“Homeostasis” is not a topic commonly discussed at parties or at the dinner table. Nobody pays attention to it unless it’s severely out of order. That’s because few of us know what it is. Your body is able to control everything that goes on inside—the composition of body fluids, the physiological responses to stimuli, the maintenance of body temperature, and whatever else we need to keep equilibrium. That’s homeostasis. Nowhere in the body is it more important than in the brain. The mechanism for supporting this lies in the blood-brain barrier, the BBB. This comprises a network of capillaries that supply blood to the brain. The permeability of these particular capillaries is such that some substances are prevented from entering the brain tissue while others are allowed. Sometimes it’s only a matter of big molecules versus small molecules. The BBB was discovered by a bacteriologist named Paul Ehrlich, who found that a dye injected into the bloodstream colored the tissues of most organs except the brain.
Further study realized that the barrier is located in the endothelial (skin-like) cells of the capillaries, which are joined by tight junctions of substantial electrical resistance, providing a barrier against some molecules. The BBB is both a physical barrier and a system of cellular transport mechanisms. It restricts the passage of potentially harmful materials from the blood, yet allows the traverse of nutrients. Fat-soluble substances, such as ethanol and caffeine, are able to get through by way of the lipid membranes of the cells. Oddly, water-soluble materials, such as sodium and potassium, may not cross the barrier without an escort molecule of some type.
The BBB becomes more permeable during inflammatory attacks, allowing some medications (mostly antibiotics) and phagocytes to pass through. That’s good. A not-so-good thing is that opportunistic bacteria and viruses can get through, too. Most of them are too big, though. Therefore, brain infections are rare. One exception is the spirochete, Borrelia, associated with Lyme’s disease, which seems to be able to infiltrate blood vessel walls after causing inflammation of the central nervous system. (Rupprecht. 2008) There are very few fat-soluble small molecules that can get through, and that can cause problems when life-saving chemicals are barred entrance. (Pardridge. 2002) Other than some infectious diseases, no chronic diseases are cured by small-molecule drugs. Large-molecule drugs have the potential to heal patients with neurological conditions, but none can cross the BBB.
INSULTS TO THE BBB
What can harm the blood-brain barrier? Alcohol, fluoride, oxidized LDL and brain concussions, to name a few. Alcohol crosses the BBB (Stins. 2009) and forms metabolites that act as signaling molecules to activate enzymes leading to BBB dysfunction and to neuro-inflammatory disorders. (Haorah. 2007) Furthermore, alcohol causes oxidative neuron damage and results in cognitive deficits that characterize stupor and memory lapses, all because it inhibits the glucose transport upon which the brain depends as a source of energy. (Abdul Muneer. 2011)
As beneficial as topical fluoride might be in the prevention of tooth decay, its ingestion is another story, where elevated levels have been associated with increased rates of mental deficiency and borderline intelligence. Chinese researchers found that high fluoride levels in drinking water have a profound effect on the intelligence of developing children. (Xiang. 2003) Simultaneous study concluded that fluoride accumulates in the hippocampus—the part of the brain involved in memory—and inhibits activity of cholinesterase, the enzyme that regulates the function of the neurotransmitter, acetylcholine, which mediates synaptic activity. (Zhai. 2003) In earlier investigations, scientists found that the chemical had impact on those persons chronically exposed to industrial fluoride pollution, wherein there occurred symptoms of impaired central nervous system functioning and faulty cognitions and memories. (Spittle. 1994) From the outside, fluoride is acceptable treatment for the prevention of caries; from the inside, no.
