Chemotherapy Agents And The Bbb
In fact, radiographically and/or symptomatic brain metastatic disease does respond to systemic chemotherapy. As reviewed by Tosoni et al. , response rates to various chemotherapy agents or combinations of agents by primary disease sites are as follows: nonsmall cell lung cancer, 0% to 82% small cell lung cancer, 0% to 92% breast cancer, 0% to 58% and melanoma, 0% to 50%.
Drug levels in brain metastases and neighboring tissues, measured at time of resection or at autopsy
Ultrasound Trial Offers Hope For Brain Cancer Patients
New technique temporarily allows drugs to cross blood brain barrier to treat tumours
A technique has been developed that could revolutionise the treatment of brain cancers and neurodegenerative diseases by temporarily allowing drugs and other substances to cross the blood brain barrier a structure that separates the brains blood vessels from the rest of its tissues.
A trial in four women whose breast cancer had spread to the brain showed that magnetic resonance-guided focused ultrasound could safely deliver the antibody therapy Herceptin into their brain tissue, causing the tumours to shrink.
The blood brain barrier is a cellular wall designed to prevent substances in the bloodstream, such as toxins or microbes, from getting into the brain where they could cause irreparable damage to its tissues.
Whereas in the rest of the body there are tiny gaps between the cells lining the blood vessels that allow small substances to pass through, in the brain these spaces are fused, meaning that only water, certain gases such as oxygen, a handful of other necessary substances, and small fat-soluble drugs such as antidepressants get through.
Many, many people have been trying lots and lots of different ways of getting stuff across the blood brain barrier, but it has proved to be extremely difficult certainly to do it in a way that is temporary, said Eleanor Stride, a professor of biomaterials at the University of Oxford, who was not involved in the research.
See Oligonucleotide Therapeutics Near Approval
After their initial results with Malat1, the researchers generated HDOs for three clinically relevant genes: DMPK, which when mutated is linked to a type of muscular dystrophy glial fibrillary acidic protein , which can cause Alexander disease and human superoxide dismutase 1 , which, when mutated and engineered into mice, models amyotrophic lateral sclerosis. They found knockdowns of between about 20 and 60 percent of DMPK mRNA, depending on which central nervous system tissue they analyzed. DMPK protein levels decreased by about half in both the brain and muscles of mice that received the HDO intravenously. The targets of the other two HDOs demonstrated more modest knockdowns.
The data seem strong, Rudy Juliano, an emeritus professor at the University of North Carolina School of Medicine who did not participate in the study, writes in an email to The Scientist. Open questions, he adds, include whether most of the effect observed in the whole brain actually took place in neurons and not in supporting tissues, if the high doses the authors used50 milligrams of HDO per kilogram of body weightcan be toxic, and why this simple modification of oligo structure can overcome the extremely robust blood-brain barrier that limits the access of much smaller and much less polar molecules to the brain.
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Scientists Demonstrate The Safety Of Opening The Blood
Researchers used a noninvasive, focused ultrasound device to temporarily disrupt the blood-brain barrier and target discrete regions of the brain. This approach may open the way for new drug delivery strategies for diseases such as brain cancers and Alzheimers, conditions typically not amenable to more conventional treatments.
Using an FDA approved contrasting agent containing tiny gas-filled microbubbles, coupled with an ultrasound platform that targeted precise locations in the brains of nonhuman primates, researchers from Harvard Medical School showed that repeated treatments temporarily opened the blood-brain barrier while causing no structural or functional damage. Their results, which were published online in the journal Cancer Research, support clinical testing of this new application.
The brain is protected from most toxins and bacterial infections by the blood-brain barrier , a physical separation between the brain and the circulatory system which normally only permits small, essential molecules like oxygen and glucose through. Large molecules like chemotherapy agents and antibiotics cannot easily permeate the BBB, making it one of the primary obstacles for treating diseases of the brain.
