Acetylcholine/Never had no chance

This is going to be kind of a semi-organization of many studies I have printed out in recent months, but also others that have trickled in over the past couple of years that I didn't know what to do with yet. A lot of these posts are helpful for me in that I can go back and see an organized version of some of the reading I had been doing at that time. So this is a random post with some random thoughts I've been having and a slew of studies about acetylcholine in no particular order, really.

We are clearly not living right and headed into cataclysm with rampant diabetes spiking throughout the population, in both adults and children. The CDC's By the Numbers: Diabetes in America (Source: National Diabetes Statistics Report, 2022) states: From 2001 to 2020, diabetes prevalence significantly increased among US adults 18 and older. 37.3 million people have diabetes- that's 11.3% of the US population. 96 million US adults have pre-diabetes. People with diabetes are also at higher risk of heart disease, stroke and other serious complications like kidney failure, blindness and amputation of a toe, foot, or a leg. People with diabetes spend more on health care and miss more workdays compared to people who don't have diabetes.

And in my experience it's impossible for anyone to truly know how difficult it is being diabetic, the grueling existence of insulin dependency, unless you're living it. I've learned to accept that over the years. As Shakespeare said, "He jests at scars that never felt a wound." And who wouldn't be anything but very, very ecstatic that few if any in their life understand their suffering? Darryl from The Office said it best. He's down in the warehouse ("it's serious down there") and Michael is at his desk living his soft "Nerf ball" "sweet little Nerfy life." Of course everyone has their challenges, and I'm definitely not bitter at all about being in the warehouse, that's where I'm meant to be. Even in my worst moments with this illness, I'm certain I chose this challenge in my soul. One of my favorite movies of all time is Wes Anderson’s Rushmore. In Max’s book Diving for Sunken Treasure by Jacques Cousteau, he finds a previous reader hand-wrote one of Cousteau’s quotes on one of the pages: “When one man, for whatever reason, has the opportunity to lead an extraordinary life, he has no right to keep it to himself.” I always thought that was well said. While I don’t consider myself extraordinary in any sense, I have found myself in a predicament that I wish upon no one. My hyper-focus on the elimination of this multi-faceted disease has become something of a purpose. 

There's a newer song by the Yeah Yeah Yeahs (who I fell in love with when Maps came out in 2003) called Spitting off the Edge of the World. The lyrics really struck me: "Out in the night/Never had no chance/Nowhere to hide." I read the band intended the song to be about leaving children to cope with a dangerously warming world. Of course I also thought about the diet children are fed (exactly how many kids are having a cake pop and a Frappuccino at Starbucks in this country today I wonder?) and the very devastating mental and physical health consequences that can manifest from the continual addiction to these foods into adulthood. And the dream, the hope, for change: "Dark, dark, places shall be none."

Here is some intriguing research I've come across. This topic can very much be elaborated on, each study can be its own post with many similar studies validating it, expanding upon it, but today I'll just condense it to a quick twenty studies or less overview:

The 2012 paper Acetylcholinesterase is associated with apoptosis in beta cells and contributes to insulin-dependent diabetes mellitus pathogenesis states: "Here, we investigated the role of acetylcholinesterase (AChE) in the development of insulin-dependent diabetes mellitus (IDDM) and analyzed protective effects of AChE inhibitors...Induction and progressive accumulation of AChE in the pancreatic cells were associated with apoptotic beta cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels...Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM."

The 2019 paper Involvement of Acetylcholine Receptors in Cholinergic Pathway-Mediated Protection against Autoimmune Diabetes noted: "It has been postulated that the development of autoimmune diabetes (T1D) and other autoimmune diseases is triggered by a dysfunction of the autonomic nervous system followed by a recruitment of inflammatory cells. Failure or insufficient efferent vagus nerve cholinergic output might allow the overproduction of inflammatory cytokines and, therefore, a dysfunctional immune and metabolic regulation that in normal conditions would not occur. Our previous work demonstrated that increased cholinergic pathway activation through a chronic administration of paraoxon, an irreversible specific inhibitor of acetycholinesterase, protected against development of T1D in MLD-STZ mouse model. Acetylcholine signals through two different types of receptor, muscarinic and nicotinic, both present on pancreatic and immune cells."