Oxidized LDL (oxLDL), which appears when LDL spends too much time in the blood before getting repackaged as fat by the liver or being taken up by peripheral tissue, is capable of inducing cell injury. When cerebral endothelial cells are exposed to OxLDL, their viability decreases in a concentration- and time-dependent manner, and their programmed cell death is hastened. Intracellular reactive oxygen species are increased, and mitochondria become dysfunctional. (Chen. 2007) A blow to the head can cause a concussion, but so can violent jarring or shaking. This sudden change of momentum (the resistance to changes in motion or stability) may evoke unconsciousness or disruption of vital functions of the brainstem. The increased pressure that may result will render the BBB increasingly permeable, particularly at the site of insult. (Beaumont. 2001)
Is there a way to protect the BBB? Yes, but there is space here to address only a few. Caffeine—we all know how to get that—has been shown to block disruption of the blood brain barrier in a rabbit model of Alzheimer’s disease (AD). So, what do rabbits have to do with people? Lab animals are selected based on their organ systems’ similarity of function to corresponding systems in humans. In a cholesterol-induced model of AD, scientists found that caffeine was able to block substances that compromise the integrity of the molecules (called occludins) that hold the tight junctions of the BBB together. (Chen. 20081) Perhaps caffeine and related drugs may be useful to treat AD. But there’s more. In Parkinson’s disease (PD), similar BBB disruptions are characteristic, and caffeine again was the rescue agent. (Chen. 20082) (Chen. 2010)
Indian neurologists have studied the effects of curcumin (from turmeric) on patients with AD, and have found the herb’s anti-oxidant and anti-inflammatory properties to be beneficial in treating dementia and traumatic brain injury. The pharmacological effects of curcumin have decreased beta-amyloid plaques, delayed degradation of neurons, and decreased microglia formation while improving overall memory in AD patients. (Mishra. 2008)
Valproic acid (VPA), a histone deacetylase inhibitor, is a drug used to prevent seizures and to stabilize mood, used mostly in epilepsy treatment. Histone acetylation plays an important role in the regulation of gene expression. Keeping it intact is vital. Valproic acid and others of its kind do just that. It protects against cerebral ischemia (decrease of blood supply) and prevents disruption of the BBB. The effects of VPA are mimicked by a companion molecule, sodium butyrate, a compound available as an OTC supplement. (Wang, et al. 2011) Inflammation and macrophage infiltration follow a cerebral ischemic attack. Injected sodium butyrate or VPA was found to be effective at reducing the area of infarction and inhibiting inflammatory markers, as long as administration occurred within a three-hour window. The potential for use in stroke patients is being studied. (Kim. 2007)
One of the hottest supplements on the market is resveratrol, the magical ingredient in grapes, peanuts and red wine that purports to protect against aging. Whether it can do that or not is insignificant in light of its use as an anti-mutagenic, anti-inflammatory, and anti-oxidant agent, which render it useful in addressing cardiovascular disease and some cancers. Scientists in Taiwan have found resveratrol to protect the BBB from the damaging effects of oxLDL attack on its tight junctions and the substances responsible for its integrity. (Lin. 2010) (Chang. 2011) In normal aging the BBB seems to remain intact, but its permeability becomes an issue. Certain drugs and physical conditions, such as hypertension, may have deleterious effects on its stability. The reactive oxygen species (ROS) spawned by these vehicles can be attenuated by a low molecular weight substance known as alpha-lipoic acid, a sulfurated fatty acid (a thiol) regarded as a member of the B vitamin family and used to metabolize carbohydrates. One of lipoic acid’s claims to fame is the capability to regenerate and to recirculate both the fat-soluble vitamin E and the water-soluble vitamin C, while simultaneously raising intracellular glutathione levels. In this regard it was cited as a meaningful tool in the treatment of oxidative brain damage and neural disorders involving free radicals, such as would arise from ischemia, excitotoxic amino acid brain insult, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism and other causes of neural damage. What is deemed the most important thiol anti-oxidant, glutathione, is not usually directly administered, whereas alpha-lipoic acid may be. (Packer. 1997) Analysis of studies on alpha-lipoic acid finds it to be a participant in processes of cell growth and differentiation, thus adding to its moniker, anti-oxidant of anti-oxidants. (Bilska. 2005)
No mention of anti-oxidants would be complete without vitamin C, the oxidized version of which—dehydroascorbic acid—can cross the BBB via glucose transporters. Though best known for its anti-oxidant powers, vitamin C is also involved in enzyme reactions and the manufacture of collagen in conjunction with amino acids. Because it can traverse the BBB, vitamin C (ascorbic acid) has welcome anti-oxidant potential in the central nervous system. (Agus. 1997). Its use in the treatment of cerebral compression insult, as from a concussion, has preserved BBB integrity and rescued somatosensory function from debilitation. (Lin. 2010)
For years, the failures of clinical trials in the treatment of neurological diseases have been blamed on the tested substances’ ineffectiveness, when the whole time none could get past the blood-brain barrier.
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. Epub 2010 Nov 16.
Abraham Al Ahmad, Carole Bürgi Taboada, Max Gassmann and Omolara O Ogunshola
Astrocytes and pericytes differentially modulate blood–brain barrier characteristics during development and hypoxic insult
Journal of Cerebral Blood Flow & Metabolism 31, 693-705 (February 2011) |
D B Agus, S S Gambhir, W M Pardridge, C Spielholz, J Baselga, J C Vera and D W Golde
Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters.
