May 21, 2019 Written by Dr. Thomas Wnorowski

The Blood Brain Barrier

For a long time, the blood-brain barrier—BBB—has been viewed as just a wall that separates the brain from outside agents and enemies.  But it’s more than that. It’s a mélange of physiological activity that integrates information from the outside with information from the inside so that specific cerebral pursuits may be engaged.  Prominent about the BBB is the presence of tight junctions. And you thought tight junctions were limited to your gut, eh? Lots of people do. These protein structures restrict the flow of molecules from the blood to the central nervous system (CNS).  In most parts of the body, nutrients squeeze between blood vessel endothelial cells (cells that lie flat and form a kind of pavement along the inner tube of a body cavity) to reach the organs they intend to feed. Not so the brain. There’s barely enough space even for water to pass through.

The BBB is not designed to keep everything out, but to escort specific substances in an orderly fashion to the CNS so the brain can acquire the glucose, electrolytes and amino acids it needs.  These materials are guided by protein transporters that chaperone nutrients to their assigned stations. An example is the Parkinson’s drug L-dopa, an amino acid that uses another large, neutral amino acid transporter type 1 to reach the brain, where it’s converted to dopamine.  (In case you’re interested, the type 1 transporter is named 4F2hc/LAT1). This transporter, though, can carry any material disguised by scientists as a legitimate fare, and trick the brain into absorbing it. Another example here, is the disguise of glutathione by masking it in a liposome to encase the anti-cancer drug doxorubicin, made from the Streptomyces peuceticus bacterium, allowing an enhanced dose of the medication to reach its target.  Other transporters of note include a glucose transporter called GLUT1, monocarboxylate transporters called MCT1 and 2, and ion transporters that carry essential elements to the brain.  Occasionally, there are errors in which heavy metals may be carried, resulting in neurotoxicity. It’s simple to figure that GLUT1 carries glucose, but not so easy to see that MCT1 and 2 carry lactate and ketones.

Gluten and the Blood Brain Barrier

Sometimes there are leaks in the barrier.  This hyper-permeability may allow harmful substances to enter the brain and cause inflammation that leads to cognitive problems and even mental illness.  Several factors contribute to “leaky brain” syndrome, including systemic inflammation, oxidative stress, infections, head trauma, excess alcohol use, leaky gut and environmental toxins, to name a few.  Household mold fits the last category. But there’s a sneaky molecule that we’d never think was involved in BBB upset…gluten. We all know about its relationship to celiac disease and gliadin sensitivity, but how did it get wrapped up with the BBB?   In 2000, a team of researchers at the U. of Maryland Medical School, led by Alessio Fasano, discovered a protein that modulates the permeability of tight junctions, called zonulin, a haptoglobin activated by gliadin, a protein component of the gluten common to wheat.  No matter what else it does, zonulin increases tight junction permeability. This is the only recognized physiological modulator of intercellular tight junctions (Fasano, 2012), having the potential to allow uncontrolled influx of dietary and microbial antigens, leading to the development and progression of chronic inflammatory disorders (Sturgeon, 2016). No one ever imagined that non-celiac gluten sensitivity would be the driver behind a type of psychosis that responds to the removal of gluten from the diet.  It’s been found that neuro-psychiatric disorders that include schizophrenia, autism and depression are associated with reactions to gluten (Lionetti, 2015). Unfortunately, the complete pathogenesis has not yet been elucidated, but it is established that gluten peptides cross the tight junctions in both the intestine and the BBB.  Diagnosis is complex, with many cases unresolved. Later study realized a mechanistic connection between the BBB and the intestinal epithelial barrier, where zonulin values are elevated in both instances of permeability. Especially in multiple sclerosis, zonulin increases levels of inflammatory interleukins and interferons, opening the tight junctions to additional assault (Rahman 2018).  