The 2018 study Beta-cell mass restoration by alpha-7-nicotinic acetylcholine receptor activation summarized: "We have demonstrated that systemic alpha-7 nicotinic acetylcholine receptor activation in mice progressively improves STZ-induced hyperglycemia and beta-cell failure by retaining functional beta-cell mass."

The 2019 paper Beyond neurotransmission: acetylcholine in immunity and inflammation states: "Immune cells are not the only non-neuronal cells that produce acetylcholine (ACh). Pancreatic beta cells are also choline acetyltransferase (ChAT)+ and produce ACh, perhaps partially explaining why increased ACh signalling is protective in the streptozotocin (STZ) induced mouse model of type 1 diabetes...George et al showed that blocking acetylcholinesterase prevented the development of hyperglycemia following STZ treatment."

The 2017 study Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity states: "The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus may predispose to Alzheimer's disease (AD)...The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD." The study found: "Metformin inhibited 50% of the AChE activity at micromolar concentrations and seemed to be selective towards AChE since it presented low anti-butyrylcholinesterase activity."

The 1992 study Change in Serum Cholinesterase Activity in Jamaican Diabetics determined: "Results suggest an associated increase of serum acetylcholinesterase with triglyceride levels in diabetics and may point to a possible association between increased serum acetylcholinesterase and vascular complications in Jamaican diabetics."

The 2007 study Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease stated: “Plasma levels of C-Reactive protein, interleukin-6, tumor necrosis factor alpha and lipid peroxides are elevated and concentrations of endothelial nitric oxide decreased in type 2 diabetes mellitus and Alzheimer’s disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer’s disease. Acetylcholine has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen in type 2 diabetes and Alzheimer’s disease.”

The 2020 study Cholinesterase inhibitors in patients with diabetes mellitus and dementia found “reductions in mortality in patients with diabetes mellitus and Alzheimer’s disease or mixed-pathology dementia treated with cholinesterase inhibitors, specifically donepezil and galantamine were associated with the largest benefit.”

According to the 2004 study Inhibition of acetylcholinesterase by Tea Tree oil: "Pediculosis is a widespread condition reported in schoolchildren. Treatment commonly involves the physical removal of nits using fine-toothcombs and the chemical treatment of adult lice and eggs with topical preparations. The active constituents of these preparations frequently exert their effects through inhibition of acetylcholinesterase...In this study, two major constituents of Tea Tree oil, 1-8-cineole and terpinen-4-ol, were shown to inhibit acetylcholinesterase...four samples of Tea Tree oil tested showed anti-acetylcholinesterase activity...The results supported the hypothesis that the insecticidal activity of Tea Tree oil was attributable, in part, to the anticholinesterase activity of Tea Tree oil."

The 2022 study Acaricidal and Antioxidant Activities of Anise Oil and the Oil's Effect on Protease and Acetylcholinesterase in the Two-Spotted Spider Mite concluded: "Anise oil exhibited acaricidal activity against T. urticae and that this was highly correlated with the inhibition of acetylcholinesterase and protease activities in the mites."

The 2019 study Phytochemical compounds of anise hyssop and antibacterial, antioxidant and acetylcholinesterase inhibitory properties of its essential oil states: "This is the first report of its kind to present acetylcholinesterase inhibitory activity of A. foeniculum essential oil...The obtained essential oil from A. foeniculum possessed strong antioxidant and moderate antimicrobial and acetylcholinesterase inhibitory activity."

The 2017 study Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis is summarized as follows: "Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumor necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis."

The 2021 study The ChAT-acetylcholine pathway promotes group 2 innate lymphoid cell responses and anti-helminth immunity concluded: "Choline acetyltransferase (ChAT) deficiency in group 2 innate lymphoid cells (ILC2s) leads to defective ILC2s responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection." 

The 2022 study Innate type 2 immunity controls hair follicle commensalism by Demodex mites found: "Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased hair follicle inflammation and decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin group 2 innate lymphoid cells and interleukin-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathological infestation by colonizing hair follicle mites."

I was reading an interesting 2021 US Patent Application Publication called "Treatment of Ophthalmological Conditions with Acetylcholinesterase Inhibitors." The applicant, Frank Anthony Spallitta of Denver, Colorado, essentially details killing Demodex mites with acetylcholinesterase inhibitors. "Embodiments of the invention are useful for treating ocular afflictions caused by Demodex-induced inflammatory eye conditions, including meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia, blepharitis and dry eye disease."

