Naturally Negating Neuroinflammation

Inflammation is a common component of a lot of chronic illnesses. But the idea of neuro inflammation is a relatively new concept, according to Leonid Ber, MD, senior medical scientist with the practitioner-specific Protocol For Life Balance, a division of Illinois-based NOW Foods.

“Neuro inflammation started gaining attention because it attempted to explain the commonalities between the factors leading to the development of neurodegeneration and dementia in the aged population, particularly Alzheimer’s disease (AD),” he said. “It has been suggested that neuro inflammation might be the shared mechanism attributed to all known AD factors such as amyloid beta (Aß) protein accumulation, high cholesterol, proteasome inhibition, oxidative stress, hypertension, as well as the presence of AD- associated gene variants and infection.”1 

Today, AD is the most prevalent neurodegenerative condition, with one in six people over the age of 65 being affected in the U.S., and about 35 million people worldwide.2 Because the steady growth of the elderly population is expected to continue, neuro inflammation will remain an important target in the preventative and therapeutic Protocols, said Ber.

While brain health and neuroinflammation are typically thought of as concerns for the aging, Jared M. Skowron, ND, author of 100 Natural Remedies For Your Child, expressed that autism, ADHD (attention deficit hyperactivity disorder), anxiety, depression, AD, dementia, sensory development disorders and multiple sclerosis all have ties to neuroinflammation, and these conditions affect the polar ends of our lives.“As a child, our newly developing immune system is susceptible to alterations and toxins. If vaccines are a potential cause of these conditions, this is obviously the time that we are exposed to the majority of them,” said Dr. Skowron, who practices at Harvest Park Naturopathic Medicine in Wallingford, CT. “As an older person, through poor diet, exer- cise and the oxidation of life, we are more susceptible to all disease.” 

He noted that there has been an enormous increase of neuroinflammatory conditions over the past 10 years, and they affect all ages.“Some of the most evident are the growths in the areas of autism, PDD (pervasive development disorder), ADHD and sensory delays in our children. Also, the high amounts of Dementia and Alzheimer’s in our elderly pop- ulation reflect the increase of neuroinflamma- tory conditions,” he said. “We cannot ignore the increase of anxiety and depression med- ications prescribed over the past 10 years, which is related to the increase of emotional extremes caused by neuroinflammation.” 

Causes 

Bryan See, regional product manager with New Jersey-based raw material supplier Carotech Inc., pointed out that the brain is highly susceptible to oxidative damage “due to high oxygen consumption which is continuous, independent of degree of activity.Furthermore, the high lipid content of the brain makes it susceptible to lipid peroxida- tion in an antioxidant-poor environment. Increased oxidative stress triggers a series of inflammatory responses.

“Neuroinflammation has been found to be closely followed by neuronal damage, neuronal circuits impairment, leading to neu rodegeneration or loss of cognitive function due to prolonged accumulation of neurotoxic proinflammatory compounds,” See added.

Similar to inflammation affecting parts of the body, Leo Galland, MD, FACP, FACN,Director of The Foundation for Integrated Medicine, founder of Pilladvised.com and author of the weekly Pill Advised Newsletter, divides neuroinflammation into two categories: silent and flagrant.

“The much more insidious and common form of chronic inflammation is silent, which isn’t felt directly, but can be measured, and we can see its effects in heart disease, diabetes, blood pressure and cancer,” said Dr. Galland, noting that this chronic, silent inflammation in the brain may occur in two types of cells. “The first are the blood vessels feeding the brain. Inflammation in blood vessels would impair blood flow, which produces symptoms that are the result of a lack of oxygen and nourishment.” 

The second types of cells where inflammation can occur in brain tissue are the glial cells, or non-neuronal cells that maintain homeostasis, form myelin, and provide sup- port and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomic nervous system. “They basically surround neurons and are essentially cells that have immunologic activity,” Dr. Galland continued. “Impairment in blood flow due to inflammation in blood vessels or glia activation are two phenomenon associated with chronic degenerative disorders with the brain and may contribute to memory loss, or to degenerative neurologic conditions. They may also contribute to depression and mood changes.”

