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What Is a “Leaky” Blood-Brain Barrier & Can You Improve it?

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Nattha Wannissorn
Puya Yazdi
Medically reviewed by
Nattha Wannissorn, PhD, Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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In this post, we cover the science behind a highly controversial concept: “leaky brain.” Read on to see which factors are proposed to protect or improve the state of the blood-brain barrier and whether any are supported by evidence.

What is the Blood-Brain Barrier?

A Major Discovery

A scientist named Paul Ehrlich made an accidental discovery about 100 years ago. He was injecting blue dye into animals to study their physiology, when he realized that the dye wouldn’t pass into their brains. When he injected dye directly into the animals’ brains, it wouldn’t pass into the rest of their bodies [1].

Ehrlich realized that the blue dye he was using had reached a seemingly impenetrable obstacle. He concluded that the brain is protected from the bloodstream with this special membrane, which later became known as the blood-brain barrier [1].

Can the Blood-Brain Barrier be “Leaky”?

Like the gut barrier, the blood-brain barrier is lined with one layer of cells that separate the blood from the brain. It only allows a few substances like oxygen, hormones, and certain cytokines in, while blocking out others [1].

When this protective layer is compromised, the brain is thought to be vulnerable to damage from chemicals, inflammatory cytokines, and immune cells [2, 1].

New Perspectives & Limitations

“Leaky brain” was coined as a non-medical term for increased blood-brain barrier permeability [2].

This term is still relatively new and research is sparse. The whole theory is theoretical and it has yet to be verified in proper human studies. Findings are still mostly limited to cell culture or brain tissue studies [2, 1].

That said, limited research has linked a compromised blood-brain barrier with “brain fog” or cognitive dysfunction, chronic fatigue, anxiety/depression, neurodegenerative diseases, and other neurological conditions. There’s not enough evidence to support any of these associations [2, 1].

When to See a Doctor

If your goal is to increase the integrity of your blood-brain barrier to improve your neurological issues – including those of cognitive problems, mood imbalances, or serious inflammation – it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.

Your doctor should diagnose and treat the condition causing your symptoms.

Factors Proposed to Improve “Leaky Brain”

Caveats

Remember that the existing evidence does not suggest “leaky brain” causes any disorder. Complex disorders always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Therefore, you may try the strategies listed below if you and your doctor determine that they could be appropriate. Read through the approaches we bring up and discuss them with your doctor before trying them out. This is particularly important if you plan to take any dietary supplements.

Most of the lifestyle, dietary, and supplement factors listed in this article rely on animal and cellular data. These findings can’t be applied to humans. Clinical research is needed before the safety and effectiveness of any approach listed in this post is determined.

Additionally, changes in brain physiology are not something that people can change on their own with the approaches listed below. Instead, the factors listed here are meant to reduce daily stress and support overall brain health and well-being.

Finally, have in mind that none of these strategies should replace what your doctor recommends or prescribes.

Address the Underlying Cause

As the permeability (“leakiness”) of the blood-brain barrier can increase as a result of many diseases, the most important thing is to work with your doctor to address any potential underlying health condition.

Here are some potential underlying issues your doctor may take into account:

Blood Sugar

High blood sugar increases oxidative stress and inflammation, which kills the pericytes and may cause a leaky brain [3, 4].

Infections and Toxins

Infections and toxins can damage the blood-brain barrier. It is therefore important to resolve and clear these infections accordingly.

High Homocysteine

High levels of homocysteine disrupt tight junction function and cause BBB dysfunction [5].

Read this post to learn more about testing for and lowering homocysteine levels.

Medication

Glucocorticoids

There is currently no conventional treatment for increased blood-brain barrier permeability or “leaky brain,” since doctors don’t yet have clear criteria to make this diagnosis.

The only medically-accepted therapeutic approach that can be used to increase the int the blood-brain barrier integrity are glucocorticoids (synthetic cortisone) [6].

