Today’s post highlights a paper with some very concise insights into how microglial cells become “activated” resulting in the “exaggerated inflammatory response” that many people with autism experience on a daily basis.
This is very relevant to treatment, which is not usually the objective of much autism research.
I recall reading a comment from John’s Hopkins about neuroinflammation/activated microglia in autism; they commented that no known therapy currently exists and that, of course, common NSAIDs like ibuprofen will not be effective. But NSAIDs are effective.
As we see in today’s paper, there a least 4 indirect cytokine-dependent pathways leading to the microglia, plus one direct one.
NSAIDs most definitely can reduce cytokine signaling and thus, indirectly, reduce microglial activation.
The ideal therapy would act directly at the microglia, and as Johns Hopkins pointed out, that does not yet exist with today's drugs. If you read the research on various natural flavonoids you will see that “in vitro” there are known substances with anti-neuroinflammatory effects on microglial activation. The recurring “problem” with such substances is low bioavailability and inability to cross the blood brain barrier.
Back to Today’s Paper
It was a conference paper at the 114th Abbott Nutrition Research Conference - Cognition and Nutrition
The paper is not about autism, it is about more general cognitive dysfunction. It is from mainstream science (I checked).
It explains how inflammation anywhere in the body can be translated across the BBB (Blood Brain Barrier) to activate the microglia. This of course allows you to think of ways to counter these mechanisms.
It also raises the issue of whether or not anti-inflammatory agents really need to cross the BBB. While you might think that ability to cross the BBB is a perquisite to mitigate the activated microglia, this may not be the case. Much can be achieved outside the BBB, and we should not rule out substances that cannot cross the BBB.
Very many known anti-inflammatory substances do not cross the BBB.
From Inflammation to Sickness and Cognitive Dysfunction: When the Immune System Subjugates the Brain
extracts from the above paper ...
Example – Influenza and Cognition
Neurological and cognitive effects associated with influenza infection have been reported throughout history.
The simplest explanation for these neurocognitive effects is that influenza virus makes its way to the brain, where it is detected by neurons.
However, most influenza strains, including those responsible for pandemics, are considered non-neurotropic, neurological symptoms associated with influenza infection are not a result of direct viral invasion into the CNS.
Moreover, neurons do not have receptors to detect viruses (or other pathogens) directly.
Cells of the immune system do, however, as the immune system’s primary responsibility is to recognize infectious pathogens and contend with them. For example, sentinel immune cells such as monocytes and macrophages are equipped with toll-like receptors (TLR) that recognize unique molecules associated with groups of pathogens (i.e., pathogen-associated molecular patterns). Stimulation of TLRs that recognize viruses (TLR3 and TLR7) and bacteria (TLR4) on immune sentinel cells can have profound neurological and cognitive effects, suggesting the immune system conveys a message to the brain after detecting an infectious agent. This message is cytokine based.
Macrophages and monocytes produce inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor-α [TNF-α]) that facilitate communication between the periphery and brain.
Cytokine-dependent Pathways to the Brain
Several cytokine-dependent pathways that enable the peripheral immune system to transcend the blood-brain barrier have been dissected.
Inflammatory cytokines present in blood can be actively transported into the brain.
But there are also four indirect pathways:-
1. Cytokines produced in the periphery need not enter the brain to elicit neurocognitive changes. This is because inflammatory stimuli in the periphery can induce microglial cells to produce a similar repertoire of inflammatory cytokines. Thus, brain microglia recapitulates the message from the peripheral immune system.
