Blood brain barrier thiamine

Blood Brain Barrier Integrity and Early Thiamine Deficiency

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In my quest to understand oxythiamine (oxythiamine is an anti-thiamine molecule that appears to be synthesized in individuals with kidney disease), I stumbled upon a study from the mid-nineties where researchers examined blood brain barrier (BBB) integrity in early and late thiamine deficiency. They found that BBB breakdown not only preceded the pathogenesis of the more commonly considered white matter lesions associated with severe and chronic thiamine deficiency, but that BBB disintegration drives the deficiency-induced brain damage. This makes sense, of course, given thiamine’s role in energy metabolism and the fact that barrier function is energy intensive. If metabolic energy declines, then the barrier’s ability to prevent noxious molecules from reaching the brain will decline, as will its ability to filter out endogenously created waste products and other toxins. The entire exchange process will be weakened and across time, brain damage will accumulate.

Insofar as the gut barrier and the brain barrier are intimately connected, might we surmise that if BBB disintegration precedes and drives much of the brain damage evoked by thiamine deficiency, then would not ‘leaky gut’ and the symptoms therewith come before the leaky brain? I believe so. This was not part of this experiment and in no way indicated directly, but there were some hints that point me in this direction and certainly research published over the last decade or so supports this.

In this particular study, the investigators were looking at the patterns of dysfunction that arose when thiamine deficiency was induced by different mechanisms. To explore these differences, they used four groups of mice:

  • Group 1: Mice fed a thiamine-free diet and given pyrithiamine, a thiamine antagonist that readily crosses the BBB.
  • Group 2: Mice fed a thiamine-free diet and given oxythiamine, a competitive thiamine antagonist that blocks the transketolase enzyme, but does not appear to cross the BBB.
  • Group 3: Mice fed a thiamine-free diet and given pyrithiamine for 10 days, and then fed a normal diet and given thiamine (20mg/kg) injections. This was to determine whether recovery was possible.
  • Group 4: The control group fed a normal diet.

Groups 1, 2, and 4 were sacrificed on days 8, 9, and 10, while group 3 was sacrificed on day 14.

I should note that estimates equating mouse lifespan with human lifespan propose that 9 days in the life of a mouse is equivalent to about one human year. In contrast, for rats, researchers estimate that 13.2 days equal one human year. Keep these numbers in mind when considering animal research. Other differences apply, of course, but lifespan differences are huge.

With that in mind, in this particular study where thiamine was completely abolished from diet and blocked using anti-thiamine molecules, neurological symptoms appeared after 10 days of thiamine deprivation in mice and if thiamine was not repleted, the animals died within 48 hours thereafter. In contrast, rodents can live up to 4-5 weeks before succumbing to the effects of thiamine deficiency.

This would seem to suggest that we, as humans, might survive the complete absence of thiamine from diet, plus anti-thiamine blockade via pyrithiamine, for up to a year. This is unlikely. However, experiments using extremely low doses of thiamine (.15-.45mg p/day) have shown survival, with severe neurological deficits and damage, but survival nevertheless, for up to 6 months. We also have reports of patients with significant, lab tested deficiency who, though quite ill, live for years.

In contrast to the experimental conditions though, with human thiamine deficiency, especially as it develops later in life (genetic defects that appear at birth are a different story), there is rarely a complete blockade of thiamine or absence of thiamine from diet. Dietary consumption and anti-thiamine factors vary considerably from day to day and year to year and so the trajectory from deficiency to illness in humans will be prolonged and non-linear. That being said, there are some things we can learn from experimental protocols such as this one. Namely, that the mechanism of deficiency matters as it will affect which body compartments are affect most prominently in the early stages.

The Compartmentalization of Thiamine Deficiency

In this study, we saw the effects of long term thiamine deficiency in different tissues generated by the different anti-thiamine molecules. Pyrithiamine affected the brain and nervous system, while the effects of oxythiamine were most prominent in the periphery, likely the GI system and in the heart, although these were not tested.