Glucocorticoids are generally the treatment for certain autoimmune disorders. Some research suggests that they can improve blood-brain barrier integrity in patients with multiple sclerosis [6].

Scientists are also investigating whether the glucocorticoid dexamethasone can increase TIMP1, occludin, claudin-5, and other anti-inflammatory proteins that help repair the BBB in cells [7, 8, 9].

1) Reduce Stress

Stress is hypothesized to induce “leaky gut” and overall inflammation. In addition, acute stress activates brain mast cells that secrete proinflammatory cytokines that disrupt the BBB. Stress also has many other detrimental health effects. Look to find ways to de-stress on a daily basis [10, 11].

2) Get Enough Sleep

Chronic sleep loss decreases glucose transport across the BBB, increases inflammation, and impairs BBB permeability. Plus, getting enough quality sleep supports overall brain health and general wellness [12].

3) Healthy Brain Circulation

Poor brain circulation reduces the amount of oxygen and nutrients available to the brain. Studies suggest that this may increase oxidative stress. Some scientists claim that when oxidative stress is increased in glial cells and pericytes, the blood-brain barrier and its tight junctions may become damaged [13, 14].

4) Don’t Overeat

High calorie and high-fat diets are proposed to increase “leaky gut,” which might cause LPS (a bacterial toxin) to enter the bloodstream. LPS aside, eating more calories than you need (especially from fast food and sugar) is known to be harmful in the long run. It can cause obesity and other health issues [10].

According to one hypothesis that has yet to be verified, leaky gut might also damage the blood-brain barrier [15, 16].

5) Lose Weight (If Obese)

Directly tied to overeating, some scientists think that obesity-induced inflammation can also cause problems in the blood-brain barrier (BBB) [17].

People who are overweight should aim to lose extra pounds to improve their overall health, but this step might support brain health too.

Anti-Inflammatory Diets?

Anecdotally, anti-inflammatory diets are claimed to support brain health by reducing inflammatory food triggers. This approach isn’t backed by science.

The lectin avoidance diet is an elimination diet that is claimed to help reduce inflammation by avoiding substances that may trigger the immune system.

The blood-brain barrier is also sealed by tight junction proteins that resemble those in the gut. They are also proposed to be regulated by the protein called zonulin, suggesting that they may – in theory – be disrupted by gluten. This is purely hypothetical, though [18, 19].

Supplements

Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

Additionally, supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. That’s why it’s so important to consult your healthcare provider before supplementing and let them know about all drugs and supplements you are using or considering.

Here are some supplements to discuss with your doctor that are being researched:

1) Acetyl L-Carnitine

Acetyl L – carnitine (ALCAR) is being investigated for protecting mitochondria in cells [20].

When mitochondria are damaged, reactive oxygen compounds might leak out into the cells and damage them. ALCAR is claimed to help repair the BBB by reversing the mitochondria decay caused by oxidative damage, but this hasn’t been proven in humans [21].

2) Alpha-Lipoic Acid

Some researchers hypothesize that Alpha-lipoic acid may prevent immune cells from invading the brain and damaging BBB, based on studies in rats with experimental allergic encephalomyelitis. Human data are lacking [22].

Others are researching if lipoic acid stabilizes the blood-brain barrier and preserves BBB integrity by reducing oxidative stress [23, 24].

3) Alpha-GPC

Alpha glycerophosphocholine or alpha-GPC is claimed to increase the level of the neurotransmitter acetylcholine [25].

In rats, GPC partially reverses the changes in BBB caused by damage to brain vessels. Human studies are missing [25].

4) Angelica (Dong Quai) Extracts

In rats with a severe form of brain stroke that involves brain bleeding, a component extracted from Angelica sinensis, Z-ligustilide, seemed to reduce brain swelling and strengthen the BBB [26].

5) Astragalus

Astragalus is often used in Chinese herbal remedies. Researchers have theorized that injecting an astragalus extract through IV to rats that have suffered stroke might strengthen the blood-brain barrier compared to the control group of animals [27].

