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Neuroinflammation Treatment Options
1st Jul, 2020

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Neuroinflammation Enhanced

Treatment Options

Diet

  • Include a wide variety of fruits and vegetables in the diet to ensure adequate intake of polyphenols, flavonoids and anti-oxidants to help prevent and reduce both systemic and neuroinflammation (1).
  • The Mediterranean diet reduces neuroinflammation by anti-inflammatory and anti-oxidative activities (2,3).
  • Limit saturated fat and sugar intake, and reduce exposure to fluoride and alcohol to avoid oxidative stress in the brain and microglia activation(4,5,6).
  • Include green tea in the diet. EGCG activates the Nrf2 pathway  (7).
  • Garlic is another Nrf2 activator (7).

Supplements

  • Probiotics minimise systemic inflammation and consequent neuroinflammation via increased intestinal barrier integrity and immune activation (8,9).
  • Resolvins  derived from DHA and EPA actively turn off the inflammatory response (10,11). The brain tissue content of DHA depends on the amount of omega-3 PUFA in the diet (12).
  • Antioxidants reduce reactive oxygen species (ROS) levels in the brain (13). Examples include vitamin E, Coenzyme Q10 (CoQ10), N-Acetyl cysteine (NAC)
  • Resveratrol (200 - 500mg/day) inhibits pro-inflammatory cytokine expression, reduces ROS levels, modulates transcription factors, increases brain derived neurotrophic factors (BDNF) and activates the Nrf2 pathway  (7,14,15,16,17,18).
  • Folic acid (1,250 μg/day). Low folate levels impair vitamin B12 absorption, which in turn may lead to an inflammatory state (19).
  • Thiamine deficiency increases pro-inflammatory mediators and should be addressed if present (20).
  • Nrf2 activators such as glutathione, curcumin, resveratrol, lycopene, capsaicin, garlic, EGCG, sulforaphane, spirulina, and a ketogenic diet should be considered. Nrf2 suppression in the brain is linked to oxidative stress and inflammation (7,21,22).

 

Mechanisms of action

Most dietary components which help to regulate neuroinflammation do so via their anti-inflammatory and/or anti-oxidant properties.

  • The increase in pro-inflammatory adipokines and cytokine levels promotes neuroinflammation as well as inhibition of neuronal proliferation and synaptic plasticity in the hippocampus (3).
  • Inflammation induces oxidative stress and DNA damage, which leads to the overproduction of ROS by macrophages and microglia
  • Oxidative stress can directly activate glial cells  at the injury site. In turn, the direct contact of activated glial cells with neurons may generate immune mediators that spread inflammation in the CNS (23).

 

Flavonoids and Polyphenols

Suggested anti-neuroinflammatory mechanisms include (1,24,25,26,27)

  • Downregulation of pro-inflammatory transcription factors, such as NF-κB, via their influences on glial and neuronal signalling pathways
  • Improvement of the regional cerebral perfusion 
  • Inhibition of:
    • Cytokine release (e.g. IL-1β and TNF-α)
    • Nitric oxide production from activated microglia
    • The activation of NADPH oxidase and subsequent ROS generation in activated glial cells
    • Misfolded protein aggregate  formation

 

 

Figure 1. The neuroprotective effects of garlic components on oxidative stress, neuroinflammation and neurodegeneration (22) CC BY 4.0

Neuroinflammation and Nutrition - Hub Enhanced Fig 1 

 

Table 1. Mechanism of action of neuroprotective dietary components

Dietary component

Mechanism of action

Extra-virgin olive oil
  • Contains particularly high levels of caffeic acid and tyrosol which reduce markers of neuroinflammation (2)
  • Displays free radical scavenging/antioxidant action, lipid peroxidation inhibition, anti-inflammatory, glutathione restoration, and anti-apoptotic properties (28,29)

Zinc

 
  • Improves insulin sensitivity; reduces inflammation and oxidative stress (30)

Tocotrienols

 
  • May suppress NF-κB-mediated neuroinflammation (31)

Ketogenic Diet

 
  • Ketone bodies may mitigate neuroinflammation (32)
  • A ketogenic diet activates Nrf2 nuclear accumulation in the hippocampus (21)

Luteolin
  • Can cross the blood brain barrier (BBB) and mitigate microglia-mediated neuroinflammation via antioxidant and anti-inflammatory mechanisms (3,14,33)

Epigallocatechin-gallate (EGCG)

 
  • Inhibits TNF-α release in primary glial cells (34)
  • Reduces prostaglandin synthesis and suppresses ROS generation in the glial cells (35)
  • Activates Nrf2 (7)

Resveratrol

 
  • Inhibits pro-inflammatory cytokine expression and reduces ROS levels
  • Modulates transcription factors and increases BDNF
  • Activates Nrf2 (3,7,14,16,17,36,37)

Curcumin, quercetin,  vitamin C

 
  • Downregulates the expression of COX-2 and pro-inflammatory cytokines in activated microglia (14,17,34,38)
  • Decreases the production of ROS (39)
  • Activates Nrf2 (7)

Folic Acid

 
  • Low folate levels impair vitamin B12 absorption, which in turn may lead to an inflammatory state (19)

Vitamin D

 
  • Suppresses reactive oxygen species (ROS) generation and inflammatory cytokines (40)
  • Activates Treg  cells within the immune system and regulates the expression of glial cell-line derived neurotrophic factor (GNDF) (41)