They didnt have any trouble with memory. They were smart, and were just as fast and adept at it as they were before. They could discriminate 26 different tiny symbols, said Livingstone, who ran the tests. We couldnt pick up anything wrong.
Cannabidiol And Diseases Involving Bloodbrain Barrier Breakdown
The breakdown of the BBB architecture is a usual consequence of encephalitis induced by lipopolysaccharide and may be produced by endothelial tight junction disruptions induced principally by cytokines. The augment of BBB permeability causes derivative lesions that exacerbate as long as the time period of a septic shock and aggravate the outcome . Intravenous CBD effects on inflammation and BBB damage in an in vivo model of sepsis induced by i.v. LPS injection were investigated. Experiments demonstrated that the cannabinoid inhibited the arteriolar and venular vasodilation and leukocyte margination caused by LPS, abolished the enhancement of tumor necrosis factor-alpha and cyclooxygenase-2 expression, and expression of the enzyme inducible-nitric oxide synthase. Preservation of BBB integrity was also induced by CBD attenuation of LPS-induced modifications in the diameter and permeability of vessels and margination of leukocytes . These results further suggest that CBD could be considered to develop a new strategic approach to protect BBB. Strategies for BBB protection are important because changes of this anatomical gateway have been found in people affected by CNS diseases, such as epilepsy, mental, and neurodegenerative disorders .
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The Bbb Can Be Broken Down By:
Bbb In Vitro Permeability Assays
TEER is a measure of barrier integrity and was determined using the Millicell ERS-2 volt-ohm meter . TEER was calculated by subtracting the resistance of blank inserts from that of the inserts with cells and multiplying the subtracted values by the area of the insert. Barrier function was further analyzed by measuring the permeability of the cell monolayer to EBD-labeled albumin and fluorescein sodium salt . Hanks balanced salt solution was added to the abluminal side, while the luminal side was loaded with HBSS containing 170 g/ml EBD, 20 g/ml NaFl, and 10 mg/ml bovine serum albumin. The cells were incubated at 37°C for 60min, and the levels of NaFl and EBD in the abluminal side were measured using a fluorometer with excitation/emission wavelengths of 485/530nm for NaFl and excitation/emission wavelengths of 540/680nm for EBD. EBD and NaFl concentrations were determined using a standard curve. The permeability coefficient for EBD and NaFl was calculated according to the equation: P = VB/ × , where VB is the volume in the basolateral compartment, S is the surface area of the filter membrane, CA is the initial concentration in the apical compartment, and CB/t is the change of concentration over time in the basolateral compartment.
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Core Concept: Circumventing The Bloodbrain Barrier
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If the brain is the bodys central processing unit, then the bloodbrain barrier is its firewall. A specialized network of cells that lines the brains vascular system, the bloodbrain barrier selectively ushers in nutrients and other essential biomolecules while denying entry to most everything else. But the same system that protects the brain also stymies many therapeutics that could potentially treat disease.
In November 2015, researchers at Sunnybrook Health Sciences Centre in Toronto began a clinical trial to noninvasively breach the bloodbrain barrier with focused ultrasound in an attempt to deliver chemotherapy to brain tumors. Image courtesy of Doug Nicholson .
A handful of drugs slip into the brain by passive diffusionamong them, antidepressants and medications for schizophrenia and epilepsy, along with caffeine, alcohol, and nicotine. These molecules are exceedingly small. They also can readily dissolve into the lipid membranes that encase bloodbrain barrier cells. But new drug leads of this type are growing more elusive. Most of the small molecule combinations have been explored, says biomedical engineer Peter Searson at Johns Hopkins University in Baltimore, MD.
Avoid Smoking And Drinking
You know about the dangers of smoking, but did you know that nicotine can also cause a leaky brain? A 2004 study found that chronic nicotine exposure increases BBB permeability along with altering tight junction protein distribution in the brain.3
Alcohol is also problematic for the blood-brain barrier. While moderate amounts of wine may have a beneficial effect, research shows that excess alcohol can lead to BBB damage.4
The overall quality of sleep is also important for blood-brain barrier health. If you get 8 hours of sleep but still wake up tired and groggy, you may not be getting the deep sleep your body needs. A sleep study can help determine whether sleeping soundly is an issue for you.