J Clin Invest.(December 1, 1997);100(11):2842–2848.
Beaumont A, Marmarou A, Fatouros P, Corwin F.
Secondary insults worsen blood brain barrier dysfunction assessed by MRI in cerebral contusion.
Acta Neurochir Suppl. 2002;81:217-9.
Bilska A, Włodek L.
Lipoic acid – the drug of the future?
Pharmacol Rep. 2005 Sep-Oct;57(5):570-7.
Carman Aaron J, Jeffrey H. Mills, Antje Krenz, Do-Geun Kim, and Margaret S. Bynoe
Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier
The Journal of Neuroscience, 14 September 2011, 31(37): 13272-13280
Chang HC, Chen TG, Tai YT, Chen TL, Chiu WT, Chen RM.
Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells.
J Cereb Blood Flow Metab. 2011 Mar;31(3):842-54.
Chen TG, Chen TL, Chang HC, Tai YT, Cherng YG, Chang YT, Chen RM.
Oxidized low-density lipoprotein induces apoptotic insults to mouse cerebral endothelial cells via a Bax-mitochondria-caspase protease pathway.
Toxicol Appl Pharmacol. 2007 Feb 15;219(1):42-53.
Chen X, Gawryluk JW, Wagener JF, Ghribi O, Geiger JD
Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer’s disease.
J Neuroinflammation. (1) 2008 Apr 3;5:12.
Chen X, Lan X, Roche I, Liu R, Geiger JD.
Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum.
J Neurochem. (2) 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.
Garbuzova-Davis S, Louis MK, Haller EM, Derasari HM, Rawls AE, Sanberg PR.
Blood-brain barrier impairment in an animal model of MPS III B.
PLoS One. 2011 Mar 7;6(3):e16601.
Haorah J, Knipe B, Gorantla S, Zheng J, Persidsky Y.
Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release.
J Neurochem. 2007 Jan;100(2):324-36.
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.
Lin JL, Huang YH, Shen YC, Huang HC, Liu PH.
Ascorbic acid prevents blood-brain barrier disruption and sensory deficit caused by sustained compression of primary somatosensory cortex.
J Cereb Blood Flow Metab. 2010 Jun;30(6):1121-36.
Lin YL, Chang HC, Chen TL, Chang JH, Chiu WT, Lin JW, Chen RM.
Resveratrol protects against oxidized LDL-induced breakage of the blood-brain barrier by lessening disruption of tight junctions and apoptotic insults to mouse cerebrovascular endothelial cells.
J Nutr. 2010 Dec;140(12):2187-92.
Mishra S, Palanivelu K.
The effect of curcumin (turmeric) on Alzheimer’s disease: An overview.
Ann Indian Acad Neurol 2008;11(1):13-19
Packer L, Tritschler HJ, Wessel K.
Neuroprotection by the metabolic antioxidant alpha-lipoic acid.
Free Radic Biol Med. 1997;22(1-2):359-78.
William M. Pardridge, MD
Targeting Neurotherapeutic Agents Through the Blood-Brain Barrier
Arch Neurol. 2002;59:35-40.
Rupprecht TA, Koedel U, Fingerle V, Pfister HW.
The pathogenesis of lyme neuroborreliosis: from infection to inflammation.
Mol Med. 2008 Mar-Apr;14(3-4):205-12.
Shah GN, Mooradian AD.
Age-related changes in the blood-brain barrier.
Exp Gerontol. 1997 Jul-Oct;32(4-5):501-19.
Psychopharmacology of fluoride: a review.
Int Clin Psychopharmacol. 1994 Summer;9(2):79-82.
STINS, MONIQUE F.
ALCOHOL MEDIATED BLOOD BRAIN BARRIER DYSFUNCTION
U.S. Dept. of Health and Human Services
Research Portfolio Online Reporting Tool, 2009
Q Xiang , Y Liang , L Chen , C Wang , B Chen), X Chen , M Zhou
Effect of fluoride in drinking water on children’s intelligence.
Fluoride 2003; 36(2): 84-94
Zhai JX, Guo ZY, Hu CL, Wang QN, Zhu QX.
Studies on fluoride concentration and cholinesterase activity in rat hippocampus.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2003 Apr;21(2):102-4.
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
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