A leaky blood-brain barrier is a hallmark of all neurological and psychiatric disorders, including cognitive dysfunction (brain fog), Alzheimer’s disease, depression, and schizophrenia.

It is important to note that leaky brain does not always start in the brain. Diseases and other problems elsewhere in the body, such as diabetes or leaky gut, may trigger a leaky brain.

In this post, we cover 11 surprising factors and disease states that can disrupt the blood-brain barrier and cause a leaky brain.

Leaky Brain – Part Two of a Three-Part Series

Brain Injuries Disrupt the Blood-Brain Barrier

1) Stroke Disrupts the Blood-Brain Barrier

Strokes cause a lack of glucose and oxygen. This leads to a rise in potassium, the depletion of ATP, and a release of glutamate, which all contribute to blood-brain barrier disruption [R].

Under stroke conditions, the tight junctions that help prevent substances from entering the brain have compromised integrity. This means that the tight junctions are weaker and increase BBB permeability [R].

After a stroke, reperfusion (restoration of blood flow to the brain or tissue) occurs. Reperfusion may cause additional tissue damage and an increase in inflammation, which also worsens the blood-brain barrier’s condition [R].

Blood-brain barrier breakdown after cerebral ischemia/reperfusion. Source: https://www.nature.com/articles/ncomms10523/figures/10

In a study of human brain tissues from five cases of fatal strokes, MMP9 levels were higher in the affected areas. Higher MMP9 levels are a good indicator of increased BBB permeability [R].

2) Traumatic Brain Injuries Induce Blood-Brain Barrier Breakdown

https://www.ncbi.nlm.nih.gov/pubmed/25624154

After traumatic brain injury, the blood-brain barrier also becomes dysfunctional. This leads to the leakage of proteins and negatively affects immune cells [R].

BBB breakdown may last from several days to weeks after head trauma. In some cases, the BBB can be dysfunctional for years [R].

Head trauma injures blood vessels in the brain. It leads to impairments in brain-blood flow, BBB permeability, and metabolic processes. It also reduces oxygen levels in the brain, which further induces BBB breakdown [R].

Traumatic brain injuries also cause damage to the neurovascular unit. When the nerve cells die quickly, it causes another cycle of injury after the initial brain injury [R].

After traumatic brain injury, excessive superoxide reacts with nitric oxide to form peroxynitrite. Peroxynitrite contributes to BBB leakage [R].

In traumatic brain injury-induced adult male rats, treatment to reduce peroxynitrite also decreased BBB leakage. S-nitroso-glutathione (GSNO) helps stop BBB dysfunction and provides protection to nerve cells [R].

3) Brain Tumors Cause Blood-Brain Barrier Breakdown

There is a loss of tight junction molecules in brain tumor blood vessels. Tumors also affect cell formation and prevent the release of factors necessary for blood-brain barrier (BBB) function [R].

Brain tumors also cause fluid to leak into the brain. The open tight junctions cause brain edema [R].

In a study of 10 patients with brain tumors, brain scans showed an increase in BBB permeability [R].

Another study of mice with brain tumors had similar results. The mice had an increased BBB permeability to sodium fluorescein (a marker for BBB integrity). BBB breakdown is also associated with faster cancer growth [R].

It is difficult to treat brain tumors because the BBB prevents the transport of drugs into the brain. Scientists are currently studying new therapies that are able to cross the blood-brain barrier [R].

4) Hypertensive Encephalopathy

An increase in brain blood pressure may cause hypertensive encephalopathy. Symptoms include a severe headache, confusion, and impaired judgment and memory. Coma, convulsions, and other brain problems can occur afterward [R].

Breakdown of the blood-brain barrier (BBB) during increased brain blood pressure leads to reduced blood flow and excess fluid in the brain [R].

Normally, hypertension (high blood pressure) activates pathways to maintain the BBB. However, in animal models of hypertensive encephalopathy, hypertension overrides the BBB [R].

During hypertensive encephalopathy, BBB dysfunction is widespread. It can cause brain edema, which is the life-threatening excess accumulation of fluid in the brain. Although there are methods to stop brain edema, there are no treatments that specifically target the BBB [R].

Obesity, Poor Diet, and High Blood Sugar Cause Leaky Brain

4) Obesity and Metabolic Syndrome Increases Barrier Permeability

Obesity causes a variety of inflammation-related disorders. Together, they are referred to as metabolic syndrome. The obesity-induced inflammation also causes problems in the blood-brain barrier (BBB) [R].

