The Brain on Fire: More understanding of leaky blood-brain barrier and chronic neuro-inflammation and the potential connection to cancer protection and treatment
Reviewer: Paul Anderson, NMD
Title: The Brain on Fire: More understanding of leaky blood-brain barrier and chronic neuro-inflammation and the potential connection to cancer protection and treatment.
Reference: Lopez-Ramirez, M. A., Wu, D., Pryce, G., Simpson, J. E., et.al. MicroRNA-155 negatively affects blood– brain barrier function during neuroinflammation. FASEB J. 28, 2551–2565 (2014).
Design: Animal model proof of concept.
Before discussing the mechanics and relativity of this data to neurological symptoms I would like to describe the process I will use in this review: What is it? How does it work and cause disease? What else do we know about this? And most importantly; What can we do about it? I say this as the topic sounds so microscopic and arcane in nature, but as always what we will see is that natural medicine can profoundly impact this emerging cause of human pathology and suffering.
What is MicroRNA and how can it be so impactful in pathologies?
From the Abstract:
“Blood–brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE).”
In the last few years, I have reviewed other papers that place the majority of focus of pathologic triggering in neuro-inflammatory disorders on the inflamed and incompetent BBB. This lack of control due to BBB inflammation leads to a host of disorders including neurological autoimmunity, psycho-emotional disorders, infectious diseases and even depression. So the more we understand about the genesis of the inflamed or “leaky” BBB the more we can target its healing. The elucidation of the implication of microRNA activity in CNS and BBB dysfunction is yet another step in knowing exactly the cause we are supposed to treat.
What else do we know about miRNAs / miR-155?
In addition to inflammation and dysfunction of the BBB and CNS, miR-155 is known to be implicated globally in multiple immune system regulatory processes. The activity of miR-155, and miRNAs in general crosses over multiple immunological parameters including cancer control or stimulation1 and infectious disease2 as well as generally providing counter regulation over the immune system.
MicroRNAs are considered “non-coding” RNA which formerly were of unknown significance and even occasionally categorized as “junk” in the genome. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized and are showing themselves to be a deep well of potential in actual cell to cell regulatory function.
Examples form oncogenesis include the following: Inactivation of mismatch repair (MMR) is the “cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10– 40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer.”3 Overexpression of miR-155 significantly down-regulate core MMR proteins, inducing a mutator phenotype and MSI. This is a mechanism of miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
In infectious disease one highly studied pathogen, Mycobacteria, have been used to map out part of the effect MicroRNA have on immune function. “microRNA-155 (miR-155) plays an essential role in regulating the host immune response by post-transcriptionally repressing the expression of target genes. However, little is known regarding its activity in modulating autophagy, an important host defense mechanism against intracellular bacterial infection. Mycobacterial infection triggers the expression of miR-155, and the induction of miR-155 in turn activates autophagy by targeting Rheb, a negative regulator of autophagy. miR-155-promoted autophagy accelerates the maturation of the mycobacterial phagosome, thus decreasing the survival of intracellular mycobacteria in macrophages.”4
As these few papers show the activity of MicroRNA and miR-155 specifically have far reaching effect in many aspects of immune function.
How can we use this data to improve or enhance clinical interventions in integrative medicine?
I do get accused of “geeking out” over immunology, cytokine activity and all manner of minutia in medicine and that of course is true. It is certainly cool to know information like this but the crucial factor is what does this add to our knowledge and ability to effectively help people? This is an example of essentially one more data set (yes, delving deeply into immunology) providing evidence that natural therapies can affect the human system very deeply in either keeping or moving back toward balance and health-promoting chemistry and communication. For example, we have seen that many natural products can help rebalance TH-1/TH-2/TH-17 and other factors. The use of natural agents to help keep normal function in and restore normal function to miR-155 (thereby causing more robust health and immune function) is also studied. A summary below of known effectors of miR-155 follows. The major take home message to me is that in cases of CNS/BBB dysfunction, infectious illness and cancer, caring for the miR-155 portion of the immune system is crucial and can be aided with traditional natural products.
General nutritional cell regulators such as Vitamin D, Folate, Indoles, Polyphenols, Retinoids and the like are shown to promote balanced function of miR-155.5
Herbal medicines used the world over (although some are more common in Asia) which have been studied include Berberine, Curcumin, Camptothecin, Resveratrol, Ginsenoside, Luteolin, Isoflavones, Matrine, Aidi Injection, Ganoderma, Coptidisrhizoma, Mistletoe lectin-I and Honokiol.6 Specific Chinese formulas including Hedyotis diffusa plus Scutellaria barbata have been studied in miR-155 activity in bladder cancers as well.7
When one reads the list above it is of course a “who’s who” of mostly common natural therapies used in immune conditions including CNS inflammation and cancer. Some surprised me from the point of view of their being very common traditional naturopathic and or Asian medicine treatments – but then the surprise was not that they would work but that there are yet more scientific data supporting what we have done for centuries. This paper gave me a wonderful insight into additional ways to heal CNS/BBB dysfunction which is ubiquitous in the chronic disease patient population. In looking for the supporting references it led to many happy surprises in correlating those therapies with improving immune function in cancer and chronic infections.
1 Valeri et al. Modulation of mismatch repair and genomic stability by miR-155. PNAS. April 13, 2010. vol. 107. no. 15. 6985.
2 Wang J, Yang K, Zhou L, MinhaoWu, Wu Y, et al. (2013) MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb. PLoS Pathog 9(10): e1003697. doi:10.1371/journal.ppat.1003697.
3 Hui Ling, Muller Fabbri & George A. Calin. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nature Reviews Drug Discovery 12, 847–865 (2013) doi:10.1038/nrd4140.Published online 31 October 2013.
4 Wang J, Yang K, Zhou L, MinhaoWu, Wu Y, et al. (2013) MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb. PLoS Pathog 9(10): e1003697. doi:10.1371/journal.ppat.1003697.
5 ShahMS, DavidsonLA and Chapkin RS. (2012). Mechanistic insights into the role of micro RNAs in cancer: influence of nutrient crosstalk. Front.Gene. 3:305. doi:10.3389/fgene.2012.00305.
6 Ming Hong, Ning Wang, Hor Yue Tan, Sai-Wah Tsao and Yibin Feng. MicroRNAs and Chinese Medicinal Herbs: New Possibilities in Cancer Therapy. Cancers 2015, 7, 1643-1657; doi:10.3390/cancers7030855.
7 Li-Tao Pan, Yip Sheung, Wen-Peng Guo, Zhi-Bin Rong, and Zhi-Ming Cai. Hedyotis diffusa plus Scutellaria barbata Induce Bladder Cancer Cell Apoptosis by Inhibiting Akt Signaling Pathway through Downregulating miR-155 Expression. Evidence-Based Complementary and Alternative Medicine Volume 2016, Article ID 9174903.