Written by Dr. John Saman, MD & Christina Frank, BSc, CE

Inflammation is the body’s response to negative environmental stimuli. Its purpose is to eliminate the aggressor agent and to restore tissue physiology. However, when inflammation without resolution is present (ie, chronic inflammation), we know that it has deleterious effects on surrounding tissues. Chronic inflammation in the CNS (neuroinflammation) can be particularly damaging.

What is neuroinflammation?

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord that can be initiated by a variety of harmful stimuli, such as infection, disease, trauma, toxins, or stress. This complex biological response involves the activation of resident immune cells and the production of cytokines, chemokines, reactive oxygen and nitrogen species, and secondary messengers.

woman on couch laying down and holding head

Neuroinflammation could be at the root of brain-related symptoms.

How does neuroinflammation damage the brain?

Neuroinflammatory processes are believed to play a critical role in pathways leading to neuronal death in neurodegenerative diseases. (1)(2) In the brain, microglia—a type of glial cell—are key players of the immune response, which is intimately linked to inflammation. As the resident immune cells, microglia, monitor the microenvironment for insults (eg, toxins, pathogens, injury, damaged or unnecessary neurons, etc.), and they are critical to overall brain maintenance. For instance, they remove dead neurons, plaques, and other cellular debris that may get in the way of neuronal signal transmission. (3) However, microglia exert dual roles: they act as both guardians of brain homeostasis and as instigators of damage. (4)

How do microglia instigate damage? Through overactivation. Microglia are said to be in a steady state or in an active state. When microglia become activated or “primed,” they become inflammatory. (3)

Persistent microglial activation and the production of neurotoxic mediators, such as cytokines (eg, IL-1β, IL-6, and TNF-α), not only propels further microglial activation and proliferation but also propagates nitrosative and oxidative stress that may negatively impact neuronal mitochondria and blood-brain barrier (BBB) permeability. (2)(5)(6)(7) Not only can this neuroinflammatory process slow nerve transmission speed and reduce nerve conductivity, but also a vicious cycle develops within the brain that can ultimately result in neuronal death. (8)

Persistent microglial activation

Aside from a traumatic injury to the brain, direct triggers of microglial cells may include toxic metabolites, microbes, lipopolysaccharide (LPS), any neurotoxic substance (pollutants, heavy metals, drugs, etc.), aging, vascular occlusion, ischemia, cell death, and inflammatory cytokines. (9)(10)(11)

Blood-brain barrier compromise

Loss of BBB integrity serves as a major promoter of microglial activation. Loss of BBB integrity may occur with alcohol exposure, stress responses, elevated homocysteine, hyperglycemia, prostaglandin imbalances, and oxidative stress. (12)(13)(14)(15)(16)(17) These factors may lead to the infiltration by environmental compounds, dietary proteins, or pathogenic organisms, which expose themselves to microglia and activate a neuroinflammatory response.

Systemic inflammation

Peripheral or systemic inflammation also contributes to brain inflammation and cognitive dysfunction through the production of cytokine messages. (18)(19)(20) Decreasing exposure to inflammatory stimuli may be an important first step for functional medicine practitioners. Such stimuli may include the Western diet, gluten, obesity, dysbiosis, environmental toxins, psychosocial stress, excessive alcohol consumption, and poor sleep quality. (2)(21)(22)(23)(24)(25)(26)(27)(28)(29)

Natural neuroinflammation interventions

Due to the side effects associated with pharmaceutical treatments for inflammation and its awareness in a more educated public, more and more patients are seeking out natural solutions. Historical practices and modern science point to a number of natural interventions to dampen inflammatory processes and improve the brain microenvironment, including vagus nerve exercises, dietary and lifestyle modifications, and dietary supplementation.

Vagus nerve exercises

As the prime component of the parasympathetic nervous system, the vagus nerve is the longest of the cranial nerves. It extends from the brainstem and through the abdomen by way of multiple organs. It is the sensory network that tells the brain what’s going on in the organs, and it regulates the homeostasis of the “resting” state—opposite the “fight or flight” state.

There is an “inflammatory reflex” transmitted in the vagus nerve that inhibits the production of TNF-alpha and other cytokines via cholinergic anti-inflammatory pathways. (30) Electrical stimulation of the vagus nerve has been shown to reduce inflammatory cytokine production (eg, TNF-alpha) and attenuate disease severity in experimental models and in patients with rheumatoid arthritis. (30)(31)(32)

man sitting in a yoga position

Deep breathing promotes vagal tone.

