From John Toohey –
A stroke of genius or amazing serendipity.
Ascorbyl palmitate is an ester. Under normal conditions in the digestive tract, it would certainly be broken into the constituent parts by pancreatic enzymes which hydrolyze fatty acid esters (the enzymes are called esterases or lipases). Therefore, taken by mouth, AP would have no effect different from that of taking ascorbic acid alone. However, your patient was getting no less than three proven or probable esterase inhibitors!!! (trehalose, baicalein, and donezepil – structures shown in the attachment). The inhibitors would prevent the cleavage of ascorbyl palmitate permitting it to get absorbed intact and reach the brain. Experiments would be needed to prove this mechanism but, at present, it is the best explanation for the effect that you observed.

From John Toohey (to whom many thanks for guidance and advice)

Andrew: You may be surprised to learn that your findings may have propelled you to the frontier of chemistry known as “green chemistry” – in an vivo form. I will try to explain as briefly as possible. The literature is very large and in citing a few examples below, I am leaving out numerous other papers repeating and confirming the observations.

You included baicalein in your PIPmixND and you cite a paper relating it to AD; there are other papers on baicalein e.g. (1). But baicalein is only one of many flavones of plant origin that have similar structures and similar effects when tested with models of AD. The list includes quercetin (2), fisetin (3), cromolyn (4), ellagic acid (5) and its parent punicalagin (6) as well as ascorbic acid (7). This is not a complete list. All of these have shown effects in preventing dementia in mouse models and some studies have remarkable brain histology showing blockage of amyloid formation (e.g. fisetin and cromolyn).

All of these compounds are α,β-unsaturated carbonyls – a structure which allows them to undergo special reaction known as the “Michael addition” in which an alcohol (or, as found later, a thiol) undergoes a facile 1,4-addition. When the adduct is a thiol the reaction is called the “thiol Michael addition” (8). This is sophisticated chemistry and is now at the forefront of drug synthesis. It is called “green chemistry” because it uses few harmful solvents and chemicals and little expenditure of energy. To explain it, is necessary to go back to some elementary organic chemistry.

The simplest addition reaction involving carbonyl groups is the “aldol condensation” in which an alcohol adds to the carbonyl: R1 -C-OH + R2-C(O)H → R1-C(OH)-OR
R-SH compounds can replace the alcohol: R1-SH +R-C(O)H > R1-C(OH)R.
Long ago, Michael found that α,β-unsaturated cabonyl compounds undergo a similar reaction but it is a 1,4 addition. R1-CH=CH-C(O)H + R-SH > R1-CH(SR)-CH(OH)-R

The revolutionary chemistry began only 20 years ago when it was found that this reaction could be applied to numerous acceptor moleculs (maleimides, vinyl sulfone, acrylates, acryalamines, acrylonitriles, and more) – yielding routes to an incredible number of products many with drug function (9,10). The reactions are extremely facile and require no heating but some need to occur over several days (attractive features for occurring in vivo).

Relevance to Dementia. It is probably no coincidence that all of thecompounds that show effects in AD are prime candidates for undergoing the thiol Michael reaction. That provides circumstantial evidence for my previous prediction that these compounds are trapping and removing toxic sulfur compounds from the brain. Specific chemical testing for each compound is needed; the predicted reaction involving ascorbic acid has already been reported (11) and I have other unpublished data for H2S.

But what are the toxic sulfur compounds that need to be removed? Homocysteine itself is known to have many harmful effects but the main culprit is probably sulfane sulfur/hydrogen sulfide derived from the excessive homocystine. In HHE, the homocysteine occurs in the form of mixed disulfides one of which is the mixed disulfide with cysteine, cy-S-S-hcy. Research now in progress in New York is showing that this mixed disulfide is a highly active substrate for the enzyme cystathionase. The enzyme catalyzes C-S lysis resulting in the formation of cysteine persulfide cy-S-S-hcy > NH3 + ketobutyrate + cy-S-SH. Although this form of sulfur is required in many regulatory functions, it is highly toxic at supraoptimal concentrations and is a likely cause of the homocysteine-related dementia. Homocysteine is now a recognized cause of dementia (12) and the whole scenario seems to come together in a paper in which methionine feeding was used to induce hyperhomocysteinemia and the resulting brain pathology was corrected by ascorbic acid (13).

I know that most of this will be unintelligible to a lay person but I am sending it to you so that you can refer it to experts in the field (AD Smith, Refusm). to get their opinion. Some of the preliminary labwork is missing but the results from animal models, your observations, and the theoretical background suggest that it is apropos to embark on a full scale clinical trial.
_________________________

An note on a different subject to correct your terminology “palmitoyl ascorbate” .
The International Union of Pure and Applied Chemsitry (IUPAC) has clearly defined rules for naming chemicals. Esters are named with the alcohol first ending with “yl” and the acid last ending with “ate”. See, for example, ethyl acetate.
Therefore, the compound in question is “ascorbyl palmitate”. You say that your term is used in UK but IUPAC does not make exceptions.

1. Li Y, et al., Therpeutic potential of baicalein in AD and PD. CNS Drugs, 31 (8), 639-52(2017) doi 10.2007/s40263-017-0451-y

2. Quercetin: Sabagol-Guaqueta AM et al. Neuropharmacol. 93, 134-145 (2015)
doi 10.1016/j.neuropharm.2015.01.027

3. Fisetin :a) Kumar H et al, Can J. Physiol.Pharmacol., 95(1), 32-42 (2017).
b) Nabavi SF et al., Curr.Topics Med. Chem., 16(17) 1910-5 (2016).
c)Currais A. et al., Afing Cell, 13(2), 379-90 (2014).

4. Cromolyn:a) Zhang C et al., Sci. Reports, 8, 1144 (2018) 10.1038/s541598-018-19641-2
b) same group, J. Biol. Chem., 290(4) 1966 (2015) doi 10.1074/jbc.M114.586602

5. ellagic acid: Bansal N, Yadar P, Kumar M, Drug Res., 67(7) 425-431 (2017).

6. punicalagin: Rojanathammanu L. et al J Nutr. 143 (5) 597-605 (2-13) 10.3945/jn.112.169616

7. Ascorbic acid: a) Basambomba LL, Carmichael PH et al., Ann. Pharmacother., 51(2), 118-124 (2017)

b) Charleton KE, et al., J. Nutr. Health Aging,8(2), 99-107 (2004)

8. Nair P et al. The thiol Michael addition Click reaction: a powerful and widely-used tool in materials chemistry. Chem. Materials. 26(1), 724-44 (2014). 1.1021/cm402180t

9. Sharma A. et al., This-Michael addition; and emerging stratefy in organic synthesis. Asian J. Org.Chem., 10.1002/ajoc.201700609

10. Li CJ, Trost BM, Green chemistry for chemical synthesis. PNAS, 105 (36), 13197-13202 (2008). doi 10.1073/pnas.0804348105

11. Drake BB et al. Complexes of dehydroascorbic acid with three sulfhydryl compounds. J.Biol. Chem., 143, 89-98 (1942).

12. Smith et al.: Homocysteine and dementia: an international consensus statement. J. Alz. Dis., 62(2), 561-570 (2018) doi 10.3233/JAD-171042

13. Boyacioglu M, et al…Exp. Toxicol. Pathol. 66(9-10), 407-13 (2014) 10.1016/j.etp.2014.06.004