Diet-induced obesity leads to an increase in proinflammatory cytokines, which increases BBB permeability [R].

Obesity also causes C-reactive protein levels to be elevated. In rats, high doses of C-reactive protein increase BBB permeability, which impairs brain function. It mainly affects tight junction function [R].

High-fat diets and obesity cause blood vessel problems, damaging the BBB integrity. In a study of male rats, in comparison to mice fed a healthy diet, a high-fat diet increased BBB permeability [R].

Moreover, the results from this study suggest that vitamin D supplementation helps protect the BBB. Although it does not seem to have any effect on the control group, vitamin D treatment significantly improved BBB integrity in rats fed a high-fat diet [R].

Meanwhile, the rats that were fed a high-fat diet but did not receive vitamin D supplementation had higher BBB permeability [R].

5) Diabetes Increases Blood-Brain Barrier Permeability

Blood-brain barrier permeability is increased in diabetic patients and animals. Diabetes may result in the disruption of the blood-brain barrier [R, R].

Elevated glucose levels increase oxidative stress in the brain and the pericytes. This kills the pericytes (by apoptosis) and disrupts the blood-brain barrier (BBB). By blocking glycolysis (the breakdown of glucose), BBB pericytes are protected [R].

During diabetes mellitus, reactive oxygen species accumulate at the blood-brain barrier. This causes oxidative damage, further damaging the BBB and increasing its permeability [R].

Researchers tested BBB selectivity in diabetes-induced rats. Results indicated that diabetes caused the loss of tight junction proteins and increased MMP-9 activity, which led to an increase in BBB permeability [R].

Infections, Leaky Gut and Inflammation Cause Leaky Brain

6) Leaky Gut Contributes to Leaky Brain

Disease initiation process when there is leaky gut

Disease initiation pathway. Depicted is a proposed model of the initiation of autoimmune disease. In this model, an initiating factor is found in the environment (lumen of the gut) that is kept separate from the mucosal immune system by a competent epithelial barrier. Abrogation of this barrier by any mechanism allows for initiation of the disease process.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856434/

Leaky gut happens when the permeability of the intestine increases. A leaky gut also contributes to a leaky brain [R].

The blood-brain barrier (BBB) helps relay information between the brain and the gut. The BBB transports peptides and proteins from the brain to the gut and vice versa [R].

Stomach hormones affect BBB function. Gut peptides may also inhibit or increase the release of cytokines from brain cells [R].

Changes in the gut also influence the permeability of the BBB. The blood-brain barriers of mice are vulnerable to changes in the gut microbiota. In germ-free mice (with no gut bacteria at all), exposure to gut microbiota from pathogen-free mice reduced BBB permeability [R].

In addition, a leaky gut occurs in many inflammatory diseases, including diabetes. Leaky gut may contribute to the onset of inflammation and diabetes, which also contributes to BBB damage [R].

7) HIV Infection Damages the Blood-Brain Barrier

HIV infection and viral proteins damage the blood-brain barrier’s integrity. This also contributes to the progression of HIV-associated brain disorders [R].

During HIV infection, the HIV virus infects CD4+ T cells and monocytes, which then cross the blood-brain barrier (BBB) and spread the infection. Because the BBB does not allow for easy transfer of foreign molecules, it is hard to treat HIV [R].

In the HIV-infected tissue, the BBB had high permeability, cell death, and abnormal interactions with blood vessels [R].

Following HIV invasion, proinflammatory cytokine levels also increased. Inflammation also increases BBB permeability [R].

HIV gp120 protein causes an increase in reactive oxygen species. The increase in oxidative damage also contributes to BBB dysfunction [R].

Although combination antiretroviral therapy helps decrease viral load in the body, it cannot lower virus levels in the brain. Nanocarriers have the potential to cross the BBB and reduce HIV virus levels. More studies are needed to be performed before an effective therapy is found [R].

8) Meningitis Increases Blood-Brain Barrier Permeability

Bacterial meningitis infection disrupts the blood-brain barrier (BBB). During meningitis, TNF-alpha damages blood vessels, causing an increase in BBB permeability [R].