Cell-based research is exploring if astragalus, combined with ligustrazine, can increase the level of proteins responsible for BBB strength, such as occludin and claudin, and decrease MMP9 [28].

6) Astaxanthin

Some researchers think that astaxanthin can decrease inflammation during injuries [29].

They found that astaxanthin decreased inflammatory molecules and protected the BBB in rats that had brain bleeding, but human studies are needed [29].

7) Apigenin

Apigenin is a color compound naturally found in plants. Administration of apigenin in rats suffering from brain injury and bleeding in the brain blocked inflammatory proteins (TLR4 and cytokines) and increased tight junction proteins [30].

8) B12-B6-Folate Mix

A mix of vitamin B12, vitamin B6, and folate in a small study of patients with mild cognitive impairment was posited to make the BBB stronger and improve the overall condition of their health. These findings haven’t been replicated [31].

10) Berberine

In mice with experimental encephalomyelitis and mice with brain injuries, berberine blocked the activity of MMP9 and reduced inflammation [32, 33].

11) Bitter Melon

Bitter melon (Momordica charantia) extract seems to protect the blood-brain barrier (BBB) against disruption caused by a high-fat diet in lab animals [34].

In mice that were fed a diet with a lot of fats, bitter melon extract prevented leaks in the brain and excessive activity of brain immune cells and decreased the concentration of inflammatory proteins [34].

12) Butyrate

Sodium butyrate given to mice with brain trauma reversed the decrease in the concentration of BBB proteins occludin and ZO-1 and prevented damage to nerve cells [35].

Butyrate is often produced by bacteria in the gut [36].

In healthy mice, the lack of necessary butyrate-producing bacteria in the gut weakened the blood-brain barrier [36].

If germ-free mice (healthy mice that previously had no bacteria in the gut at all) are given those bacteria afterward, their BBB becomes stronger [36].

13) Chlorogenic Acid

Chlorogenic acid is found in green coffee beans [37].

Injections of chlorogenic acid in rats with experimental stroke decreased the level of MMP-2 and MMP-9 [38].

14) Citicoline

Injections of citicoline into mice with traumatic brain injury strengthened the BBB and partially reduced brain swelling [39].

15) Collagen

Collagen (type IV) is hypothesized to be important for BBB structure and function of the cell that forms it [40].

16) Curcumin

In a cell-based study, curcumin increased the concentration of tight junction proteins in mice brain vessel cells. This increase appeared to protect them from injury [41].

In a model of rat brain injury, curcumin decreased brain swelling and prevented the disruption of the BBB by increasing an antioxidant protein Nrf2 [42].

Curcumin in a nanoparticle format was reported to improve the state of the BBB better than traditional curcumin [43].

17) Vitamin D3

Vitamin D3 is thought to protect the BBB by increasing the level of BBB proteins occludin, claudin-5 ZO-1, and by blocking MMP9 [44].

Supplementation appears to be protective in animals in cases where the blood-brain barrier is disrupted because of inflammation from a high-fat and high-calorie diet. This hasn’t been verified in humans [45].

Also, sun exposure typically increases vitamin D3 levels, but we don’t know how it affects the BBB.

18) Ellagic Acid

Ellagic acid decreased BBB permeability in rats with traumatic brain injury [46].

19) Fish Oil

Fish oil (EPA, DHA) in rats with brain injury made the BBB stronger, decreased the damage to the limbs, and blocked MMP9 [47].

20) Ginseng

In a model of ischemic stroke in rats, a chemical extracted from ginseng, ginsenoside R1, strengthened the BBB that was weakened after stroke [48].

Chemicals obtained from ginseng were also able to support the development of new nerve cells after stroke in rats [49].

21) Goji Fruit

In mice, pre-treatment with Goji fruit extract (10 mg/kg/day) before they experienced stroke prevented the leaks in the BBB and reduced glial cell inflammation [50].