The Blood Brain Barrier Function

There are times when we want the BBB to be sufficiently permeable to accept substances that ameliorate physiological upsets as in the case of Alzheimer’s disease, one of the most feared pathologies of our time, particularly among those who carry the APOE-4 allele. It is accepted that APOE-4 carriers respond well to the DHA in fish, but not so well to supplemental DHA. If the difference be that fish carry the fatty acid as a phospholipid, then it makes sense to supply a supplement in the same fashion. Proposed by research from the U. of CA at San Francisco, free DHA is transported across the outer membrane leaflet of the BBB by passive diffusion, and DHA-PC combination crosses the inner leaflet by superfamily domain protein 2A, leading to the inference that APOE-4 carriers lack the capacity to carry the free molecule but not the phospholipid combination.  Doing so, then, provides the means to decrease risk of AD (Patrick, 2019). A few years prior to this, French scientists likewise appreciated that DHA is altered in the Alzheimer and Parkinson brains, noting that targeted intake of the fatty acid to the brain could compensate for these deficits (Hachem, 2016).  It seems that both pairs of tight junctions have more common attributes than originally thought.  While it was initially conjectural that mending the gut would also mend the brain, it has been shown that an intact BBB can be promised with a gut occupied by a sound microbiome.  In tests using mice free of a normal biome, a permeable and compromised BBB was seen. As soon as a normal microbiome was restored via fecal transplant, so was the BBB (Braniste, 2014). Protection of the BBB might be realized from the most mundane sources. Caffeine blocks disruption of the barrier by preventing extravasation of IgG and fibrinogen caused by a very-high-cholesterol diet (Chen, Apr 2008) and by the mere stabilization of the epithelium (Chen, Nov 2008).  By suppression of NF-kB, butyrate and valproic acids attenuate cerebral artery occlusion and subsequent brain edema (Zhifei, 2011) (Kim, 2007). Magnesium, a mineral involved in more than three hundred biochemical reactions in the body, supports mitochondria, protects against alcohol damage to the brain, and seriously reduces hyperpermeability of the BBB (Esen, 2005) (Kaya, 2004) (Euser, 2008).  Although DHA may be found as a separate supplement, it most conveniently is part of fish oil, all of which is not equal. That which is extracted by supercritical carbon dioxide, at very low temperatures, with deliberate fractioning, such as BodyBio’s Kirunal, is most efficacious because the integrity of the fatty acids is maintained, and its bioactivity enhanced.  In tests that induced local vertebral ischemia in lab animals, DHA diminishes BBB injury (Hong, 2015). Where matrix-metalloproteins contribute to the neuroinflammation of MS, n-3 fatty acids are able to decrease their levels and prevent the breakdown of basement membranes (Shinto, 2011).

The Blood Brain Barrier and the Brain

Because the brain has no pain receptors, nociception is not something we have to face. Therefore, for most people, the brain is ignored.   As time goes by and some aspects of life dwindle ever so slowly, we need to attend to the brain before it gets too tired to carry on. Counting on a jellyfish that glows in the dark when its chemistry mixes with calcium to throw a blue light is not a long-term fix.  Nor is it necessarily a quick one. Yes, too much calcium upsets the electrolyte balance required to send electrical signals through the body. When there are too many calcium ions causing a traffic jam, the signals are blunted, and memory deficits appear. Jellyfish juice helps to control that gridlock with its main ingredient, apoaequorin, which is a calcium-binding protein.  However, research from the Einstein College of Medicine in New York City, prefers a cholesterol-bound calmodulin complex to a cholesterol-free jellyfish protein as a supplement for memory maintenance (Morrill, 2017). Cholesterol is actually a memory augmentation (Mielke, 2005) (Elias, 2005) (van den Kommer, 2009). BodyBio PC provides the liposomal foundation for the carriage of nutrients to the BBB*. Butyric Acid in the form of butyrate supports healthy inflammation response while maintaining tight junctions.  BodyBio Balance Oil offers the ratio of omega-6 and omega-3 fats needed for membrane fluidity. And, it is always prudent to remember to engage your vagus nerve with breath. Try this: count inhalation to 5, hold briefly, and exhale to a count of 10 for a few minutes a day. 

References

Abdul Muneer PM, Alikunju S, Szlachetka AM, Haorah J.  Inhibitory effects of alcohol on glucose transport across the blood-brain barrier leads to neurodegeneration: preventive role of acetyl-L: -carnitine.

Psychopharmacology (Berl). 2011 Apr;214(3):707-18.

 

Banks WA.  Characteristics of compounds that cross the blood-brain barrier.  BMC Neurol. 2009 Jun 12;9 Suppl 1:S3.

 

Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, Korecka A, et al.  The gut microbiota influences blood-brain barrier permeability in mice.  Sci Transl Med. 2014 Nov 19;6(263):263ra158.

 

Chen X, Lan X, Roche I, Liu R, Geiger JD.  Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum.  J Neurochem. 2008 Nov;107(4):1147-57.

 

Chen X, Ghribi O, Geiger JD.  Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases.  J Alzheimers Dis. 2010;20 Suppl 1:S127-41.

 

Elias PK , Elias MF, D'Agostino RB, Sullivan LM, Wolf PA.  Serum cholesterol and cognitive performance in the Framingham Heart Study.  Psychosom Med. 2005 Jan-Feb;67(1):24-30.

 

Esen F, Erdem T, Aktan D, Orhan M, Kaya M, Eraksoy H, Cakar N, Telci L.  Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study.  Crit Care. 2005 Feb;9(1):R18-23.

 

Euser AG, Bullinger L, Cipolla MJ.  Magnesium sulphate treatment decreases blood-brain barrier permeability during acute hypertension in pregnant rats.  Exp Physiol. 2008 Feb;93(2):254-61.

 

Fasano A.  Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.  Physiol Rev. 2011 Jan;91(1):151-75.

 

Fasano A.  Zonulin, regulation of tight junctions, and autoimmune diseases.  Ann N Y Acad Sci. 2012 Jul;1258:25-33.

 

Fernandes S, Salta S, Bravo J, Silva AP, Summavielle T.  Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity.

Mol Neurobiol. 2016 Jan;53(1):408-422.

