Neuroinflammation is swelling in the brain. It’s bad news. Swelling occurs in many neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease. Alternatively, diseases such as hypertension or diabetes lead to stroke, which in turn triggers neuroinflammation. Or bad luck strikes and someone suffers a traumatic brain injury, which leads to neuroinflammation. Neuroinflammation is a common issue in various brain conditions. Consequently, neuroinflammation affects millions of people every year.
Not surprisingly, chronic brain swelling causes many problems. Swelling may not be the primary cause of the condition, but it exacerbates the disease’s effects. Remarkably, there is a common thread of gut-brain inflammation that features in neurodegenerative diseases, traumatic brain injury, and stroke. It’s revealing that despite these conditions having such differing pathologies, all share the feature of gut-brain involvement. This speaks to the deep connection between brain disease and the gut’s microbiome.
Neurodegenerantive Diseases & Neuroinflammation
For instance, it appears that Parkinson’s disease either starts in the olfactory bulb in the brain or in the gut. The evidence for a gut-brain connection in Parkinson’s disease is strong. The vagal nerve transmits a gastrointestinal signal for swelling to the brain, where it causes neuroinflammation and worsens the symptoms of the disease. Likewise, there is evidence that inflammation spreads from the gut to the brain in Alzheimer’s disease. Misfolded proteins play a role in many neurodegenerative diseases and cause neuroinflammation.
Elsewhere, I have discussed proteostasis, the body’s production and degradation of proteins. It’s fascinating and covers the protein physiology that underlies misfolded proteins. Furthermore, that post helps to understand some of the concepts in this discussion. This post uses some long words that may be unfamiliar. Don’t worry, they’re mostly just the names of chemicals. I discuss remarkable processes in the brain and body. While the discussion is technical, it’s easy to understand.
Stroke & Neuroinflammation
Gut microbiota imbalances contribute to the occurrence and progression of ischaemic stroke. Of importance ischaemic stroke affects gut microbial composition, which influences recovery and outcome. Experimental and clinical studies have demonstrated that the restoration of a healthy gut microbiome improves stroke treatment outcomes. Specific changes in the composition of gut microbiota follow a stroke, and normalisation improves outcome.
TBI & Neuroinflammation
In addition, and remarkably, it turns out gut-brain changes arise after traumatic brain injury (TBI) and lead to neuroinflammation. Furthermore, and of great concern these gut-brain alterations undermine the recovery process. In particular, gut dysbiosis after TBI impairs neurogenesis in the hippocampi. That means the process of creating new nerves no longer works like it should. Moreover, this failure is happening in structures (the hippocampi) that are crucial to learning and memory. In addition, we have learnt that even mild TBI triggers transient gut dysbiosis, which can contribute to neuroinflammation.
In what follows, I’ll discuss neuroinflammation and what to do about it. If you, or someone you know, has a brain condition, you’ll find pertinent and interesting information. You’ll find guidance on practical daily life steps to take to reduce cerebral inflammation. Although the focus of the discussion is on natural treatments for brain swelling, for completeness I also briefly cover mainstream pharmacological treatments.
Current Research and Therapeutics for Neuroinflammation
A frequent cause of neuroinflammation is when proteostasis goes wrong and brain proteins become misfolded. Proteostasis is our body’s way of maintaining the integrity of all our proteins. Unfortunately, as we age, our capacity to maintain proteostasis deteriorates. Additionally, exposure to environmental toxins, like pesticides and pollution, compromises proteins. Moreover, production errors start to creep in. Protein misfolding occurs during protein synthesis. It figures that misshapen proteins don’t function well. When misfolding happens, that’s when we get ill.
The exciting part is that we can mitigate the effects of neuroinflammation. In particular, we need to promote the clearance of toxic protein aggregates and reduce associated neuroinflammation. That’s the trick!
Addressing Mitochondrial Dysfunction from Misfolded Proteins and Neuroinflammation
Reduce Oxidative Stress
Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Misfolded proteins often accumulate in mitochondria, impairing their function and leading to oxidative stress and energy deficits. We could use antioxidants, of which there are some great natural alternatives. Likewise, we could use PPAR-gamma coactivator 1-alpha (PGC-1α) activators to boost mitochondrial biogenesis. Hah! Now that’s an interesting option! Best of all the activators are all 100% natural. You’ll have to talk to me and I’ll explain. (Yep, not everything in life is free.)