While traditionally considered neurodegenerative in nature, many neurological dis- eases in addition to AD, including multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and age-related macular degeneration, are now known to be associated with chronic neuroinflammation and elevated levels of several different cytokines, according to Beth Baldwin-Lien, ND, medical affairs and edu- cation with Connecticut-based Vital Nutrients. “While most of these diseases have a genetic component, it is theorized that inflammatory challenges might trigger the expression of genetic vulnerabilities that contribute to neuronal dysfunction and death,” she said. “Stroke, hypoxia and trauma also indirectly trigger neuroinflammation, as Microglia (migratory phagocytes within the central nervous system) are activated in an attempt to limit further injury.”

Protocol’s Dr. Ber noted that only about five to 10 percent of AD is distinctly linked to hereditary factors and appears at an early age (before 65). “The etiology of the remaining cases is elusive, but neuroinflammation seems to play a central role,” he said. “The current understanding of the low-grade inflammation in the central nervous system is that aging brain resident immune cells, microglia, acquire a pro-inflammatory acti- vation profile and display a heightened and prolonged response to immune stimuli as compared to young microglial cells.”3 

Turning From Traditional Treatments 

Traditional treatments for neuroinflammatory conditions mostly revolve around changing brain chemistry levels, said Dr. Skowron, noting that antidepressants and anti-anxiety medications can help moderate symptoms, but are not curative. “Most patients are try- ing to find natural alternatives because of the side effects of the medications (such as weight gain), but more importantly, people are realizing the limitations of pharmaceutical medicine, and want to find a cure to help themselves feel better,” he said.

Dr. Ber added that the central nervous system has traditionally been viewed as a region mainly spared from immune attacks.“Inflammation was thought to occur as sec- ondary to neuronal damage, and no special- ized microglia-targeted interventions were available,” he said, noting that from epidemi- ological studies and clinical trials, there are some observations that chronic use of NSAIDs may offer limited protection from neurodegenerative disease such as AD and Parkinson’s disease.4 

“With the establishment of the central role of microglia in the inflammation- mediated neurodegeneration, the need for targeted therapy has become evident. However, pharmacological candidates are still emerging and not readily available out- side the clinical trials,” said Dr. Ber. “This makes natural approaches for managing neuroinflammation especially valuable in the physician’s practice.” 

Diet & Lifestyle 

As Dr. Galland has written in numerous articles as well as in his book, Fat Resistance Diet, diet and inflammation are integrally linked, and this is no different when it comes to the brain.

“Diet is the foundation. We know inflammation is promoted by diets high in satu- rated fats or trans fats, and also by high dietary intakes of omega-6 fats,” he said.“Meanwhile, omega-3 fats have an anti- inflammatory effect. The higher the omega- 6 consumption, the greater the need for omega-3s.” 

Dr. Galland offered two additional dietary components for inflammation, the first being flavonoids, carotenoids and related phytonutrients, meaning that practitioners should encourage patients toward a high intake of colored fruits and vegetables.He also offered that high glycemic index (GI) diets are associated with more inflammation than low GI diets.

“From a dietary perspective, the same principles helpful for inflammation in the body will be helpful for neuroinflammation and create a foundation,” said Dr. Galland, noting that a good rule of thumb is a largely plant-based diet of fruits and vegetables with fish making a contribution.

With regard to diet, Protocol’s Dr. Ber said that one of the most valuable natural approaches for reducing risk of cognitive decline due to neuroinflammation is thoughtful caloric intake restriction.