22) Hydrogen Water

Rats prone to stroke and high blood pressure were given hydrogen-rich water [51].

The animals that drank hydrogen-rich water had fewer leaks from the brain and lower MMP 9, which the authors interpreted as an improvement in the state of the BBB [51].

The use of hydrogen water in humans is highly controversial and remains unproven.

23) Licorice

Glycyrrhizin, an active component of licorice, protected the BBB from damage in rats with brain injury by blocking inflammatory proteins TNF-α, IL-1β, and IL-6 [52].

It also blocked a protein HMGB1, which is thought to drive traumatic damage in the body [52].

Have in mind that glycyrrhizin can have detrimental health effects, especially in people prone to heart problems. It’s typically removed from supplements nowadays, as in Deglycyrrhizinated Licorice (DGL).

24) Lycopene

In rats with brain bleeding, lycopene led to less damage to the BBB, protected nerve cells from cell death, and decreased brain swelling [53].

25) Myoinositol

Myoinositol is a molecule that is considered to be important for brain function. Some scientists think it can pass through the blood-brain barrier, but this hasn’t been proven in humans [54].

It seems to restore the proper function of the BBB in rats with experimental diabetes [55].

26) Magnesium

In rats with sepsis (severe and life-threatening bacterial infection), magnesium sulfate given in the muscles restored the BBB and prevented brain swelling in rats sick with sepsis [56].

It also made the BBB stronger in pregnant rats that had high blood pressure [57].

Magnesium sulfate could also directly counteract damage to the BBB induced by injection of mannitol in rats [58].

Magnesium also protected the BBB in cases of traumatic brain injury and high blood sugar in rats [59, 60].

27) Melatonin

Melatonin is hypothesized to block MMP9, an enzyme that may lead to a leaky blood-brain barrier [61].

In a cell-based study, melatonin pre-treatment protected rat brain blood vessel cells taken from inflammatory molecules [61].

Melatonin is also thought to be anti-inflammatory and is being researched for its broader effects on the brain [62].

28) Methylene Blue

Methylene blue decreased the level of damage to the BBB by blocking the production of nitric oxide. Methylene blue is often contaminated with impurities and industrial methylene blue shouldn’t be ingested [63].

29) Olive Leaf Extract

Olive leaf extract appeared to reduce BBB permeability and brain swelling in rats with brain stroke [64].

30) Oxaloacetate

Oxaloacetate seems to gather up glutamate, a molecule important for brain function, but one that also may damage the brain if there is too much of it [65].

In a rat model of brain bleeding, oxaloacetate protected the BBB through blocking glutamate from damaging the BBB and brain [65].

31) Parthenolide (Feverfew)

In rats with brain artery blockage, a chemical parthenolide protected the BBB by lowering the content of inflammatory protein and increased the level of the BBB protein claudin – 5 [66].

32) Pterostilbene

Pterostilbene is a component of blueberry [67].

Treatment of mice after stroke with pterostilbene protected against the BBB damage and brain swelling by decreasing the concentration of dangerous oxygen types [67].

33) Resveratrol

Resveratrol is an antioxidant [68].

It is being researched for stabilizing the BBB and protecting it from damage [68].

In rats, resveratrol protected the BBB by increasing levels of TIMP-1, which reduces activities of MMP9 [69].

In rats that have Alzheimer’s disease, resveratrol blocked MMP9 activities and increased the level of claudin-5, strengthening the BBB and protecting it from destruction [70].

34) Rosmarinic Acid

Rosmarinic acid protected against blood-brain barrier damage permeability in diabetic rats after stroke by lowering inflammation [71].

35) Shilajit

Shilajit reduced BBB damage and brain damage as a whole in rats with brain trauma [72].

36) Selenium

Selenium decreased BBB damage during seizures in baby rats, especially in male rats [73].

