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Blood-brain barrier question
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Blood-brain barrier question

Hello fellow warriors!

I'm searching for information about HCV, the meds we're taking, and whether they can cross the blood-brain barrier.

I just read that the HCV virus has been proven to penetrate that barrier (see article at: http://www.birmingham.ac.uk/news/latest/2012/01/17Jan-HCV-Press-Release.aspx ). The article states that 4 out of 10 HCV patient autopsies had the virus in their brains.

Years ago, I remember reading a theory that a post tx relapse could have been caused by HCV virons hiding behind the dense blood-brain barrier and after treatment, the virus replicated and relapse occurred. At the time, peg and ribavirin were the normal treatment, and those molecules were thought to be too large to penetrate that barrier. That was before the protease inhibitors came along.

Is there any information about whether the newer treatments, PIs plus peg & riba, can penetrate this blood-brain barrier? Any ideas or theories out there?

BTW, I am on a phase 3 BI201335 trial- once a day, 240 mg. PI plus peg and riba SOC- week 14. Barely hanging in there- it's been brutal!

Best to you all!

newb




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23 Comments Post a Comment
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163305_tn?1333672171
Um, maybe I'm not understanding this correctly. Since hep C is in our blood why wouldn't it be everywhere our blood is, brains included?
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1765684_tn?1333822768
Because our brain and spinal column is separately by this "blood brain barrier".  Keeps critters 'n stuff (that's a scientific term, where I come from) present in our bodies from entering the brain and spinal column.

I don't know the answer to that question, though. :)
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1815939_tn?1377995399
Viruses can cross the blood-brain barrier. Many other substances, including most bacteria, cannot. Unfortunately neither can many drugs.

http://www.newworldencyclopedia.org/entry/Blood-brain_barrier

The foloowing is only a very small section of the article:

"The blood-brain barrier helps to separate the brain from the bloodstream, allowing the select filtering of molecules and objects that are allowed to enter the brain. Certain substances that are harmful are prevented from entering the brain from the bloodstream, such as toxins and bacteria. Other substances that are necessary for the metabolic activities of the brain, such as glucose for energy, oxygen for respiration, and amino acids for building proteins, are allowed to pass through this barrier. In addition, the barrier helps to maintain the volume of the brain fluid, since the brain is located in a rigid skull. This it does by limiting the movement of salts and water from the blood into the extracellular fluid and the BBB secretes brain extracellular fluid at a controlled rate to help maintain brain volume (Segal 2001).

The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare. However, since antibodies are too large to cross the blood-brain barrier, infections of the brain that do occur are often very serious and difficult to treat. Viruses easily bypass the blood-brain barrier, however, attaching themselves to circulating immune cells. The HIV virus uses the brain as a sanctuary, hiding behind the blood-brain barrier from the defense mechanisms of the body (Segal 2001).

Several areas of the brain are not "behind" the BBB. One example is the pineal gland, which secretes the hormone melatonin "directly into the systemic circulation" (Pritchard and Alloway 1999).

Segal (2001) notes that the blood-brain barrier is found in all vertebrates, as well as in squids and octopuses, with an analogous structure in insects. In humans, it is formed by the third month of gestation."
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1711722_tn?1356491154
Wow.  This is one of those obscure subjects I actually know a little bit about.  I have followed the career of Dr. Keith Black (brain surgeon), who developed a way to get past the blood brain barrier.  I don't have an answer to your question but think he would be one of the best people to help with your question:

http://www.cedars-sinai.edu/Patients/Programs-and-Services/Cancer-Center/Expert-Team/Neuro-Oncology/Keith-L-Black.aspx

"Dr. Black pioneered research on designing ways to open the blood-brain barrier, enabling chemotherapeutic drugs to be delivered directly into the tumor"
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Avatar_n_tn
This really is a fascinating subject, and is going to provide lots of fertile ground for future research.  The finding of HCV replication in the brain actually goes beyond what most HCV researchers previously had believed.  Most had believed that this 'compartment' (the brain) was not compromised by HCV infection.  We now know that it can and frequently DOES happen...and now the researchers need to determine what this means...in areas like...HCV extrahepatic symptoms...(brain fog anyone?)...and relapse, as was mentioned above...questions like does the virus in the brain go away after we reach SVR???  How and why do some people develop the brain infection and others apparently do not???  What does the virus do to our brains and CNS over long periods of time?etc.  