“In studies, independent of physical activity, caloric restriction was shown to decrease the expression of pro-inflammatory markers associated with microglia activation. At the same time, implementing caloric restriction should not diminish consumption of the key antioxidant nutrients, such as vitamin E and C shown to reduce microglia activation in cultures,” he said, agreeing with Dr. Galland by adding that a variety of phytonutrients (flavonoids, gin senosides, curcuminoids, carotenoids, cate chins, stilbenes etc.) are being continuously investigated for their potential role in the prevention and management of neuroin- flammation.5 

Beyond diet, Dr. Ber offered that aerobic exercise has also been shown to be a powerful natural approach to fending off neu- roinflammation. “Exercise provides plethora of anti-aging benefits and has systemic immunomodulatory effect,” he said. “It has also been shown to have direct effect on microglial cells in mice. Specifically, it was able to attenuate the age-dependent increase in pro-inflammatory microglia activity.” 

Neuronutrients 

Dr. Galland offered several supplements with Anti-inflammatory effects that should be considered for patients with neuro inflammatory conditions. A great place to start would be omega-3s. “In clinical trails we’ve seen that EPA is most effective for mood, however DHA has a superior benefit for helping with circulation and perhaps for supporting neuro function itself. Personally, I like to use mixtures of both in supplementation,” he said.

Another supplement garnering great interest is curcumin, according to Dr. Galland, but that absorption is an important consideration. “Curcumin tends to get bound and inactivated rapidly in gastroin- testinal tract, so there’s a lot of work being done to enhance its bioavailability to tis- sues,” he said. “Curcumin does amazing things in test tube, yet its clinical perform- ance has been challenging, but promising— it shows promise as a neuroprotective inflammatory substance at a dosage that’s hard to achieve from food alone (2-4 g per day), so supplementation is a viable option.” 

Finally, Dr. Galland noted that vitamins C And E may also be helpful.

Carotech’s See agreed with Dr. Galland’s suggestions, adding that products containing natural full spectrum tocotrienol complex, such as his company’s Tocomin SupraBio (a natural vitamin E derived from non-GMO palm oil); omega-3 fatty acids (DHA) and curcumin have been recommended for brain health/neuroinflammation.

“One of the natural approaches to treatment is through supplementation, e.g. DHA and vitamin E (tocopherols and tocotrienols—lipid antioxidant). In general, these products address neuroinflammation through anti-inflammatory properties and by modulating the signaling pathway,” said See.

He pointed to recent studies completed at the Karolinska Institute in Sweden and Perugia University of Italy showing that high plasma levels of full spectrum vitamin E (alpha, beta, gamma and delta-tocotrienol; alpha, beta, gamma and delta-tocopherol) are associated with a reduced risk of AD in very old people6; and low plasma levels of full spectrum vitamin E is directly linked to increased risk of developing mild cognitive impairment (MCI) and AD.7 

Dr. Skowron said it has been his experience that natural treatments for brain chem- istry modification as well as the immune system are helpful for patients.

“We always suggest natural products with our patients, as we find these more curative, more beneficial, and with fewer side effects,” he explained. “We always perform genetic testing (MTHFR, COMT, MAO) to help patients balance their brain chemistry to improve symptoms.” Dr. Skowron and his associates will often prescribe methylfolate, activated B vitamins, GABA, 5-HTP, probi otics, fish oil and vitamin D, and offered a compelling study showing vitamin D modulating Parkinson’s and multiple sclerosis.8 

A Supplemental Approach 

Gerard McIntee, President of New York- based Patient One MediNutritionals, noted that neuronutrients have been extensively studied for the benefits they provide in cognitive function, including promoting sharper focus, improved memory, mental clarity and enhanced mood; protecting existing brain cells and promoting neurogenesis (the creation of new brain cells); creating brain energy; supporting neurotransmitter production; and supporting healthy cerebral circulation.

Patient One MediNutritionals offers four products in the cognitive support category.Its flagship brain health support formula, NeuroOne, is a multi-faceted “all-in-one” cognitive support formula packed with 11 Synergistic neu- ronutrients, four of which are trademarked or patented ingredi- ents that are extensively researched.

