Mannitol and the blood brain barrier

[rebtar]

This may be a question that has been discussed elsewhere but I can't find it. My understanding is that Mannitol opens the blood brain barrier. isn't that a problem?

[chartist]

There is concern about the idea that mannitol can increase the blood brain barrier (BBB) permeability but this effect of increasing permeability of the BBB by mannitol is short lived as in 10 minutes or less.

link.springer.com/article/1...

Such a short window of opportunity makes me think that the actual benefit of mannitol is due to increased butyrate production and other Short Chain Fatty Acids (SCFAs) leading to reduced inflammation of the gut microbiome and a possible reason that mannitol does not help all PwP is because some PwP no longer have enough of the specific gut bacteria that mannitol interacts with to increase production of butyrate, hence no increased butyrate production and no benefit in terms of symptom relief.

Mannitol is thought to reduce clumping of alpha synuclein in the brain and is the usual reason suggested for its use and benefit in PwP, but this seems more like a longer term effect that might not be so readily apparent in early use, while users report early benefit from mannitol suggesting there is some other activity at play, such as butyrate.

Butyrate has also shown to decrease intestinal permeability, which is increased in PwP.

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pmc/articl...

Butyrate also acts as a histone deacetylase inhibitor(HDACi) which should be very useful for PwP by potentially acting as a neuro protectant.

sciencedirect.com/science/a...

pubmed.ncbi.nlm.nih.gov/302....

PwP have reduced Regulatory T Cells or TREGs.

ncbi.nlm.nih.gov/pmc/articl...

Butyrate increases Tregs .

nature.com/articles/s41598-....

Butyrate enhances BDNF expression which is good for PwP.

google.com/search?q=does+bu...

Art

[rebtar in reply to chartist]

Thanks Art! That’s very interesting. Would taking a butyrate supplement have the same effect? I take one.

[chartist in reply to rebtar]

In one study I read, it suggested that oral butyrate will not have all of the benefit as butyrate that is formed in the body, but that is just one study and some butyrate has to be better than no butyrate. Another consideration is that oral butyrate does not come with the other two dominant short chain fatty acids (SCFAs), propionate and acetate which also have activity in the gut. Whereas when mannitol makes SCFAs in the gut, it makes all three.

Art

[sharoncrayn in reply to chartist]

you are referencing in Springer "intracarotid infusion" of mannitol, which is not oral. very different. therefore your theory ("Such a short window of opportunity makes me think that the actual benefit of mannitol is due to increased butyrate production") is potentially questionable.

"Mannitol is thought to reduce clumping of alpha synuclein in the brain" = in flies

[chartist in reply to sharoncrayn]

Yes, I don't think the beneficial effects of mannitol reported by PwP are due to reduced clumping of aSyn in the brain of flies or humans. It seems more likely that it is because butyrate degrades aSyn and offers protective effects for dopaminergic cells against aSyn.

pubmed.ncbi.nlm.nih.gov/318...

europepmc.org/article/med/2...

The following new study suggests that butyrate suppressed microglia over activation, decreases inflammatory markers including iNOS, reduced aSyn activation by 132% and 159% in the Substantia Nigra pars compacta, significantly increased the content of tyrosine hydroxylase (TH) by 12.3% and 20.2% and alleviated PD-induced motor disorder.

The study concluded the following :

Consequently, sodium butyrate could inhibit neuroinflammation and alleviate neurological damage of PD.

pubmed.ncbi.nlm.nih.gov/339...

It is only a mouse study, but it is a start in moving studies in this direction and further highlights the potential of butyrate in PD and other diseases.

Overall, the use of mannitol as a butyrate promoter seems like it should be very useful for PwP because of its multiple effects against many aspects of the disease. It has a safety profile that seems on par or better than many of the drugs currently prescribed for PD and some PwP have found significant benefit from it already.

Art

[sharoncrayn in reply to chartist]

"Bacteria involved in butyrate production in the rats used in this study were likely C. indolis andlactobacilli. Predominant detection of C. indolis with lactate-producing bacteria may explain the stimulation of butyrate production, because C. indolis was recently isolated from human feces as a predominant lactate-utilizing butyrate producer."

Most likely, Mannitol on its own doesn't promote butyrate.

also read: Sodium Butyrate Exacerbates Parkinson's Disease by Aggravating Neuroinflammation and Colonic Inflammation in MPTP-Induced Mice Model

[chartist in reply to sharoncrayn]

I don't have access to the full study, so I don't know the answer on the bacteria.

Yes, there are at least two bacteria needed for mannitol to promote butyrate and this is why I think mannitol does not work for some PwP because these same butyrate producing bacteria are low or depleted in some PwP and in PD in general as described in this human meta analysis from this year.

nature.com/articles/s41531-...

Yes I have seen the study you referenced and I have seen another mouse study which showed similar, but the 2021 study I linked to showed butyrate as very beneficial in PD model mice. Human studies show butyrate as healthful for humans in the amounts produced in a healthy gut, but butyrate is lower in PwP .

Art

[sharoncrayn in reply to chartist]

"Human studies show butyrate as healthful for humans in the amounts produced in a healthy gut, but butyrate is lower in PwP." Art

I don't remember any human study of any significance in PD or ALZ in terms of supplementation efficacy or of mannitol providing it. (Yes, a few re colon cancer which is not the issue here)

In summary,

"A few studies using oral administration of sodium butyrate indicate beneficial effects in PD animal models; however, prebiotic fibers that generate butyrate locally in the gut may be more effective. The design and selection of butyrogenic prebiotic fibers would allow preclinical studies to evaluate how gut-derived butyrate could affect PD pathophysiology."