Its going to open up a whole new area of investigation, I believe...and will make HCV become known as more than a  "Liver Virus" only.

I am curious to hear other comments and interpretations from our members.

DoubleDose
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Avatar_f_tn
This blood-brain barrier issue is a puzzle, isn't it? More questions come to mind:

What causes some people to have the HCV virus in their brain, while others don't - is it the length of time with the virus that determines that? If so, wouldn't it be logical that the people who have had HCV for the longest time also be more likely to have compromised liver health? If true, are people with cirrhosis more likely to have HCV inside their brain and have a lower success rate with tx? Is it virus hiding in the liver or behind the bbb that causes relapse?

Another question: since the bbb protects the brain from viral and bacterial invasions, and those of us on tx have horribly compromised immune systems, how safe would it be to allow the possibility of harmful critters to penetrate our blood-brain barrier? Would it be possible to allow some meds to enter the barrier, but keep others out?

Wish there was more info out there about this. Maybe it would be better to turn on the TV, just keep taking my meds and quit dwelling on it!  

Best to you all!
newb
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1815939_tn?1377995399
I think this is an interesting topic also.

Actually, viruses do cross the blood-brain barrier which is how HIV and HCV (as well as other viruses) get into the brain.

Below I have included links and exerpts from some (longer) articles:

"The blood-brain barrier is an intricately coordinated mechanism for protecting the brain. It is essential for the functioning of the complex brain of vertebrates. The breakdown of the blood-brain barrier is implicated in several diseases, including meningitis, epilepsy, and multiple sclerosis. However, even when functioning properly, the blood-brain barrier cannot protect against the entry of some harmful substances, such as viruses, which have developed mechanisms to bypass the barrier. The blood-brain barrier also restricts the entry of antibodies that help to fight bacterial infections that do occur and makes it difficult for the delivery of water-soluble drugs that have been developed to treat diverse conditions. However, an understanding of the mechanism of the blood-brain barrier has allowed researchers to develop means to deliver such drugs."

"The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare. However, since antibodies are too large to cross the blood-brain barrier, infections of the brain that do occur are often very serious and difficult to treat. Viruses easily bypass the blood-brain barrier, however, attaching themselves to circulating immune cells. The HIV virus uses the brain as a sanctuary, hiding behind the blood-brain barrier from the defense mechanisms of the body (Segal 2001)."

http://www.newworldencyclopedia.org/entry/Blood-brain_barrier

This article is also interesting:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697631/
And this also is an interesting article:
http://www.thebody.com/content/art233.html

"Vitamin C could provide a key to unlock the blood-brain barrier, which stops many drugs from getting into the brain where they could potentially treat diseases such as Alzheimer's or epilepsy, according to preliminary findings from researchers in Italy. Dr. Stefano Manfredini and colleagues found that drugs used to treat neurological disorders appear to slip past the blood-brain barrier more easily when a vitamin C molecule is attached.

"Ascorbic acid works like a sort of a shuttle. Theoretically, it could transport onto the brain any compound," Manfredini told Reuters Health.