37) Sulforaphane

If Sulforaphane is given to rats before induction of a stroke, it prevents the destruction of brain blood vessels and the BBB by increasing the level of the antioxidant proteins Nrf2 and HO-1 [74, 75, 76].

Sulforaphane also reduced BBB dysfunction by decreasing inflammation proteins in animals[77].

38) Ursolic Acid

Ursolic acid is a plant component. In rats with bleeding in the brain, it blocked dangerous oxygen species and through this mechanism, prevented nerve cell death and BBB damage [78].

Other Experimental Substances & Pathways

The following hormonal factors and neurotransmitters are theoretical. They aren’t backed up by solid science. We bring them up for informational purposes.

Too Much Glutamate

Glutamate is an important neurotransmitter and the most abundant one in the brain. However, overstimulation of glutamate receptors in the brain might break down the blood-brain barrier, according to some animal and cell-based studies [79].

In the brain, glutamate is present in balance with GABA. Defects in the enzymes (GAD) that convert glutamate to GABA, such as from autoimmune attacks, may theoretically increase glutamate levels.

Read this post to learn more about these enzymes and factors that may affect them.

Dietary Glutamate

Typically, glutamate in the blood does not cross the blood-brain barrier. But anecdotally, some people with a leaky blood-brain barrier report brain symptoms in reaction to dietary free glutamate. Scientific research is lacking to back up this link.

With the exception of monosodium glutamate, most foods that are high in glutamate are also high in histamine-like substances. It is unclear whether the reaction comes from the glutamate or the histamine-like substances. Human studies are needed.

Blocking Glutamate Receptors

Substances that block glutamate receptors, such as memantine, are used as a treatment for neurological diseases that also involve high glutamate levels and, possibly, a leaky blood-brain barrier [80]. These include Alzheimer’s, vascular dementia, and Parkinson’s disease.

Nonetheless, it’s unclear how glutamate blockers affect BBB integrity. Clinical trials are required.

MMP Inhibitors

GM6001, also known as Ilomastat or galardin, is an experimental broad-spectrum inhibitor of matrix metalloproteinases. Its safety and effectiveness in humans haven’t yet been investigated [81].

In mice with experimental autoimmune encephalomyelitis (EAE) (a multiple sclerosis model), GM6001 seemed to slow the development of the disease [82].

Another group of synthetic MMP inhibitors, BB-1101 and BB-94, also helped repair the damage to BBB in mice that had their BBB damaged by lipopolysaccharide (a bacterial toxin) [83].

Angiotensin

In rats with an injury to brain blood vessels, treatment with a protein involved in blood vessel activity, angiotensin Ang(1-7) protected their BBB [84].

Ang(1-7) blocked MMP9 and increased the concentration of TIMP-1 in the rats with brain injury and protected BBB from more damage [84].

However, angiotensin – as part of the renin-angiotensin-aldosterone system – raises blood pressure and abnormal levels can be detrimental.

Progesterone

Progesterone lowered inflammation and supported BBB in rats after brain injury [85].

Progesterone is available with a doctor’s prescription, and it is FDA-approved for specific indications.

Can Some Supplements Disrupt the Brain Barrier?

Proposed Compounds

It’s unknown if some supplements can disrupt the blood-brain barrier. This hasn’t been researched in humans.

Also, in some cases, increasing the permeability of the BBB is desired – especially if the goal is to get certain substances into the brain.

Animal studies and cellular research is investigating:

  • Andrographis/Andrographolide – and whether it can disrupt the layer of brain blood vessel cells when added into cell culture [86].
  • L-Arginine, which might force the blood-brain barrier to open up [87].
  • Zinc in rats with epilepsy [88].

On the other hand, the addictive tobacco compound nicotine seems to make the BBB less strong by re-shuffling blood-brain barrier proteins responsible for keeping it together [89].

Learn More in the “Leaky Brain” Four-Part Series

You can read about the introduction to the blood-brain barrier and possible causes of “leaky brain” in Parts 1 and 2.

About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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