 

Freund Levi Y, Vedin I, Cederholm T, Basun H, Faxén Irving G, Eriksdotter M, Hjorth E, Schultzberg M, Vessby B, Wahlund LO, Salem N Jr, Palmblad J.  Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.  J Intern Med. 2014 Apr;275(4):428-36.

 

Hachem M, Géloën A, Van AL, Foumaux B, Fenart L, Gosselet F, Da Silva P, Breton G, Lagarde M, Picq M, Bernoud-Hubac N.  Efficient Docosahexaenoic Acid Uptake by the Brain from a Structured Phospholipid.  Mol Neurobiol. 2016 Jul;53(5):3205-3215.

 

Sung-Ha Hong, Larissa Khoutorova, Nicolas G Bazan and Ludmila Belayev.  Docosahexaenoic acid improves behavior and attenuates blood–brain barrier injury induced by focal cerebral ischemia in rats

Experimental & Translational Stroke Medicine. 28 Jan 2015; 20157:3

 

Kaya M, Gulturk S, Elmas I, Kalayci R, Arican N, Kocyildiz ZC, Kucuk M, Yorulmaz H, Sivas A.  The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.  Life Sci. 2004 Nov 26;76(2):201-12.

 

 

Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM.  Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action.  J Pharmacol Exp Ther. 2007 Jun;321(3):892-901.

 

Li Q, Wang S, Xiao W, Huang C, Li H, Sun M.  BBB: Permeable Conjugate of Exogenic GABA.  ACS Omega. 2017 Aug 31;2(8):4108-4111.

 

Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C.  Gluten Psychosis: Confirmation of a New Clinical Entity.  Nutrients. 2015 Jul 8;7(7):5532-9.

 

Mielke MM, Zandi PP, Sjögren M, Gustafson D, Ostling S, Steen B, Skoog I.  High total cholesterol levels in late life associated with a reduced risk of dementia.  Neurology. 2005 May 24;64(10):1689-95.

 

Morrill G1, Kostellow AB, Gupta RK.   Computational comparison of a calcium-dependent jellyfish protein (apoaequorin) and calmodulin-cholesterol in short-term memory maintenance.  Neurosci Lett. 2017 Mar 6;642:113-118.

 

Omarch G, Kippie Y, Mentor S, Ebrahim N, Fisher D, Murilla G, Swai H, Dube A.  Comparative in vitro transportation of pentamidine across the blood-brain barrier using polycaprolactone nanoparticles and phosphatidylcholine liposomes.  Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):1428-1436.

 

Patrick RP.  Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.

FASEB J. 2019 Feb;33(2):1554-1564.

 

Rahman MT, Ghosh C, Hossain M, Linfield D, Rezaee F, Janigro D, Marchi N, van Boxel-Dezaire AHH.

IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases.  Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):274-279.

 

Russell KL, Berman NE, Gregg PR, Levant B.  Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury.

Prostaglandins Leukot Essent Fatty Acids. 2014 Jan;90(1):5-11

 

Shinto L, Marracci G, Bumgarner L, Yadav V.  The effects of omega-3 Fatty acids on matrix metalloproteinase-9 production and cell migration in human immune cells: implications for multiple sclerosis.  Autoimmune Dis. 2011;2011:134592.

 

Sturgeon C, Fasano A.  Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases.  Tissue Barriers. 2016 Oct 21;4(4):e1251384.

 

Tian J, Dang H, Wallner M, Olsen R, Kaufman DL.  Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis.  Sci Rep. 2018 Nov 8;8(1):16555.

 

Todd N, Zhang Y, Arcaro M, Becerra L, Borsook D, Livingstone M, McDannold N.  Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain.  Neuroimage. 2018 Sep;178:414-422.

 

Todd N, Zhang Y, Power C, Becerra L, Borsook D, Livingstone M, McDannold N.  Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.  Neuroimage. 2019 Apr 1;189:267-275.

 

 

van den Kommer TN, Dik MG, Comijs HC, Fassbender K, Lütjohann D, Jonker C.  Total cholesterol and oxysterols: early markers for cognitive decline in elderly?  Neurobiol Aging. 2009 Apr;30(4):534-45.

 

Vanuytsel T, Vermeire S, Cleynen I.  The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease.  Tissue Barriers. 2013 Dec 1;1(5):e27321.

 

Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, Harrington MG, Chui HC.

Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review.  JAMA Neurol. 2017 Mar 1;74(3):339-347.

 

Yuan BO, Zhao Y, Dong S, Sun Y, Hao F, Xie J, Teng L, Lee RJ, Fu Y, Bi YE.  Cell-penetrating Peptide-coated Liposomes for Drug Delivery Across the Blood-Brain Barrier.  Anticancer Res. 2019 Jan;39(1):237-243.

 

Zhifei Wang, Yan Leng, Li-Kai Tsai, Peter Leeds and De-Maw Chuang.  Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition.  Journal of Cerebral Blood Flow & Metabolism (2011) 31, 52–57