Engaging the vagus nerve, and thereby improving “vagal tone,” is a method that functional medicine practitioners can suggest to their patients to help reduce chronic inflammation. Non-device methods that some practitioners suggest to increase vagal tone include slow diaphragmatic breathing (as done in yoga and meditation), gargling with water, or singing loudly. (8)(33)

Lifestyle and dietary improvements for neuroinflammation

Being fit and active; getting quality sleep; making healthy, organic food choices; avoiding cross-reactive dietary proteins, like gluten; and reducing stress and exposure to toxins all help reduce the potential for triggering inflammatory processes in the brain. (34)(35)(36)(37)(38)(39)(40) Additionally, there are various nutraceuticals that help reduce inflammation.

Neuroinflammation: supplementation considerations

Animal research suggests that some nutraceutical ingredients are able to cross the BBB and exert their effects directly in brain tissue or positively influence BBB integrity. These include the following:

Other nutritional compounds, such as alpha lipoic acid (45) and ginger, (46) help reduce systemic inflammation and the circulation of inflammatory cytokines that may contribute to neuroinflammatory processes. When supplementing to address neuroinflammation, considering the totality of mechanisms at work is critical.

Neuroinflammation is a key concept discussed in Mastering Brain Chemistry, a three-day seminar developed and written by Datis Kharrazian, PhD, DHSc, DC, MS, MMSc, FACN. This seminar is designed to review the key concepts of brain chemistry and to help clinicians recognize patterns of imbalances and improve overall clinical competency in the neurochemical assessment. Consider attending this seminar for a deep understanding of neuroinflammatory processes and how to address them as well as many other areas of brain chemistry that affect mental and neurological health.

The bottom line

Emerging research continues to validate the roles of glial activation and neuroinflammation as major contributors to the pathophysiology of neurodegeneration. Recognizing the earliest signs of neuroinflammation, such as brain fog, depression, low brain endurance (mental fatigue), or food intolerances, and acting sooner rather than later may be the key to dampening and, in some cases, reversing the damage. (3)(8)

Fullscript simplifies supplement dispensing.

Create your dispensary today I'm a patient

All information, data, and material contained, presented, or provided is for general information purposes only and is solely the opinion of the author. The information presented is not a claim regarding any product or its ingredients.

