Optimal Performance

Assembling The Acetylcholine Puzzle : Part 1

acetylcholineI find concentrating on one dimension of cognitive enhancement without taking into account the underlying metabolic needs of that enhancement often produces short-lived or sub-optimal results. This is especially true when it comes to the use of racetams, PDE4 inhibitors and forskolin for cognitive enhancement and the increased demands that they put on the brain’s cholinergic systems.

By better understanding the relationships of various molecular biological processes we can gain a deeper understanding of the theoretical underpinnings needed to make the most out of these cognition and metabolism enhancing pathways.

With regards to understanding how to optimize the benefits of piracetam, research has indicated that acetylcholine utilization is increased when taking piracetam [1].  This is the reason for the often heard advice that piracetam stacks should include choline.   The addition of acetylcholine has produced profound effects in animal models [2] but the results in human trials with elderly dementia patients has been mixed [3].  One aspect of this relationship between choline and acetylcholine that I believe is overlooked is that to generate acetylcholine in the brain it not only takes choline or an analog of choline, but also a readily available source of  the acetyl group.  In neurons this acetyl group usually originates from acetyl-CoA.

The reaction that produces acetyl-CoA in cells requires a cofactor derived from thiamine, also known as vitamin B1.  Thiamine is an essential nutrient present in many foods. Severe deficiency of thiamine has been historically associated with the disease Beriberi often brought on by high carbohydrate diets of white rice that were deficient in thiamine [4].  More recently, thiamine deficiency caused by alcoholism, that can lead to the serious neurological condition known as Wernicke encephalopathy, has been a subject of much research [5].  The current RDA of thiamine for adults is 1.2 mg per day [6].  Supplementation of 50 mg per day of thiamine in healthy individuals has resulted in improved mood and reaction times [7].

The thiamine derivative thiamine pyrophosphate produces acetyl-CoA in a reaction that processes carbohydrates into cellular energy.  It does this by aiding in the conversion of pyruvate, derived from glucose over several steps, into acetyl-CoA and NADH as part of the pyruvate-dehydrogenase complex (PDHC) [8].  Acetyl-CoA, besides its role in making acetylcholine is best known for being the input to the krebs cycle which generates cellular energy in the mitochondria of all aerobic organisms.

In the brain, the highest activity of the PDHC was found in the hippocampus [9], which is the part of the brain primarily responsible for long term memory [10].  Some production of acetyl-CoA in the brain is used to donate an acetyl group to choline to produce acetylcholine.  This is done with the aid of the enzyme choline acetyltransferase (ChAT) [11].  Acetyl-Coa is also transported out of the mitochondria and into the cytosol by l-carnitine as acetyl-l-carnitine, as I mentioned in my previous article [12].  Studies have suggested that optimal acetyl-CoA levels in neurons is one of  the most important factor in maintaining the health of the brain and preventing neurodegenerative diseases [13].

As was discussed earlier, one of the cofactors in acetyl-CoA production is thiamine pyrophosphate.  What’s the best way to supplement thiamine as a precursor to thiamine pyrophosphate?  One supplement source of thiamine is as thiamine hydrochloride. Studies have shown that it is readily absorbed when given orally [14]. An even more bioavailable form is benfotiamine [15].  However, benfotiamine is generally not well absorbed by the brain [16].

Another source of vitamin B1 is sulbutiamine which is a dimer of thiamine that can pass through the blood-brain barrier [17].  It has been shown in studies to increase concentrations of vitamin B1 in the brain [18].  Sulbutiamine has been used for the treatment of asthenia, meaning physical weakness brought on usually as the result of an infection [19].  It has also shown the ability to improve memory in an animal model when testing for retention of information after 24 hours through a possible cholinergic mechanism [20].  This memory improvement is similar to the results seen in memory tests of the PDE4 inhibitor rolipram, where short-term memory was not affected but memory after 24 hours was significantly improved [21].

It would make sense then that the co-factors needed to make acetyl-CoA, including thiamine, pyruvate and pre-cursors to coenzyme-A, the CoA part of acetyl-Coa, such as vitamin B5 and other nutrients should be readily available in the in brain in order to optimize the production of acetylcholine.  Given acetyl-CoA’s participation in the Krebs cycle, increasing the availability of acetyl-CoA precursors and cofactors should have broader cellular energy enhancing benefits as well.

