↑ | |||
IL-6 ↓, TNF- |
Anti-inflammation ↑ and innate immunity ↑ | |||
Neuroimmunity | Glial activation ↓, NF- |
Anti-inflammation ↑, antioxidation ↑, and antiapoptosis ↑ | [ | |
Tau aggregation ↓ and neurotoxicity ↓, in neurons | Neuroprotective effect ↑ | |||
Resveratrol | Gastrointestinal health | Occludin ↑ and zonula occluden (ZO-1) ↑, in IECs | Intestinal mucus integrity ↑ | [ |
ROS accumulation ↓, SOD ↑, and HO-1 ↑ | Antioxidation ↑ | |||
T helper cells ↓, Treg cells ↑, and IEC proliferation ↑, in ileitis | Gut barrier function ↑ and microbiota dysbiosis ↓ | |||
Lactobacilli ↑, bifidobacteria ↑, and enterobacteria ↓ | Colonic mucosa architecture ↑ | |||
PGE-2 ↓, Cox-2 ↓, PGE synthase ↓, and NO ↓, in colonic mucosa | Antioxidation ↑ and anti-inflammation ↑ | |||
Systemic immunity | Cytokines (TNF- |
Antioxidation ↑ and anti-inflammation ↑ | [ | |
Neuroimmunity | Glial activation ↓, NF- |
Neuroprotective effect ↑, on cortical neurons | [ | |
Lymphocyte infiltration ↓, protein IL-17A ↓, matrix metalloproteinases, ↓, and tight junction proteins ↑, in BBB-disrupted mice | BBB integrity ↑ | |||
Propolis (flavonoids, CAPE, or chrysin) | Gastrointestinal health | Occludin ↑, ZO-1 ↑ and colon fibrosis ↓, in IECs | Epithelial barrier function ↑ | [ |
NF- |
Antioxidation ↑ and anti-inflammation ↑ | |||
Systemic immunity | Phagocytosis↑ and cytotoxicity (IL-1 |
Cellular immunity ↑ | [ | |
Circulating proinflammatory cytokines (TNF- |
Systemic inflammation ↓ | |||
NO ↓, MAPK ↓, and NF- |
Antioxidation ↑ and anti-inflammation ↑ | |||
Neuroimmunity | NF- |
Antioxidation ↑, and anti-inflammation ↑, for neurons | [ | |
PUFAs ( |
Gastrointestinal health | NF- |
Anti-inflammation ↑, in gut | [ |
TRPA1 activation ↑ | Gastrointestinal function ↑ | |||
Intestinal mucosa permeability ↓, gut microbiota ↑, IL-15 ↓, TNF- |
Gut immune barrier function ↑ | |||
Systemic immunity | IL-17 ↓, IL-6 ↓, IL-23 ↓, and Treg cells ↑, in spleen | Anti-inflammation ↑ and immune function ↑ | [ | |
Neuroimmunity | Glial activation ↓, |
Neuroprotection ↑, anti-inflammation ↑, and brain innate immunity ↑ | [ | |
Ginsenosides (Rb1, Rb2, Rg3, Rh2, Rh3, Rg1, Rg2, and Rh1) | Gastrointestinal health | TNF- |
Anti-inflammation ↑ and gastrointestinal function ↑ | [ |
Systemic immunity | NF- |
Anti-inflammation ↑ and enteric nutrition ↑ | [ | |
Phagocytic uptake ↑ and ROS generation ↑ | Innate immunity ↑ | |||
Neuroimmunity | Glial activation ↓, ROSs ↓, TNF- |
Anti-inflammation ↑ and antioxidation ↑ | [ | |
CD14 ↓, NO ↓, TNF- |
Notes: ↑: increased; ↓: decreased; IECs: intestine epithelial cells; abbreviations are shown in the text.
Communication between gut function, systematic immunity, and neuroinflammation. Gastrointestinal function improvement by many phytochemicals can stimulate vagal reflex to affect brain neuroinflammatory response, modulate gut functional secretion of hormones and cytokines, and facilitate systemic innate immunity, leading to neuronal functional improvement or damage reversal. There are at least four approaches connecting gut function, systematic immunity, and neuroinflammation, determining neuroinflammatory or neuroprotective outcomes through dietary intervention of the phytochemicals.
Arachidonic acid
Alzheimer’s disease
Alpha-linolenic acid
Amyotrophic lateral sclerosis
Blood-brain barrier
Brain-derived neurotrophic factor
Caffeic acid phenethyl ester
C-C motif ligand
Central nervous system
Cycloxygenase-2
Damage-associated molecular patterns
Docosahexaenoic acid
Eicosapentaenoic acid
Extracellular regulated protein kinase
Huntington’s disease
Heme oxygenase-1
Intercellular adhesion molecule-1
Interleukin
Interferon-induced protein-10
Lipopolysaccharide
Mitogen-activated protein kinase
Monocyte chemotactic protein-1
Multiple sclerosis
Nuclear factor-
Nitric oxide
Nitric oxide synthase
Pathogen-associated molecular patterns
Peripheral blood mononuclear cells
Parkinson’s disease
Prostaglandin E2
Polyunsaturated fatty acids
Reactive nitrogen species
Reactive oxygen species
Senescence-associated secretory phenotype
Superoxide dismutase
Transforming growth factor
Toll-like receptors
Tumor necrosis factor
Regulatory T cells.
All authors declare no conflicts of interest.
JTW designed, organized, and wrote the review manuscript; YTS and ZC provided research facilities and conditions; SL helped design and review this paper; and all authors approved the final draft of the manuscript.
This work was supported by the funding (JT Wang) from the Milstein Medical Asian American Partnership (MMAAP) Foundation (