Additionally, follow these tips to ensure that you get enough quality sleep:
- Sleep in a dark room or wear a sleep mask
- Dont use a computer or cell phone before bed
- Eat your last meal at least 2-3 hours before bed.
- Consider taking a melatonin supplement
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Cell Lines For Research
A major challenge for the development of in vitro models of the BBB is the availability of appropriate cell lines, particularly BMECs. An in vitro model of the human BBB should exhibit restricted paracellular transport , BMECs with the morphology and characteristics typical of the BBB, expression of BBB-specific markers and transporters, and be readily available, convenient to use, and reproducible . While primary human BMECs are often considered preferable for in vitro models, the difficulties in harvesting and purification of these cells can significantly limit accessibility and reliability . In general, primary cells are used only at very low passage numbers to avoid down-regulation of BBB characteristics . In contrast, currently available cell lines can overcome limitations associated with accessibility and convenience, but do not exhibit all of the required features of the human BBB . Nevertheless, specific cell lines may recapitulate properties that are necessary for some physiological, pathological, or pharmacological applications. Common sources for animal BMECs include rodent, bovine, and porcine brain cortices. Primary astrocytes and pericytes can also be extracted from the brain cortex . Advances in stem cell engineering suggest that differentiation of stem cells to BMECs and astrocytes may ultimately solve the problem of limited cell lines.
A Barrier To Progress: Getting Drugs To The Brain
Getting drugs across the blood-brain barrier could be key to developing more successful therapies to treat central nervous system disorders, such as Alzheimers disease, depression and epilepsy. Scientists are investigating a number of ways to achieve this, from using Trojan horses to smuggle drugs across the barrier, to temporary disruption of the barrier using ultrasound, to allow drugs into the brain.
Carol & Mike Werner / Science Photo Library
Medicating the brain is tricky, as pharma giant Eli Lily recently discovered. In 2016, the company abandoned development of its Alzheimers drug solanezumab, after it failed several late-stage clinical trials. This adds to a long list of central nervous system drug failures. According to a 2014 study, CNS therapeutics take more than a year longer to develop than other drugs and are less than half as likely to obtain marketing approval. One of the reasons why finding successful neurological therapies is so hard is the blood-brain barrier evolutions mechanism for protecting the brain.
Figure 1: Crossing the blood brain barrier
The blood-brain barrier is like a regular cell barrier on steroids
Working out how to get drugs through the BBB could be the key to more successful therapies for CNS disorders. Several methods to achieve this are being investigated, from using Trojan horses to smuggle drugs across the barrier to temporarily disrupting the barrier to allow drugs into the brain.
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The Blood Brain Barrier
More than 100 years ago it was discovered that if blue dye was injectedinto the bloodstream of an animal, that tissues of the whole body EXCEPTthe brain and spinal cord would turn blue. To explain this, scientiststhought that a “Blood-Brain-Barrier” which prevents materials fromthe blood from entering the brain existed. More recently, scientists havediscovered much more about the structure and function of theBBB.
Cannabinoid Receptors And Bloodbrain Barrier
CB1R is principally situated at the luminal side of the endothelium of BBB and expression of brain CB1Rs was shown in astrocytes, microglial cells, pericytes . Even though not at the same level of CB2R also is involved in neuroinflammation. It has been shown that neuronal expression of CB1R plays a key role to control experimental autoimmune encephalomyelitis and mediates formation of interleukin-6 induced by the endocannabinoid anandamide in astrocytes in this experimental model .