Additional posts by Abelard Lindsay (@ciltep):

[expand title=”References:”]

  1. Spignoli G, Pedata F, Giovannelli L, Banfi S, Moroni F, Pepeu G. Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition. Clin Neuropharmacol. 1986;9 Suppl 3:S39-47. PMID 3594455
  2. Bartus RT, Dean RL, Sherman KA, Friedman E, Beer B. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging. 1981;2(2):105-11. PMID 7301036
  3. Vernon MW, Sorkin EM. Piracetam. An overview of its pharmacological properties and a review of its therapeutic use in senile cognitive disorders. Drugs Aging. 1991;1(1):17-35. PMID 1794001
  4. Lanska DJ. Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handb Clin Neurol. 2010;95:445-76. PMID 19892133
  5. Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke’s Encephalopathy and Korsakoff’s Psychosis. Alcohol Alcohol. 2006;41(2):151-8. PMID 16384871
  6. Food and Nutrition Board, Institute of Medicine. Thiamin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:58-86. (National Academy Press)
  7. Benton D, Griffiths R, Haller J. Thiamine supplementation mood and cognitive functioning. Psychopharmacology (Berl). 1997;129(1):66-71. PMID 9122365
  8. Smolle M, Prior AE, Brown AE, Cooper A, Byron O, Lindsay JG. A new level of architectural complexity in the human pyruvate dehydrogenase complex. J Biol Chem. 2006;281(28):19772-80. PMID 16679318
  9. Butterworth RF, Giguere JF, Besnard AM. Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy: 1. The pyruvate dehydrogenase complex. Neurochem Res. 1985;10(10):1417-28. PMID 4069311
  10. Haettig J, Stefanko DP, Multani ML, Figueroa DX, Mcquown SC, Wood MA. HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner. Learn Mem. 2011;18(2):71-9. PMID 21224411
  11. Dobransky T, Rylett RJ. Functional regulation of choline acetyltransferase by phosphorylation. Neurochem Res. 2003;28(3-4):537-42. PMID 12675142
  12. Dolezal V, Tucek S. Utilization of citrate, acetylcarnitine, acetate, pyruvate and glucose for the synthesis of acetylcholine in rat brain slices. J Neurochem. 1981;36(4):1323-30. PMID 6790669
  13. Szutowicz A, Bielarczyk H, Jankowska-kulawy A, Pawełczyk T, Ronowska A. Acetyl-CoA the key factor for survival or death of cholinergic neurons in course of neurodegenerative diseases. Neurochem Res. 2013;38(8):1523-42. PMID 23677775
  14. Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol. 2012;12:4. PMID 22305197
  15. Xie F, Cheng Z, Li S, et al. Pharmacokinetic Study of Benfotiamine and the Bioavailability Assessment Compared to Thiamine Hydrochloride. J Clin Pharmacol. 2014; PMID 24399744
  16. Volvert ML, Seyen S, Piette M, et al. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 2008;8:10. PMID 18549472
  17. Van reeth O. Pharmacologic and therapeutic features of sulbutiamine. Drugs Today. 1999;35(3):187-92. PMID 12973384
  18. Volvert ML, Seyen S, Piette M, et al. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 2008;8:10. PMID 18549472
  19. Shah SN. Adjuvant role of vitamin B analogue (sulbutiamine) with anti-infective treatment in infection associated asthenia. J Assoc Physicians India. 2003;51:891-5. PMID 14710977
  20. Micheau J, Durkin TP, Destrade C, Rolland Y, Jaffard R. Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation. Pharmacol Biochem Behav. 1985;23(2):195-8. PMID 4059305
  21. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci USA. 1998;95(25):15020-5. PMID 9844008 [/expand]

Abelard Lindsay

I am the creator of the CILTEP stack. View the thread on Longecity | @ciltep

1 comment

  • Thanks for the discussion. This goes way beyond the typical analysis that I’ve seen–the sulbutiamine aspect is really interesting; looking forward to your ongoing work.

Follow us

Don't be shy, get in touch. We love meeting interesting people and making new friends.

Most popular

Most discussed