Reducing Neuroinflammation from Misfolded Proteins
Misfolded proteins often activate microglia and astrocytes, leading to chronic inflammation and neuronal damage. To reduce inflammatiion you could try using standard anti-inflammatory drugs (NSAIDs, colchicine). However, research indicates mixed results in neurodegenerative diseases.
Better still, you could use resolvins, the wonderful specialised proresolving mediators Ormond Neuroscience supplies. Those amazing supplements flip a biochemical switch that stops or dramatically reduces inflammation. This is a powerful and direct method of dealing with neuroinflammation. Best of all, these are derivatives of good old omega-3. Unfortunately, doubling your omega-3 dose will not have the same effect! (But nice try for thinking that way 😁.) Nonetheless, there are many benefits of omega-3 in this context. Read on for more information below.
Dietary Approaches to Neuroinflammation & Restoring Proteostasis
Ketogenic Diet
A ketogenic diet shifts metabolism from glucose to ketones, reducing oxidative stress and improving mitochondrial function. Evidence suggests benefits in Alzheimer’s and Parkinson’s disease by enhancing autophagy and reducing inflammation.
Misfolded Proteins & Fasting
Fasting and caloric restriction promotes autophagy, which helps to clear misfolded proteins. Also, fasting reduces inflammatory cytokines, enhancing cellular resilience.
Mediterranean Diet
The Mediterranean Diet includes omega-3 rich foods and foods high in polyphenols.
Omega-3 & Neuroinflammation
Found in fish oil, omega-3s are anti-inflammatory and support neuronal membrane integrity. These properties may reduce susceptibility to protein aggregation and related neuroinflammation.
Neuroinflammation & Polyphenols
Foods rich in polyphenols (e.g., green tea, berries, turmeric) possess anti-inflammatory, antioxidant, and autophagy-boosting properties. Although green tea is not usually seen as a component of the Mediterranean diet, it is a good complement to the diet. Green tea contains epigallocatechin gallate (EGCG), a polyphenol that modulates protein folding and reduces inflammation.
Diet, Neuroinflammation & Parkinson’s Disease
Intriguingly, adherence to a Mediterranean diet is related to reduced probability of prodromal (early) Parkinson’s disease. Amazingly, this research showed that people who had the greatest adherence to a Mediterranean diet had an approximately 21% lower risk of developing Parkinson’s disease.
Lowering Neuroinflammation with Probiotics
Probiotics help to reduce neuroinflammation. The relationship between the gut microbiome and neuroinflammation is complex. For instance, inflammatory bowel disease increases the risk of Parkinson’s disease. Consistent with that finding, clinical studies have shown that supplementation with certain probiotics in Parkinson’s patients not only helps alleviate gastrointestinal symptoms (e.g., constipation) but also modulates systemic inflammation, including neuroinflammation.
Supplements to Reduce Misfolded Proteins
Additionally, supplements play a vital role in the control of neuroinflammation. Nutraceuticals that enhance proteostasis and reduce brain swelling include:
- Curcumin: Reduces beta-amyloid aggregation and inflammation.
- Sulforaphane: Upregulates antioxidant and chaperone systems.
- Vitamin D. An immune modulator that reduces neuroinflammation.
- Phosphatidylserine (PS) can indirectly enhance proteostasis. PS is a phospholipid that plays a crucial role in cell membrane structure and function, and it also influences protein trafficking and signaling pathways.
Reducing Protein Production
This is the “throw the baby out with the bathwater” method of reducing neuroinflammation. We nuke the bad guys but in the process we might also nuke the good guys. The prime exemplar is gene silencing therapy using antisense oligonucleotides (ASOs). ASOs are are short, synthetic, single-stranded DNA or RNA sequences that can alter RNA and reduce or modify protein expression.