"While this could result in direct actions in the brain, upper gastrointestinal tract absorption prevents most of the butyrate supplemented to reach the large intestine, where it has functions that could be relevant in PD (e.g., gut barrier function, regulation of inflammatory pathways, enteroendocrine hormone release)"

Potential of Prebiotic Butyrogenic Fibers in Parkinson's Disease

Thaisa M. Cantu-Jungles (2019)

[LAJ12345]

I thought you had to take with coffee for caffeine and it is the caffeine that open the bbb?

[sharoncrayn in reply to LAJ12345]

coffee/caffeine protects against BB leakage, i.e. integrity. therefore it doesn't 'open" the BBB. High cholesterol intake and prolonged, unprotected exposure to pesticides decreases BBB integrity.

"epidemiological studies have demonstrated repeatedly that caffeine and blockade of adenosine A2A receptors affords prophylactic protection (prevention) and not therapeutic rescue of endpoints related to PD."

" caffeine can prevent the opening of the BBB in two very different models of neurodegenerative disorders and in two different species"

from: Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer’s and Parkinson’s disease

[LAJ12345 in reply to sharoncrayn]

Thanks,

[sharoncrayn in reply to LAJ12345]

forgot about this old study...The effect of mannitol on the oral bioavailability of cimetidine

interesting study by Adkins, Davis where they found mannitol significantly SHORTENED transit time in the intestine compared to sucrose. We might extrapolate this finding to mean sinemet ir plus mannitol has a much shorter half life than sinemet ir alone, which would not be a positive. Alone, each has a similar half life (90 minutes).

"The implication of the study findings is that excipients cannot always be regarded as "inert" substances that can be incorporated into a formulation without having any deleterious effect on the overall in vivo behaviour of the product..."

in contrast, Kubo (1996) found mannitol increased bioavailability in a increasing mannitol to drug ratio (in dogs).

in TBI, stroke, ALZ, Pd, etc. the BBB is very likely damaged permanently resulting in movement and/or cognition dysfunction. coffee + mannitol will likely have very little impact when taken as a "monotherapy". Perhaps Segal and Gazit (2013, Israel) are correct about mannitol (and trehalose), perhaps not.

further, I doubt that coffee enhances mannitol's bioavailability or efficacy even though supposedly both (debated) cross the BBB.

does mannitol actually "open" the BBB?...depends on how much and how long and how given...and what study.

"In their letter, Drs. Hueng and Sytwu indicate mannitol can be used to open the BBB and, if used, could affect the study results. To support their assertion, they cite a study by Palma and colleagues.3

Nevertheless, that study did not indicate that intravenous mannitol opened the BBB but rather demonstrated that “mannitol may leak through the altered BBB near gliomas” into adjacent white matter, which is consistent with the BBB disruption associated with contrast-enhancing gliomas examined in our study.

mannitol is a BBB disrupter with pros and cons.

sharon

[rebtar in reply to sharoncrayn]

Thanks

[Gratitude60]

Thank you all for sharing your knowledge; it is very interesting. I've been taking mannitol for almost 4 months (1.5 ts, 2x per day). I also take Rasagiline, glutathione, and a few other supplements; as of now I don't need levodopa. I figured if it can't hurt me, then it was worth trying...just in case I responded similarly to the fruit flies and lab rats However, if it is potentially hurting me then, of course, I don't want to continue. Ugh....I am so confused.

[rancsikanna in reply to Gratitude60]

Hi I have read that you had great results with mannitol. It is still working for you? My husband triedbut for 3 days and it eliminated his handbtremor in50% which is unbelieveble

[Gratitude60]

Thank you for forwarded the previous postings.

[Gratitude60]

Hello Rebar,

I am no longer taking Mannitol because a few months ago I learned I had SIBO - small intestine bacterial overgrowth. It is when some of the bacteria of the large intestine gets into the small intestine. Anyway, the bacteria love sugars and since my diet has been mainly plant based with seafood, the bacteria are in heaven. I have had to change up my diet temporarily to low FODMAP foods - FODMAP stands for fermentable oligosaccharides, disaccharides, monosaccharides and polyols, which are short-chain carbohydrates (sugars) that the small intestine absorbs poorly. So, I needed to cut out mannitol.

That's probably more information than you wanted to read However, I wanted you to know why I stopped taking mannitol as I was on it for almost 2 years. I can't say it worked or didn't work since I do several interventions.

It's wonderful to hear that your husband started taking ot and found such dramatic relief. If I were him, I would continue.

[Little_apple in reply to Gratitude60]

How did you determine you have SIBO? What tests did you use? (Hope you don’t mind).

I suspect I do and that many PWP do.

[rebtar in reply to Little_apple]

my doctor ordered a test from a company called Aerodiagnostics, there are probably others.

[Gratitude60 in reply to Little_apple]

Similar to rebtar, the testing company is Aerodiagnostics. It is a breath test that measures methane and hydrogen at several 20 minute intervals after drinking lactolose. My understanding is that many PWP get SIBO probably due to the 'migrating motor complex' not working properly.