Omega-3 PUFAs

 

DHA and EPA decrease the inflammatory responses especially in microglia (1,10,13,42,43):

  • Downregulate the activity of pro-inflammatory transcription factors
  • Inhibit the release of cytokines from activated microglia
  • Inhibit the production of NO and PGE2 in response to microglia activation
  • Benefit membrane lipid composition

Mediterranean Diet

 
  • Anti-inflammatory and anti-oxidant activities due to high levels of vegetables and fruits (polyphenols, flavonoids), fish (omega-3), low saturated fat intake, high unsaturated fat intake (2,3)

 

Table 2. Mechanism of action of harmful dietary components in neuroinflammation

Dietary component

Mechanism of action

Fluorine
  • Can cross the BBB and provoke microglia activation in the hippocampus and cerebral cortex (5,45,46)

Thiamine Deficiency
  • Increases pro-inflammatory cytokines, chemokines, and interferons (20)

Alcohol
  • Repeated exposure leads to long-term activation of microglia and astrocytes (6)

Western Diet

Excessive consumption of saturated fats and sugars results in:

  • A reduction in BDNF (4,47)
  • An increase in the accumulation of toxic biological mechanisms in brain tissue which includes advanced glycation end products (AGEs), oxidative stress and insulin resistance (4,47,48)
  • Interaction with omega-3 PUFAs to diminish their anti-inflammatory activity (49)
  • Promotion of oxidative stress and neuroinflammation in the absence of any peripheral inflammatory signalling (47,50,51)

Metabolic Disorders and Obesity
  • High glucose levels and insulin resistance impact oxidative stress pathways and neuroinflammatory signals in the brain (3)
  • Obesity results in decreased anti-inflammatory adipokines and increased release of pro-inflammatory adipokines which can stimulate microglia and cause neuroinflammation (3,52)
  • Maternal obesity and maternal diet might impact foetal and offspring neurodevelopment, including neuroinflammation (53)

 

Hypothalamic inflammation

  • Persistent excess of caloric intake and diet-induced obesity results in chronic and low-grade inflammation which leads to neuroinflammation. This neuroinflammation impairs central regulatory pathways of energy balance and nutritional metabolism, leading to obesity, diabetes, CVD and other complications (8,54).
  • Fatty acids activate the innate immune system directly through Toll-like receptors and indirectly via modulation of the gut microbiota (55,56).
  • Leptin can promote a prolonged neuroinflammatory response through the sustained delivery of IL-1β (57).

 

Gut-Brain axis and probiotics

Possible mechanisms that link the microbiota to neuroinflammation include:

  • Modified immune response, enhancing response to cerebral amyloid-β (58).
  • Age-related microbiome changes are associated with the synthesis of pro-inflammatory cytokines (59,60).
  • Epidemiological links between oral bacteria and increased TNF-α production (61,62).
  • Decreased intestinal barrier integrity and consequent neuroinflammation via the vagus nerve (8,9).

 

Table 3. Food Sources of neuroprotective dietary components

Name

Sources

 

Curcumin

Turmeric

Resveratrol

Dark chocolate, skin of grapes and berries (such as blueberry, mulberry and raspberries)

Tocotrienols

Avocados, bananas, berries, cabbage, cherries, coconut, corn, kiwi fruit, green peas, onions, peaches, pears, plums, grapes, peanuts, hazelnut, cashew, lychee, cereals, wheat, olive fruit, specialty oils from palm, rice bran, barley and oats

Epigallocatechin-gallate (EGCG)

Tea (Camellia sinensis) (includes green, white, oolong and black tea)

DHA

Marine fish and algal oil

Astaxanthin

Algae, yeast, salmon, trout, shrimp and crayfish

Lutein

Green leafy vegetables, green/yellow vegetables and egg yolk

Sulforaphane

Cruciferous vegetables such as broccoli, brussel sprouts, cabbage and cauliflower

 

Table 4. Flavonoids and their sources (1,16,52)

Flavonoid

Examples

Sources

Flavones

Apigenin, luteolin

Parsley, celery, green pepper, broccoli, carrots, olive oil, chamomile plant flowers and peppermint

Flavonols

Kaempferol, quercetin

Onions, leeks, broccoli, tomatoes, radish and several other fruits and green leafy vegetables

Isoflavones

Daidzein, genistein

Soy and soy products

Flavanones/flavanonols

Hesperedin, naringenin, astilbin, engeletin

Citrus fruit, herbs (oregano) and wine

Flavanols

Catechin, epicatechin, EGCG

Green tea, red wine and chocolate

Anthocyanidins

Pelargonidin, cyanidin, malvidin

Red wine and berry fruits

 

Common markers

General markers of inflammation include:

  • C-Reactive Protein (CRP)
  • Erythrocyte Sedimentation Rate (ESR)

 

Takeaway on Neuroinflammation and Nutrition

Neuroinflammation is central to many acute and chronic brain diseases and can be prevented and modified by dietary factors.

  • A high intake of antioxidants and anti-inflammatory foods via high intake of a variety of vegetables and fruits can help to reduce peripheral and neuroinflammation.
  • Omega-3 intake (especially DHA) is crucial to brain heath.
  • Probiotics and ensuring gut integrity can be beneficial.
  • Reducing obesity and avoiding western dietary patterns can also help to reduce inflammation.

 

Visit the Neuroinflammation and Nutrition post for more information.

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