Protective effects of cannabinoids in opposition to excitotoxicity are played principally at CB1R located on presynaptic axons, through inhibition of neurotransmitter release, included glutamate . Other mechanisms suggested are opening of potassium channels followed by neuronal firing reduction, closing of voltage-sensitive calcium channels and reduction of cellular calcium influx . It has been also shown that antagonism of CB1R reduces expression VCAM-1 induced by anandamide in cerebral endothelial cells and prevents adhesion and transmigration of leukocytes in the Theilers Murine Encephalomyelitis Virus experimental model .
See Getting Drugs Past The Blood
In 2015, Takanori Yokota of Tokyo Medical and Dental University and colleagues published a study showing that a so-called heteroduplex oligonucleotide consisting of a short chain of both DNA and an oligonucleotide with modified bases paired with complementary RNA bound to a lipid on one endwas successful at decreasing target mRNA expression in the liver. Yokotas team later joined forces with researchers at Ionis Pharmaceuticals to determine whether HDOs could cross the blood-brain barrier and target mRNA in the central nervous system.
In the new study, the research team showed that an HDO designed to target a tumor-associated long noncoding RNA achieved a higher level of knockdown in the brain and spinal cord when tagged with cholesterol and injected intravenously than when the HDO was tagged with the lipid tocopherol and injecting subcutaneously. In both rats and mice, the effects of the knockdown were tied to the dose of the HDO and four dosesgiven a week apartwere most effective. An intravenously injected single-stranded oligonucleotide tied to cholesterol didnt knock down Malat1.
Duplexed oligos actually seem to be delivered much better than single-stranded oligos, coauthor Frank Rigo, vice president of functional genomics and drug discovery at Ionis Pharmaceuticals, tells The Scientist. The data seems to suggest that the single-stranded oligos may get trapped . . . and may not actually cross the vasculature as efficiently as the double strand, he explains.
How Does Alcohol Cross The Blood
The blood-brain barrier and alcohol are a dangerous duo because alcohol can quickly penetrate the barrier and damage the brain. After its been ingested, alcohol makes its way into the arteries that sit between the skull and brain. It then travels through the capillaries until it reaches brain tissue. Once alcohol passes through these capillaries, it reaches the neurons, or brain cells.2 Although the blood-brain barrier can protect the brain from many different toxins and substances, alcohol can unfortunately pass through the barrier very easily.
Alcohol is a dangerous substance that can destroy brain cells, which can result in cognitive dysfunction and other health problems. At Banyan Treatment Centers Pompano, we advise those who are struggling with an addiction to alcohol to receive treatment right away. The best thing you can do for yourself or someone else with a substance abuse problem is to get help and begin the journey to sobriety. To make recovery from alcoholism possible, we provide an alcohol addiction treatment designed to meet the specific needs of our patients.
If you or a loved one are trapped in the harmful cycle of substance abuse, call us now at to learn more about our addiction treatments and programs.
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Getting Cancer Drugs Into The Brain
The human brain has a huge appetite for glucose, and gobbles up about one-fifth of the bodys daily requirement. It is also hungry for oxygen and other nutrients, and responds rapidly to drugs such as alcohol and morphine. It even allows metastatic cancer cells to slip in from the bloodstream, using back doors that researchers do not yet understand.
But the brain is exceptionally good at keeping out most cancer drugs.
The bloodbrain barrier , a unique assembly of blood vessels that filters what goes into and out of the brain, is responsible for this quirk. And it is also the main reason why treatments for cancer that work elsewhere in the body fail routinely when directed at the brain.
In fact, many studies of such drugs in people might be doomed from the start. Clinical trials are run all the time with drugs that are known to not have good brain penetration, says Jann Sarkaria, a neuro-oncologist and radiologist at Mayo Clinic in Rochester, Minnesota. If we dont look at that brain-penetration issue, theyre destined to fail.
The current treatment toolkit for brain tumours surgery, radiation and chemotherapy falls woefully short for most people with the condition, for whom survival time is often measured in months. Researchers and drug companies are struggling to find treatments that can cross the BBB to attack tumours while sparing the rest of the brain from injury.