There are many ways that bacteria disturb the blood-brain barrier. These ways include disrupting the tight junctions through toxic effects, inducing inflammation, or interfering with junction formation [R].

In one study, 48 patients with bacterial meningitis had significantly higher levels of TNF-alpha compared to 66 controls. High levels of TNF-alpha is correlated with higher albumin levels in the brain, and its proinflammatory effects contribute to BBB damage [R].

9) Lyme Disease Compromises Blood-Brain Barrier Integrity

Lyme disease, or Lyme neuroborreliosis, is an infectious disease. It is a bacterial infection which is transmitted to humans by the bite of infected ticks. B. burgdorferi bacteria invades the immune system and also spreads to the brain and nervous system by crossing the blood-brain barrier (BBB) [R, R].

Spinal fluid samples from Lyme disease patients showed higher levels of blood proteins (fibrinogen and immunoglobulin) compared to healthy subjects. This is evidence that the BBB integrity is compromised during Lyme disease [R].

There has been very little information on how the bacteria cross the BBB to infect the nervous system.

Researchers used to think that B. burgdorferi bacteria induced plasminogen activators and MMP production. These enzymes degrade tight junction proteins that help with BBB selectivity. This increased BBB permeability and alloweds for the bacteria to cross it [R, R].

However, in a study of human cell culture, there was no indication of tight junction protein dysfunction. Therefore, the mechanism by which the bacteria lowers BBB permeability is still unknown [R].

10) Alcoholism Damages the Blood-Brain Barrier

Alcohol abuse causes blood-brain barrier (BBB) dysfunction. The increase in BBB permeability leads to brain damage [R, R].

After consumption, alcohol readily crosses the BBB. Alcohol damages the tight junctions in the gut and allow LPS (a bacterial toxin) to leak into the bloodstream. This eventually leads to the release of proinflammatory cytokines into the blood that cross the BBB [R].

Lipopolysaccharides-in-Bacteria-Cell-Wall

Lipopolysaccharides in gram-negative bacteria cell walls

Ethanol is the main alcohol in alcoholic beverages. In human cell culture, ethanol increases the activity of ethanol-metabolizing enzymes. When these enzymes metabolize ethanol, they produce reactive oxygen species that cause oxidative damage [R].

In addition, by disrupting tight junctions, alcohol disrupts BBB integrity.

(Technical: Activation of IP3R proteins causes calcium release, which activates myosin light chain kinase and disrupts tight junction function) [R].

Through this study, researchers concluded that one episode of binge drinking does not cause brain damage. However, repeat cycles of alcohol consumption and withdrawal cause severe BBB dysfunction and brain damage [R].

In rats, alcohol consumption caused the BBB to be more susceptible to damage from LPS toxin injection (simulating leaky gut). It prolonged the inflammatory response, but it suppressed programmed cell death in nerve cells. Chronic alcohol drinking makes you more susceptible to infection and inflammation-related disease by letting toxins through the BBB [R].

11) Acute Liver Failure Causes Blood-Brain Barrier Dysfunction

Acute liver failure is the sudden loss of liver function. It occurs when the patient does not have any pre-existing liver disease. Acute liver failure eventually causes patients to be in a coma [R].

The liver releases the breakdown products of injured liver cells into the bloodstream during acute liver failure. This includes pro-inflammatory cytokines like TNF-alpha, IL-1, IL-6, and ammonia. These cytokines cause brain inflammation [R].

The inflammation causes the blood-brain barrier (BBB) to become more permeable. BBB dysfunction causes fluid to accumulate in the brain. In one study of postmortem acute liver failure patients (that were comatose), 80% showed evidence of fluid in their brains [R, R].

In acute liver failure patients, the injured liver released MMP9 into the bloodstream. The circulating MMP9 damages the tight junctions at the BBB. This increases BBB permeability and allows brain damage to occur [R].

A mouse model of liver failure showed that TIMP-1, an MMP9 inhibitor, reduced BBB dysfunction. By stopping MMP9, TIMP-1 protected the tight junctions and other cells at the BBB. However, TIMP-1 is known to promote cell and tumor formation, so it is not a good therapy for stopping a leaky brain [R].

It is possible for BBB permeability to return to normal levels if the patients quickly receive a liver transplant. However, there is still a possibility that the transplant will occur too late while the brain injury still progresses [R].

Leaky Brain – Part Two of a Three-Part Series

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