Tweaking ASOs can prevent or alter protein production. So, for instance, ASOs can target mutant huntingtin in Huntington’s disease. However, doing so may have the unintended effect of also damaging the wild-type (healthy) huntingtin gene. Since huntingtin plays an important role in neuronal function, reducing healthy huntingtin could cause neurological damage.
Animal studies and initial human studies in early-stage Huntington’s patients showed that the reduction in the huntingtin gene correlated with improvements in some biomarkers. However, larger studies into safety and efficacy in human patients did not demonstrate significant clinical benefit. Longer-term follow-up research is ongoing.
In other words, to date, reducing protein production has not proved to be a successful treatment for misfolded proteins that drive neuroinflammation.
Enhancing Protein Clearance to Reduce Neuroinflammation
Passive Immunotherapy
Intense research led to the development of monoclonal antibodies (aducanumab and lecanemab) to help clear misfolded Aβ (beta amyloid) from the brains of Alzheimer’s patients. The FDA has approved both drugs. Astonishingly, the drugs caused the death of three people during the drug trials. The drugs cause micro-haemorrhaging and swelling in the brain. Aside from these alarming side effects, they are so prohibitively expensive that only the super-rich can afford them. At least in my opinion, these drugs are not a viable way of dealing with neuroinflammation and Aβ because of the side effects and cost. All the more so because there are natural methods that help to clear Aβ and which come with no side effects.
Active Immunotherapy
Vaccines to stimulate immune responses against misfolded proteins are an option. Additionally, such vaccines would reduce neuroinflammation. A vaccine for use in Parkinson’s disease (PD) and multiple system atrophy (MSA) is under development and early trials show very encouraging results. The drug does not even have a name yet, and goes by the moniker of UB-312. Its mechanism of action is to induce antibodies that bind to alpha-synuclein.
In animal models of PD, immunisation with UB-312 reduced the accumulation of alpha-synuclein in the brain and in the gut and prevented a decline in motor function. In a phase 1 trial of 20 human PD patients, antibodies to alpha-synuclein were developed within eight weeks of vaccination. Although we don’t yet know the full clinical benefits of UB-312, the presence of antibodies implies the likelihood of reduced levels of alpha-synuclein. At this stage, researchers are still investigating safety but so far it looks promising. I want to stress that these are very early findings and we are a long way from having anything ready for clinical use.
Chaperone-based Strategies:
Small molecules like arimoclomol (brand name Miplyffa) enhance molecular chaperones (Hsp70, Hsp90), improving refolding or promoting clearance of damaged neurons via autophagy. This is a mainstream pharmacological way of damping neuroinflammation.
Modulating Autophagy and Proteasome Pathways
Additionally, we could try boosting cellular clearance mechanisms. For instance, we could use mTOR inhibitors like rapamycin to enhance autophagy. That could increase lysosomal degradation of misfolded proteins. We could try proteasome enhancers. Although these are great ideas, they are largely theoretical. We need more research.
Stabilizing Protein Structures
We could use small molecules as chemical chaperones to stabilize native protein conformations and reduce misfolding. For instance, 4-phenylbutyrate (PBA) is a naturally occurring fatty acid derivative that has a number of potential therapeutic uses. For example, PBA can reduce the load of mutant or mislocated proteins in the endoplasmic reticulum (ER) in cystic fibrosis.
However, I’m only aware of animal research with PBA in the group of brain diseases we’re discussing here. There is a human trial underway currently looking at Parkinson’s patients but we await those results.
Conclusion: Reducing Neuroinflammation
Neuroinflammation is a major problem in many brain-related conditions. Moreover, it is a common denominator in diverse neurological diseases. Although the initial inflammatory response is helpful and is neuroprotective, persistent neuroinflammation becomes a problem. Chronic inflammation induces an inflammatory cascade in the brain that triggers neurodegeneration.
It follows that for anyone with a brain-related illness, neuroinflammation is an issue, and its control is crucial. As we have seen, conventional methods have limited effectiveness or come at an enormous cost, both financially and in terms of adverse side effects. It’s smart to look beyond conventional medicine to control neuroinflammation. Dietary changes, supplements, resolvins, probiotics and other natural interventions that restore a healthy microbiome are key to long-term management.