This content was contributed by Apex Energetics

  1. Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases. Curr Med Chem. 2007;14(11):1189-97.
  2. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases. Mol Med Rep. 2016;13(4):3391-96.
  3. Kharrazian D. Lecture presented: Neuroinflammation Clinical Strategies and Treatment Applications at Kharrazian Institute hosted by Hilton Garden Inn. May 18-19, 2019; Carlsbad, CA.
  4. Amor S, Peferoen LAN, Vogel DYS, et al. Inflammation in neurodegenerative diseases – an update. Immunology. 2014;142(2):151-66.
  5. Hong H, Kim BS, Im HI. Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders. Int Neurourol J. 2016 May;20(Suppl 1):S2-7.
  6. Leszek J, Barreto GE, Gąsiorowski K, Koutsouraki E, Ávila–Rodrigues M, Aliev G. Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Disord Drug Targets. 2016;15(3):329-36.
  7. Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P. Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimers Dis. 2010;20 Suppl 2:S369-79.
  8. Kharrazian D. Lecture presented: Mastering Brain Chemistry. October 19, 2012; San Diego, CA.
  9. Pogue AI, Lukiw WJ. Natural and synthetic neurotoxins in our environment: from Alzheimer’s disease (AD) to autism spectrum disorder (ASD). J Alzheimers Dis Parkinsonism. 2016;6(4):249.
  10. Harris JB, Blain PG. Neurotoxicology: what the neurologist needs to know. J Neurol Neurosurg Psychiatry. 2004;75:iii29-iii34.
  11. Kharrazian D. Why Isn’t My Brain Working? A Revolutionary Understanding of Brain Decline and Effective Strategies to Recover Your Brain’s Health. 1st ed. Carlsbad, CA.: Elephant Press; 2013.
  12. Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y. Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J Leukoc Biol. 2005 Dec;78(6):1223-32.
  13. Xu G, Li Y, Ma C, et al. Restraint stress induced hyperpermeability and damage of the blood-brain barrier in the amygdala of adult rats. Front Mol Neurosci. 2019 Feb 13;12:32.
  14. Beard RS Jr, Reynolds JJ, Bearden SE. Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood. 2011;118(7):2007-14.
  15. Kamada H, Yu F, Nito C, Chan PH. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke. 2007 Mar;38(3):1044-49.
  16. Candelario-Jalil E, Taheri S, Yang Y, et al. Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther. 2007 Nov;323(2):488-98.
  17. Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y. Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J Neurochem. 2007 Apr;101(2):566-76.
  18. Sankowski R, Mader S, Valdés-Ferrer SI. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 2015;9:28.
  19. Huang C, Irwin MG, Wong GTC, Chang RCC. Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model. J Neuroinflammation. 2018 May 17;15(1):147.
  20. Skelly DT, Hennessy E, Dansereau MA, Cunningham C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, [corrected] TNF-α and IL-6 challenges in C57BL/6 mice. PLoS One. 2013 Jul 1;8(7):e69123.
  21. Graham LC, Harder JM, Soto I, de Vries WN, John SW, Howell GR. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease. Sci Rep. 2016 Feb 18;6:21568.
  22. Daulatzai MA. Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut–brain axis dysfunction, and vulnerability for dementia. CNS Neurol Disord Drug Targets. 2015;14(1):110-31.
  23. Miller AA, Spencer SJ. Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun. 2014 Nov;42:10-21.
  24. Daulatzai MA. Obesity and gut’s dysbiosis promote neuroinflammation, cognitive impairment, and vulnerability to Alzheimer’s disease: new directions and therapeutic implications. J Mol Genet Med. 2014;S1:005.
  25. Jayaraj RL, Rodriguez EA, Wang Y, Block ML. Outdoor ambient air pollution and neurodegenerative diseases: the neuroinflammation hypothesis. Curr Environ Health Rep. 2017 Jun;4(2):166-79.
  26. Calderón-Garciduenas L, Leray E, Heydarpour P, Torres–Jardón R, Reis J. Air pollution, a rising environmental risk factor for cognition, neuroinflammation and neurodegeneration: The clinical impact on children and beyond. Rev Neurol (Paris). 2016 Jan;172(1):69-80.
  27. Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology. 2016;233:1637-50.
  28. Wang HJ, Zakhari S, Jung MK. Alcohol, inflammation, and gut–liver–brain interactions in tissue damage and disease development. WJG. 2010;16(11):1304-13.
  29. Zhu B, Dong Y, Xu Z, Gompf HS, Ward SA, Xue Z, et al. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis. 2012 Dec;48(3):348-55.
  30. Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci. U.S.A. 2016;113(29):8284-89.
  31. Meregnani J, Clarençon D, Vivier M, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 2011 Feb 24;160(1-2):82-89.
  32. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62.
  33. Wang SZ, Li S, Xu XY, et al. Effect of slow abdominal breathing combined with biofeedback on blood pressure and heart rate variability in prehypertension. J Altern Complement Med. 2010 Oct;16(10):1039-45.
  34. Dimitrov S, Hulteng E, Hong S. Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β(2)-adrenergic activation. Brain Behav Immun. 2017 Mar;61:60-68.
  35. Forsythe LK, Wallace JM, Livingstone MB. Obesity and inflammation: the effects
    of weight loss. Nutr Res Rev. 2008 Dec;21(2):117-33.
  36. Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80(1):40-52.
  37. Pandey A, Dhabade P, Kumarasamy A. Inflammatory effects of subacute exposure of roundup in rat liver and adipose tissue. Dose Response. 2019;17(2):1559325819843380.
  38. Daulatzai MA. Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia. CNS Neurol Disord Drug Targets. 2015;14(1):110-31.
  39. Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316.
  40. Block ML, Calderón-Garcidueñas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32(9):506-16.
  41. Patrick RP. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease. FASEB J. 2019;33(2):1554-64.
  42. Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer’s disease: An overview. Ann Indian Acad Neurol. 2008;11(1):13-19.
  43. Andrade S, Ramalho MJ, Pereira MDC, Loureiro JA. Resveratrol Brain Delivery for Neurological Disorders Prevention and Treatment. Front Pharmacol. 2018;9:1261.
  44. Shal B, Ding W, Ali H, Kim YS, Khan S. Anti-neuroinflammatory potential of natural products in attenuation of alzheimer’s disease. Front Pharmacol. 2018;9:548.
  45. Akbari M, Ostadmohammadi V, Tabrizi R, et al. The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Nutr Metab (Lond). 2018;15:39.
  46. Mashhadi NS, Ghiasvand R, Askari G, Hariri M, Darvishi L, Mofid MR. Anti-oxidative and anti-inflammatory effects of ginger in health and physical activity: review of current evidence. Int J Prev Med. 2013;4(Suppl 1):S36-S42.