NeuroOne includes:

• Sharp PS phosphatidylserine, which sup- ports acetylcholine levels and neurotrans- mission of serotonin, norepinephrine, and dopamine; improves the way the brain uses glucose; promotes brain cellular energy and catalyzes neurotransmitter production;

• Sharp GPC glycerophosphatidylcholine, which rapidly boosts acetylcholine levels in the brain (acetylcholine is an essential neu- rotransmitter that effects alertness, memory and learning);

• BaCognize Bacopa monnieri, which regulates serotonin receptors, key for mem- ory, mood and focus;

• Ginkgo biloba and vinpocetine, which are antioxidant botanicals that act as vasodilators and improve cerebral blood flow and cerebral oxygenation;

• Omega-3 fish oil, which raises levels of brain-derived naturo- pathic growth factor- protects neurons, improves neurotrans- mission and supports brain structure; and

• Botanical Neuro Complex, comprised of resveratrol, quercetin, ginger, grapeseed extract, rosemary extract and Perluxan hops; it controls brain inflammation and neutral- izes brain oxidative stress.

“The highly pure, concentrated form of phosphatidylserine (Sharp PS) supplied in our formula enables us to include a high potency of this important neuronutrient with room to include 10 additional ingredients within a small serving size. This sets us apart when compared to other cognitive support formulas in the marketplace,” said McIntee, who noted that the U.S. Food and Drug Administration (FDA) has supplied an approved health claim for PS.

Vital Nutrients’ comprehensive brain health product, Vital Brain Powder, also utilizes PS and GPC, in addition to acetyl L-carnitine, which crosses the blood-brain barrier and may aid production of the neu- rotransmitter acetylcholine and improve mild memory impairment, according to Dr. Baldwin-Lien. “Preliminary studies have shown GPC to benefit cognitive func- tion in Alzheimer’s patients, and both cognitive function and behavior in vascular dementia and stroke victims, particularly when started within 10 days post-stroke,” she said. “And PS has demonstrated benefits for memory, learning, concentration, word choice, mood and stress tolerance.” 

In addition, the company offers a number of products that can help support brain health, circulation, normal inflammation and neurotrans- mitter levels, and memory, including its UltraPure Fish Oil products, Ginkgo Extract 24%/6% 80 mg and its Melatonin 5, 10 and 20 mg.

Conclusion 

According to Dr. Galland, the foundation for Trying to deal with neuroin- flammation from a natural perspective is diet and lifestyle.Once those important pieces are in place, basic supplementation is a fundamental step. But beyond that, anything else would be investigational, which is really to the heart of what integrative practitioners do.

“As natural practitioners, what we’re doing is investigational with every patient. You have a foundation to try and establish a health- promoting situation, and if that’s not enough to heal completely, you investigate additional treatments may impact, such as avoiding certain foods like gluten, which is a major culprit in neuroinflammation,” he said, adding that gluten sensitivity and its affect on the brain has been extensively researched.

“It’s important to understand inflammation as a product of a chain of events,” concluded Dr. Galland. “Anything you can do to Relieve by working upstream of inflammation is more effective than dealing with inflammation itself.” 

References: 

1 Carnevale D, Mascio G, Ajmone-Cat MA, et al.Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiology of Aging. 2012;33(1):205.e219-205.e229.

2 Terrando N, Brzezinski M, Degos V, et al.Perioperative cognitive decline in the aging population.Mayo Clinic proceedings. Mayo Clinic. Sep 2011; 86(9):885-893.

3 Kohman RA. Aging microglia: relevance to cogni- tion and neural plasticity. Methods Mol Biol. 2012; 934:193-218.

4 Gorelick PB. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann N Y Acad Sci. Oct 2010;1207:155-162.

5 Choi DK, Koppula S, Suk K. Inhibitors of microglial neurotoxicity: focus on natural products. Molecules.2011;16(2):1021-1043.

6 Mangialasche F, et al. “High Plasma Levels of Vitamin E Forms and Reduced Alzheimer’s Disease Risk in Advanced Age.” J Alzheimers Dis. 20, no. 4 (2010): 1029-37.