We also see the time course of symptomology, where early on symptoms are not as noticeable until a certain threshold of damage is met. For example, neither histological lesions nor symptoms were obvious prior to day 8 of thiamine deprivation in the pyrithiamine group. This is roughly equivalent to almost a year in human life span. The animals showed an initial weight gain followed by a sharp decline on day 9 and the onset severe neurological symptoms at day 10. According to the researchers:

The initial neurological signs of thiamine deficiency appeared acutely and precisely on day 10, consisting of loss of activity, hyperactivity on acoustic or tactile stimulation, and ataxia.

Commiserate with the neurological symptoms in the pyrithiamine group, disturbed BBB function, necrosis, and numerous brain lesions were observed. If thiamine was withheld, the animals died within 48 hours. If thiamine was repleted (this was done only with the pyrithiamine group), most, but not all, of the animals survived and neurological symptoms abated. This is promising, but suggests there are still unrecognized variables that influence recovery.

In contrast, there were no lesions within this timeframe for the oxythiamine group. With oxythiamine, the only observable symptoms were weight loss and decreased activity. In fact, the oxythiamine animals maintained normal weight and activity until day 6 and then on day 8, there was observable weight loss, anorexia and decreased activity. There were no behavioral signs of neurological damage. It is not clear at what point the oxythiamine animals would have died naturally or by what means, as they were sacrificed at day 10 regardless of state.

The Heart of the Matter

Another study using rodents, points to oxythiamine affecting the heart more prominently than pyrithiamine. Here, oxythiamine treated rats showed a similar pattern of weight loss beginning after the 7th day, but also developed bradycardia and cardiac hypertrophy, which progressively worsened over the next few weeks. In contrast, the animals treated with pyrithiamine did not show heart-related changes until after developing the neurological symptoms. Moreover, the heart-related changes were not as prominent as those in the oxythiamine group. I will discuss this study more fully in a subsequent post, but it seems to suggest different mechanisms for what we call wet and dry beriberi. That is, oxythiamine results in peripheral metabolic symptoms perhaps related first to the GI system (weight loss and anorexia) and then to the heart, while blockade of thiamine via pyrithiamine results in brain and nervous system symptoms and damage. In both cases, I suspect there is disruption to gut barrier function. With pyrithiamine though barrier dysfunction seems to begin in the brain and nervous system and progress to the periphery, whereas with oxythiamine preferentially targets tissues in the periphery and only later reaches the BBB and the nervous system. Again though, this is not clear. As most of the studies I have read seem to investigate only one or the other.

Obviously, the mechanisms by which these two molecules deplete thiamine differs significantly, which then explains many of the differences observed in the animals, but what intrigues me is how closely the ‘symptoms’ align with human cases of thiamine deficiency where neither compound is administered. This begs many questions, not the least of which is whether and how we might produce these molecules endogenously or be exposed to them in everyday life. How could these patterns observed experimentally so closely align with the human experience (wet beriberi – oxythiamine, dry beriberi – pyrithiamine), where neither compound is provided. I do not know the answer. Yet. In the meantime, here is some more information on the mechanisms of oxythiamine and pyrithiamine and how we might be synthesizing them endogenously: Can We Synthesize Oxythiamine and Pyrithiamine Endogenously?

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Image by Pete Linforth from Pixabay.


Chandler Marrs MS, MA, PhD spent the last dozen years in women’s health research with a focus on steroid neuroendocrinology and mental health. She has published and presented several articles on her findings. As a graduate student, she founded and directed the UNLV Maternal Health Lab, mentoring dozens of students while directing clinical and Internet-based research. Post graduate, she continued at UNLV as an adjunct faculty member, teaching advanced undergraduate psychopharmacology and health psychology (stress endocrinology). Dr. Marrs received her BA in philosophy from the University of Redlands; MS in Clinical Psychology from California Lutheran University; and, MA and PhD in Experimental Psychology/ Neuroendocrinology from the University of Nevada, Las Vegas.

1 Comment

  1. Clearly, we need ways to measure these molecules, and also net ATP throughput.

    I observe in myself that I do badly when consuming fruit, and vetter when consuming probiotic-cultured yoghurts so I’m watching this topic closely.

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