Potential applications include not only drugs for Alzheimer's, Parkinson's and epilepsy, but also viral infections, including AIDS. "



"Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. "

This article discusses HIV drugs and the blood brain barrier:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678986/

And this is promissing:
http://www.infectioncontroltoday.com/news/2011/10/potential-new-drugs-plug-brains-biological-vacuum-cleaner-and-target-hiv.aspx


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163305_tn?1333672171
Thank you everyone for enlightening me. I've never thought much about my brain, as long as it works, I'm happy.
This is truly intriguing.
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Avatar_n_tn
This may also correlate to the MRI images of the brain that have shown various abnormalities for those who have active HCV infection.  Maybe its less from the immune system reactions to the virus in the blood, and more due to a direct reaction to virus in the brain.  Could the virus cause changes or degradation in brain tissues and 'circuits', etc.??  Is the brain virus what causes some pepole with HCV to have more severe 'extrahepatic' symptoms...like extreme fatigue, depression, behavioral issues, vertigo, coordination problems, etc?  Let's just hope that our SVR's got the brain virus along with all the other HCV in our bodies!  

DoubleDose
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148588_tn?1407125204
IFN doesn't cross the bbb very well. My thought has always been that whatever adaptation the virus has had to make to accomplish that crossing leaves it less viable or unable to cross back into the boodstream. Since the positive and negative strand RNA that 85-90% of patients show disappear from these compartments (brain, spinal column, etc.) within 8 years of SVR, the point would seem to be moot unless you get some heavy dose of immunosuppressive tx.
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Avatar_n_tn
Are there studies out there showing the eradication of the virus in the brain and spinal fluids, etc. post SVR?  I am not aware of what studies have been done to this point.  I would assume that for brain studies in SVR's it would be only on autopsy?  Let me know what you have found as far as post-SVR eradication in compartments.  Thanks.

DoubleDose
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Avatar_m_tn
While not really what you're looking for I think it has some relevance.

Hepatitis C treatment – Clearing the mind
Daniel M. Forton


"....Byrnes and colleagues report their findings
in a small patient cohort which was studied with proton
MRS and cognitive assessment before, during and after standard
antiviral treatment with pegylated interferon and ribavirin. A
second group of untreated patients was also studied at two time
points. Overall, there were no significant changes in cerebral MRS
during and after antiviral treatment. However, a sub-group analysis
of viral responders and non-responders showed significant
metabolic changes over time in the responder group only, consistent
with normalisation of the metabolites, previously reported
as elevated in HCV infection [9,10]. Significant reductions were
observed in basal ganglia Cho/Cr and mI/Cr ratios in SVRs
(n = 8) but not in non-responders or relapsers (n = 6). The authors
interpret this as an improvement in cerebral immune activation
in those who cleared the virus. Patients in the treated and
untreated groups tended to show an improvement in cognitive
function over time, which was ascribed to a practice effect on
the cognitive battery. However, when responders and nonresponders
were compared again, SVRs demonstrated significant
improvements in verbal learning, memory, and visuospatial
memory, which were not seen in the non-responders...."

http://www.natap.org/2012/HCV/PIIS0168827811008038.pdf
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1815939_tn?1377995399
That is interesting information, Mike. Thanks for posting.

I sure hope I reach SVR. I can use a brain tune-up, lol.
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148588_tn?1407125204
I think it was willing who posted a study citing the 8 year figure, but I couldn't find it in the old postings when I looked for it last night. Maybe it was dointime. I'll keep looking and will post to this thread when I find it. I can only handle so much of this site's dysfunctional search engine.
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148588_tn?1407125204
http://www.ncbi.nlm.nih.gov/pubmed/21040725

"CONCLUSIONS: Trace amounts of HCV RNA of pretreatment sequence persisted and reappeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection."

Sorry, I misremembered. This study was about plasma/lymphocytes not CNS.
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170654_tn?1330082729
So I wonder how "Occult HCV" will play into this BBB issue. From what I've heard the occult variant is not detectable in the blood but is in other organs like the brain as well as the liver.

If we have an occult HCV infection in the brain, does the treatment drugs reach them and if not can this occult infection cause you to develop HCV again after an SVR. There must be research going on somewhere on this topic. If anyone finds it please share it here.

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170654_tn?1330082729
Well here's one for starters.