7 Mangialasche F, et al. “Tocopherols and tocotrienols plasma levels are associated with cogni- tive impairment.” Neurobiology of Aging. 33 (2012): 2282-2290.

8 Magrone T, Marzulli G, Jirillo E. Immunopathogenesis of neurodegenerative diseases.Curr Pharm Des. 2012;18(1):34-42.

Preventative Repurposing

Protocol For Life Balance’s Dr. Ber emphasized the importance of developing more advanced therapies and supplements addressing neu- roinflammation. However, he noted that there is an issue as the exact mechanisms behind neuroinflammation are not fully understood. “Therefore, it is too early to settle on which dietary interventions are the most promising. We suspect there will be a lot of ‘repurposing’ of natural ingredients already known for their anti-inflammatory effect,” he said, adding that special attention will be paid to the kinetics of natural compounds, including their absorption, distribution and particularly the ability to cross the blood- brain barrier.

Protocol offers a combination pterostil- bene and resveratrol product, two anti- inflammatory ingredients shown to support a healthy cardiovascular system as well as beneficial for anti-aging.

“A combination of two stilbenes, transResveratrol and its naturally occurring methoxylated form, trans-pterostilbene, may become a viable intervention for addressing neuroinflammation in clinical practice. These phytonutrients are typically found in the diet in limited amounts,” said Dr. Ber.

In the in-vitro neuroinflammation model, resveratrol has been shown to significantly attenuate microglia activation and dramatically inhibit the subsequent synthesis and release of pro inflammatory mediators (IL-1ß, TNF-a) through the nuclear factor KB pathway.1 The results of this and similar studies indicate that stilbenes may play a critical role in the management of neuroinflammation in the central nervous system, said Dr. Ber. “Although in-vitro only studies are not sufficient to estimate the full therapeutic potential of phytonutrients, it is important to consider that resveratrol (and pterostil- bene), unlike some of the hypothetically beneficial phytonutrients, are able to cross the blood-brain barrier following oral administration.2 And, finally, because the overall bioavailability is important for delivering meaningful amount of phytonu- trients, absorption of pterostilebene, a methoxylated form of resveratrol, reaches a very substantial 80 percent level.3 

“Taken together, these findings suggest that the mixture of resveratrol and pteros- tilbene could become one of the most promising combinations for targeted microglia-mediated neuroinflammation,” concluded Dr. Ber, noting that further research is warranted.

References: 

1 Bi XL, Yang JY, Dong YX, et al. Resveratrol inhibits nitric oxide and TNFa· production by lipopolysaccharide-activated microglia. International Immunopharmacology. 2005;5(1):185-193.

2 Lin S-P, Chu P-M, Tsai S-Y, Wu M-H, Hou Y-C.Pharmacokinetics and tissue distribution of resvera- trol, emodin and their metabolites after intake of Polygonum cuspidatum in rats. Journal of Ethnopharmacology. 2012;144(3):671-676.

3 Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavail- ability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. Sep 2011;68(3):593-601.

Healthy Take Aways

Alzheimer’s disease is the most prevalent neurodegenerative condition, with one in six people over the age of 65 being affected in the U.S. 

Inflammation in blood vessels feeding the brain would impair blood flow, which produces symptoms that are the result of a lack of oxygen and nourishment.

Diet and inflammation are integrally linked, and this is no different when it comes to the brain. Exercise has also been shown to have direct effect on microglial cells.

Omega-3s, curcumin, phytonutrients and vitamins E and D are clinically proven nutrients for brain health.

FOR MORE INFORMATION:

Carotech Inc., (732)-906-1901, www.carotech.net 

Patient One MediNutritionals Research LLC, (631) -390-9669, www.patientoneformulas.com 

Protocol For Life Balance, (630) 545-9098, www.protocolforlife.com 

Vital Nutrients, (888)-328-9992, www.vitalnutrients.net