5 Supplements for Neuroinflammation

In the last post, we saw how MECFS and fibromyalgia are both characterized by chronic inflammation. Several studies have demonstrated peripheral and neuroinflammation in both conditions. This chronic inflammation explains many of the symptoms of these conditions: pain, fatigue, exercise intolerance, immune abnormalities.

Oxidative stress plays a pathogenic role in these chronic inflammatory diseases. Oxidative stress is a stimulant of inflammatory pathways. Oxidative stress creates excessive production of reactive oxygen species (ROS), also known as free radicals, that damage cell membranes and tissues and the body’s built-in antioxidant system often is unable to neutralize them.

It is still unknown why chronic oxidative stress and inflammation persists in some individuals and not in others. In the meantime, there are strategies that can be used to combat chronic inflammation. Many, many treatments are purported to reduce inflammation but one must consider the major players: TNF, NFkB, and Nrf2. While other anti-inflammatory measures, like diet, may be useful, treatments that effect these 3 elements will be most effective.

What is Neuroinflammation?

Neuroinflammation can be triggered by a number of factors: infection, traumatic brain injury, toxic metabolites, or autoimmune processes. All of these triggering factors stimulate specialized immune cells in the brain, called microglia, which function to release pro-inflammatory molecules. Chronic activation of microglia contributes to increasing oxidative stress which degrades the vital blood-brain barrier. Neuroinflammation is found in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

There is great interest in combating neuroinflammation using drugs for these and other conditions. There is some evidence that long-term use of NSAIDs reduces risk of Alzheimers disease. Other anti-inflammatory medications are currently under study for multiple sclerosis but often have side effects on normal immune responses leaving one open to infections.

Supplements for Neuroinflammation

Polyphenols have consistently been associated with reducing risk of dementia and improving cognitive performance with age. The plant compounds protect neurons against injury induced by neurotoxins and neuroinflammation. They do so by reducing oxidative stress and inflammatory cytokine signaling, but also through increasing protective signaling. Even more, polyphenols have been shown to increase blood flow to the brain.

Data shows that phytochemicals may suppress neuroinflammation by several means. This includes reducing systemic inflammation and immune cell infiltration via the blood-brain barrier (BBB), direct access to the brain tissue leading to neuroprotection, enhancing integrity of the BBB, and by gastrointestinal function signaling to the brain via the vagus nerve (gut-brain axis).

What are Polyphenols?

Polyphenols can be divided into various groups. The largest of which are flavonoids. Common flavonoids include quercetin, found in onions, leeks, and broccoli, and anthocyanidins, found in red wine and berries. Also common are the catechins, found in green tea, red wine, and chocolate. Mentioned earlier on the blog is the polyphenol sulphoraphane, a sulfur-heavy isothiocyanate. Another polyphenol, considered a non-flavonoid, is the popular compound resveratrol. Curcumin is also a popular polyphenol belonging to the group curcuminoids.

Let’s look at some of the most extensively studied supplements.

1. Curcumin

Curcumin supplementation significantly reduces the cytokine IL-6, a key regulator of the immune system, with a more pronounced effect in those with a higher degree of systemic inflammation. In those with migraine, a combination of omega-3 fatty acids and nanocurcumin significantly downregulated TNF-α, a key player in inflammatory pathways.

Preclinical and clinical studies show that curcumin can reduce gut inflammation and improve gut permeability. It also blocks the activation of T cells in the gut. All of these effects have the potential to reduce neuroinflammation by the gut-brain axis.

Read more about curcumin here.

2. Quercetin

Quercetin can reduce oxidative stress by binding with iron and inhibiting its oxidation. It also functions to reduce excess nitric oxide, by inhibiting xanthine oxidase, a main contributor to the production of free radicals. In studies of microglia specifically, quercetin can block inflammatory cascades triggered by NFkB. Quercetin also plays a major role in stabilizing mast cells to reduce histamine-associated inflammation.

3. Resveratrol

Resveratrol increases the production of anti-inflammatory cytokines such as IL-10. It also modulates key inflammatory regulator NFkB. Resveratrol supplementation significantly decreased C-reactive protein (CRP), a marker of systemic inflammation and TNF among patients with metabolic syndrome and related disorders.

The red wine polyphenol also can reduce neuroinflammation via gut-brain axis pathways. Resveratrol helps maintain gut barrier function and prevent bacterial translocation from the gut. It has also been found to increase the activity of enzymes that are protective against oxidative stress, SOD, and HO-1.

4. Sulforaphane

Sulforaphane may reduce neuroinflammation via inhibition of NFkB and upregulation of phase II detoxification enzymes in the liver. Most promising, is sulforaphanes ability to stimulate nrf2, a key regulator of anti-inflammatory pathways. Much more on sulforaphane can be found in a prior post. Read it here.

5. Berberine

Though not a polyphenol, berberine is a potent plant alkaloid with similar biological effects as polyphenols. It can down-regulate interferon, TNF, IL-1b, and IL-6, all inflammatory cytokines. It also blocks the production of nitric oxide synthase, an enzyme that produces oxidative stress via nitric oxide.

Berberine is well studied for anti-inflammatory effects. It has been shown in randomized controlled trials, to lower lipids and improve insulin resistance. In other clinical trials, berberine can reduce the risk of cardiovascular disease by reducing blood vessel inflammation.

The Problem of Bioavailability

Dietary consumption of polyphenols can average 1 gram per day. However, polyphenols are in general poorly absorbed from the intestine. Absorption is dependent on enzymatic activity by the intestine and activity of the colonic flora. If absorbed in the circulation, polyphenols are metabolized to far different forms than what naturally occurs in foods. However, once in controlled trials circulation, most polyphenols can cross the blood-brain barrier to offer neuroprotective effects.

Most polyphenols are fat soluble, so are best consumed in the presence of fats. Look for polyphenol supplements that are formed in nanoparticles, liposomes, or micelles. The bioavailability of polyphenols like curcumin and resveratrol is also enhanced in the presence of phospholipids or bioperine, a black pepper extract.

Berberine is poorly absorbed in the gut. Liposomal forms are not commonly available but are preferred over pH-buffered forms like berberine HCl.

Sulforaphane absorption can be enhanced with the addition of mustard seeds. Glucoraphanin, a sulforaphane precursor, or broccoli sprout supplements are common and found to be equally bioavailable.

Conjugated curcumins such as nanocurcumin or curcumin-like analogs are developed to increase their bioavailability and potential neuroprotective efficacy. Curcumin is fat soluble so its absorption is enhanced in the presence of fats. It’s also shown to be more bioavailable in the presence of bioperine, a compound found in black pepper.

References

Tarique Hussain, Bie Tan, Yulong Yin, Francois Blachier, Myrlene C. B. Tossou, and Najma Rahu, “Oxidative Stress and Inflammation: What Polyphenols Can Do for Us?,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 7432797, 9 pages, 2016.

Vauzour, D. (2012) Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxidative Medicine and Cell Longevity. 914273.

Frandsen JR & Narayanasamy P (2018) Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway. Redox Biol. 14:465-473.

Wang J. et al. (2018) Connection between Systemic Inflammation and Neuroinflammation Underlies Neuroprotective Mechanism of Several Phytochemicals in Neurodegenerative Diseases. Oxid Med Cell Longev. 2018:1972714.

Tabrizi R et al (2018) The effects of resveratrol supplementation on biomarkers of inflammation and oxidative stress among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Food Funct. 13;9(12):6116-6128. 

Lu DY, Tang CH, Chen YH, Wei IH. (2010) Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem. 110(3):697-705.