I understand that many of us PD sufferers benefit from vitamin B1 therapy as outlined in Dr. Constantini's publications, current Facebook group , and per many posts herein . I know it doesn't help everyone, but I was curious if there are any theories on its mechanism of action? The reason I ask is I noticed on Dr. Laura Mischley's graph of diet and PD progression that many items that seem to contain a fair amount of calcium e.g. milk, dairy, cheese, yogurt, are associated with a more rapid progression of PD. I then happened to notice in an articles recently that B1 has an effect on calcium, and that calcium dysregulation is thought to be a potential culprit in the development of PD. Just curios and by no means recommending a no-low calcium diet as we need strong bones for our falls!
The second group of experiments tested whether thiamine alters oxidant-sensitive aspects of calcium regulation including endoplasmic reticulum (ER) calcium stores and capacitative calcium entry (CCE). Thiamin diminished ER calcium considerably, but did not alter CCE. Thiamine did not alter the actions of ROS on ER calcium or CCE.
PD is a multifactorial ND with diverse molecular and neural disturbances such as autophagy and mitochondrial disruption, ER stress and deregulation of calcium hemostasis which trigger Dopaminergic (DA) neural death in the Substansa Nigra (SNs) located in the midbrain (24). Loss of calcium hemostasis causes neural cell death in SNs. Abnormal calcium hemostasis in DA neurons might be due to the consequences of mitophagy disruption, ER stress, mitochondrial dysfunction, and α-synuclein aggregation.
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- We would need first to understand how high-dose thiamine works. As there are only hypotheses about it, different mechanisms have been proposed.
- One theory is that high doses of b1 could stimulate and reactivate cellular metabolism (e.g. key enzymatic reactions in glucose and energy metabolism), overcoming a possible metabolic block caused by the effects of Parkinson's. This block would eventually prevent the cell from producing the energy needed for its metabolic processes. Together with a reduction in thiamine-dependent antioxidant and anti-inflammatory functions and in other thiamine-related effects, this would gradually lead to neuronal cell death and eventually Parkinson's symptoms.
- Some of the mechanisms suggested include: a) an inability to transport thiamine into the neuronal cell or where it is needed inside the cell (mitochondria), b) an inability to utilize thiamine, c) enzymatic abnormalities - all of which would clinically mimic thiamine deficiency, as thiamine is available but the cell would be unable to use it. High-dose thiamine would overcome these problems. Thiamine effects on dopamine release or better utilization of the exogenous levodopa have also been proposed. Mechanisms independent of thiamine coenzyme function, microglia activation, effects on intestinal microbiota, etc. and processes involved in the production of other key neurotransmitters (acetylcholine, glutamate or GABA) may also play a role.
- The above suggested mechanisms would help explain why thiamine effects would go beyond "energy production" and improve both motor and non-motor symptoms - so involving different neurotransmitters.
- YOUR QUESTION - Now, let's go back to your question: "Why does b1 overdose cause PD symptoms to return?" One could postulate that, if the thiamine dose administered is excessive for a particular individual, this "tsunami" of thiamine could actually over-stimulate the cell metabolism and become too much for the cell to handle. As a result, the overstimulation could first cause "too much energy" related symptoms (jittery feeling, "too much coffee" feeling, tremors, anxiety, sleeping problems etc.) and then cause a block to the cellular metabolic processes, similar to the one which is thought to cause Parkinson's symptoms. In fact, from the description of b1 overdose symptoms, we have seen that thiamine overdose can clinically manifest with any of Parkinson's symptoms. This would suggest that the mechanism should be similar in both Parkinson's and b1 overdose. Or, at least, that's one possible explanation.
- CONCLUSION - As b1 overdose symptoms can be the same as Parkinson's symptoms, the mechanism causing them should be similar, like an overstimulation and then block of cellular metabolic processes.
This is a very interesting idea, Drumhead. There was a thread about hyperparathyroidism a while back that got me looking into the calcium/PD connection, and I was surprised at just how much, calcium dysregulation is involved in the disease's pathogenesis, and how much research is taking place on the subject. Didn't come across anything about thiamine's role, but you seem to have identified one. This quote from your linked article caught my attention; "Thiamin diminished ER calcium considerably, but did not alter CCE."
And then there's this from a recent paper on calcium deregulation in Parkinson's, that speaks to the importance of the ER (endoplasmic reticulum) via calcium signalling; "The ER network is extensively interconnected with many organelles, including mitochondria, lysosomes, and other organelles, through Ca2+-dependent pathways [21,87,113,114,115,116,117,118,119,120,121]." ncbi.nlm.nih.gov/pmc/articl...
Makes sense that thiamine, by lowering ER calcium, could affect the functioning of the entire cell. Intracellular levels of calcium are elevated in PD, but.... calcium is vital to cell function. Perhaps the sweet spot for thiamine establishes calcium homeostasis, but too much disrupts it? Wonder if anyone has found their requirement for thiamine goes down on a dairy free diet?
It would also be interesting to know if calcium channel blockers reduce ER calcium, as they've been shown to reduce risk of PD; ncbi.nlm.nih.gov/pmc/articl...
"A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62–0.99)."
"CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study."
Thanks Rufous2, those are some great points and questions which raise more questions, like for instance, I wonder if there is a link between serum calcium levels and PD, or osteoporosis and PD, as folks with osteoporosis often have high serum calcium levels due to their body pulling calcium out of the bones.
Calcium dysregulation inside neurons has definitely been shown in PD, but that doesn't necessarily implicate high serum calcium as a cause. Some studies have shown high serum calcium in PD, others not. The association with dairy products is intriguing, but there are several theories about that that don't have anything to do with calcium content.
Calcium levels in the blood are regulated by Vit. D, phosphorus and parathyroid hormone, and disturbances in those can worsen Parkinson's as well as cause osteoporosis. Vitamin D and calcium levels are measured pretty routinely these days but I believe parathyroid hormone levels should be too. It's possible for elevated parathyroid hormone to be pulling calcium out of the bones, yet the blood calcium stays normal. Happened to my dad.
Calcium channel blockers might one day have a place in the treatment of PD, but evidence isn't strong enough yet to recommend widespread use. However, if I had PD, and hypertension that necessitated medication, I'd definitely consider a CCB. They act inside some cells in the heart, blood vessels and brain, and don't affect bone formation.
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