2. in a second pathway, inflammatory cytokines in the periphery can bind receptors on blood-brain barrier endothelial cells and induce perivascular microglia or macrophages to express cytokines that are released into the brain
3. In a third pathway, cytokines in the periphery convey a message to the brain via the vagus nerve. After immune challenge, dendritic cells and macrophages that are closely associated with the abdominal vagus have been shown to express IL-1β protein; IL-1 binding sites have been identified in several regions of the vagus as well. When activated by cytokines, the vagus can activate specific neural pathways that are involved in neurocognitive behavior. However, activation of the vagus also stimulates microglia in the brain to produce cytokines via the central adrenergic system
4. A fourth pathway provides a slower immune-to-brain signaling mechanism based on volume transmission. In this method of immune-to-brain communication, production of IL-1β by the brain first occurs in the choroid plexus and circumventricular organs—brain areas devoid of an intact blood-brain barrier. The cytokines then slowly diffuse throughout the brain by volume transmission, along the way activating microglia, neurons, and neural pathways that induce sickness behavior and inhibit cognition.
Can Flavonoids Reduce Neuroinflammation and Inhibit Cognitive Aging?
Flavonoids are naturally occurring polyphenolic compounds present in plants. The major sources of flavonoids in the human diet include fruits, vegetables, tea, wine, and cocoa. Significant evidence has emerged to indicate that consuming a diet rich in flavonoids may inhibit or reverse cognitive aging
Flavonoids may improve cognition in the aged through a number of physiological mechanisms, including scavenging of reactive oxygen and nitrogen species and interactions with intracellular signaling pathways. Through these physiological mechanisms, flavonoids also impart an anti-inflammatory effect that may improve cognition. This seems likely for the flavone luteolin, which is most prominent in parsley, celery, and green peppers.
Whereas luteolin inhibits several transcription factors that mediate inflammatory genes (e.g., nuclear factor kappa B [NF-κB]and activator protein 1 [AP-1]), it is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces the expression of genes encoding antioxidant enzymes. A recent study of old healthy mice found improved learning and memory and reduced expression of inflammatory genes in the hippocampus when luteolin was included in the diet. Thus, dietary luteolin may improve cognitive function in the aged by reducing brain microglial cell activity.
Hence, the flavonoid luteolin is a naturally occurring immune modulator that may be effective in reducing inflammatory microglia in the senescent brain.
Conclusion
In light of the recent evidence suggesting microglial cells become dysregulated due to aging and cause neuroinflammation, which can disrupt neural structure and function, it is an interesting prospect to think dietary flavonoids and other bioactives can be used to constrain microglia. But how can flavonoids impart this anti-inflammatory effect? Although in vitro studies clearly indicate that several flavonoids can act directly on microglial cells to restrict the inflammatory response, results from in vivo studies thus far do not prove that dietary flavonoids access the brain to interact with microglia in a meaningful way. This is a complicated question to dissect because flavonoids reduce inflammation in the periphery and microglia seem to act like an “immunostat,” detecting and responding to signals emerging from immune-to-brain signaling pathways. Thus, whether dietary flavonoids enter the brain and impart an anti-inflammatory effect on microglia is an interesting question but one that is more theoretical than practical because what is most important is how the immunostat is adjusted, whether that is via a direct or indirect route. However, because flavonoids are detectable in the brain they most likely affect microglia both directly and by dampening immune-to-brain signaling.
Interesting Natural Substances
In no particular order, these are several very interesting flavonoids/carotenoids. In the lab, they all do some remarkable things.
In humans, they also do some interesting things; how helpful they might be in autism remains to be seen.
Being “natural” does not mean they are good for you and have no side-effects.
Some of the following are very widely used and so you can establish if there are issues with long term use. It also makes them accessible.
Quercetin (found in many fruits, numerous interesting effects)
and two Quercetin-related flavonoids:-
Kaempferol (widely used in traditional medicine)
Myricetin (has good and bad effects)
Lycopene (from tomatoes, potent anti-cancer, does not cross the BBB)
Luteolin(in many vegetables, like broccoli)
Apigenin (from chamomile, stimulates neurogenesis, PAM of GABAA, block NDMA receptors, antagonist of opioid receptors …)
Tangeretin (from tangerines, does cross the BBB, has potent effects in vitro)
Nobiletin (from tangerines)
Hesperidin (from tangerines)
Naringin (from Grapefruit, contraindicated with many prescription drugs)
Epicatechin/Catechin (the chocolate/cocoa flavonoids, do cross the BBB, well researched)
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