Persistence of hepatitis C virus in peripheral blood mononuclear cells of sustained viral responders to pegylated interferon and ribavirin therapy.
Gallegos-Orozco JF, Rakela J, Rosati MJ, Vargas HE, Balan V.
Source
Department of Internal Medicine, Mayo Clinic, Arizona, Phoenix, AZ, USA
.
Abstract
The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression.

http://www.ncbi.nlm.nih.gov/pubmed/18594984?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Avatar_f_tn
Thanks for finding all the great study information.

I tried using Google Translate to decipher it all, but that didn't work. So, does anyone have a copy of "Translating Studies for Dummies" I can borrow? ;-)
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148588_tn?1407125204
Got something better.

http://www.medhelp.org/health_pages/Hepatitis/HepResearcher-doctor-on-various-topics/show/38?cid=64

We used to have members who are genius in the field and for a long time were willing to explain these type of topics in layman's terms. The above link is a partial collection of threads covering many topics. You might also look for threads containing postings by 'SonicBandaid'.
I personally am indebited to HR, who was willing to help me with issues relating to toxins I'm exposed to on the job. Being willing to discuss these issues is a gift beyond treasures. My long term health may eventually profit from these postings as much as my SVR.
Keep in mind these gentlemen are at the top of their field and took the time to post here.
Free.
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Avatar_m_tn
Here is a quote from the University of Birmingham:

"Scientists at the University of Birmingham have demonstrated for the first time that human brain cells can become infected with the Hepatitis C virus (HCV), it is reported today (Tuesday January 17, 2012).

The team of virologists found that the endothelial cells in the brain possess the four main protein receptors necessary for the blood-brain barrier to be targeted by HCV.

The findings, which are published online today in Research Highlights in the journal Nature Reviews Gastroenterology and Hepatology, show that cells other than liver hepatocytes can be vulnerable to HCV infection. "

So, yes, HCV causes inter-cerebral infections which are the probable cause of fatigue, etc.
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1751426_tn?1399011084
I completed this same trial on Dec.23 and was UND all the way through until my 12 wk post tx bloodwork showed I had relapsed.  I am very curious about this same topic since I wonder how the virus could have survived such an onslaught.  I also found the tx brutal in all aspects (mental, physical and emotional) and have yet to recover only to find the virus has returned.  If the virus has crossed the bbb then what will it take to reach a true SVR?  The other truly interesting point in all this for me is that it is quite possible I have had the virus for about 36 yrs and yet my fibroscan results range from 5.6 to 6.2 meaning  very little fibrosis of the liver.  It has driven home the fact that clinical trials and all tx for that matter are not to be entered into lightly.  We have come a long way but its a big forest and we're not out of the woods yet.
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Avatar_f_tn
I was saddened to read your recent post about relapsing, but couldn't find the words to write. It's unfair that we endure so much, at such great cost to our health and personal lives, only to end up back where we started, or worst. I really admire your ((what's the word??)).... acceptance?.... lack of anger?..... philosophical attitude???

An interesting part of this trial is that when people in the study are on the placebo for 12 weeks, they get put on the real treatment for as long as they need, but if those that go through the 24 weeks with 12 weeks real drug & 12 placebo fail, they are just cut loose afterward, with no further medical help. It really is a crapshoot, as it is with fibrosis. Some are lucky, but many aren't.

Best to you- I hope you start feeling better very soon. With the payoffs for the drug companies so high, there's a good chance that someone out there is working on a better tx with a 100% cure rate. We can hope!
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Avatar_f_tn
Gastroenterology. 2012 Mar;142(3):634-643.e6. Epub 2011 Dec 1.

Hepatitis C virus infects the endothelial cells of the blood-brain barrier.

Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez-Ramirez MA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, McKeating JA.


Source

Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England.


Abstract

BACKGROUND & AIMS:

Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS.

METHODS:

We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication.

RESULTS:

Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis.

CONCLUSIONS:

Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.

Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.


Interesting stuff is all I can say
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