The 2021 paper Role of Choline in Ocular Diseases states: "Choline is essential for maintaining the structure and the function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma and dry eye syndrome. Choline supplementation may be effective for treating these diseases."

The 2021 paper Functional Activation of Human Eosinophils by Acetylcholine noted: "We hypothesized that acetylcholine (Ach) may directly activate eosinophils and investigated the effect of Ach on human eosinophil functions. Ach significantly prolonged eosinophil survival and decreased apoptosis and necrosis...In conclusion, we clarified that Ach could directly activate eosinophils in various aspects and these findings may partly explain the mechanism of neuro-immune linkage in asthma pathology."

The 2002 paper Hypochlorous Acid is a Potent Inhibitor of Acetylcholinesterase (well the title says it all) noted: "It was found that hypochlorous acid inhibits purified acetylcholinesterase...The present findings indicate that HOCL can act as inhibitor of acetylcholinesterase." 

The 2016 study Anti-inflammatory and acetylcholinesterase activity of extract, fractions and five compounds isolated from the leaves and twigs of Artemisia Annua growing in Cameroon concluded: "The current study presents evidence that the ethanol extract, fractions and compounds obtained from A. Annua have AChE inhibitory activity and are able to prevent the production of NO...The activities reported here validate the traditional use of this plant against inflammatory conditions and supports the use of A. annua in the treatment of inflammatory and neurological disorders where acetylcholinesterase and nitric oxide are involved."

The 2018 paper Neuroprotective effect of the ethanol extract of Artemisia capillaris on transient forebrain ischemia in mice via nicotinic cholinergic receptor found: "Artemisia capillaris treatment showed a concentration-dependent inhibitory effect on acetylcholinesterase activity in vitro...Our results suggested that in a model of forebrain ischemia, artemisia capillaris protected against neuronal death through the activation of nicotinic acetylcholine receptors."

The 2022 study Nicotinic Acetylcholine Receptor Stimulation: A New Approach for Stimulating Tear Secretion in Dry Eye Disease states: "Because parasympathetic nerves stimulate tear secretion by the lacrimal functional unit, this neural pathway has been suggested as a therapeutic target to re-establish tear film homeostasis."

The 2010 study Taurine prevents enhancement of acetylcholinesterase activity induced by ethanol exposure states: "In this study, we investigated whether acute taurine co-treatment or pre-treatment prevented ethanol-induced changes in acetylcholinesterase activity and in oxidative stress parameters in zebrafish brain. The results showed that ethanol exposure increased acetylcholinesterase activity, whereas co-treatment with 400mg taurine prevented this enhancement."

The 1993 study Evidence for a central cholinergic effect of high-dose thiamine found: "Thiamine binds to nicotinic receptors and may exhibit anticholinesterase activity." 

The 1977 study Inhibition of Acetylcholinesterase by Thiamine: A Structure-Function Study states: "Thus, thiamine by virtue of its charge has the potential to act as a reversible acetylcholinesterase inhibitor." 

The 1984 study Impairment of acetylcholine synthesis in thiamine deficient rats developed by prolonged tea consumption found "Administration of tea to rats fed a thiamine half-deficient diet for 7-8 weeks caused not only 60% decrease in acetylcholine synthesis but also neurological symptoms."

There's a lot more to unpack with thiamine possibly in a separate post. Thiamine is decreased in coffee and tannin-rich tea drinkers, chronic alcohol consumption and in those with diets heavy in sugar and carbohydrates. There seems to be a great deal of research coming out in regard to its correlation with Alzheimer's disease. (See 2018's Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not: "We demonstrate, for the first time to our knowledge, in vivo that thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for Alzheimer's disease.") Thiamine deficiency in chronic alcoholism does induce a memory loss condition called Wernicke-Korsakoff Syndrome. There was one cool paper I read about Wernicke-Korsakoff years ago where an alcoholic was in the hospital getting IV thiamine for I don't remember how long the typical protocol was. No change was observed in his mental status. Instead of dismissing him as unlikely to ever improve (I assume the more typical outcome) the doctor(s)? kept going. And his brain damage was fully reversed. I just loved this case study- a patient who possibly had a rough road in life and who many would dismiss as permanently damaged...well they went to bat for him instead and he recovered. I found it! Complete recovery from undertreated Wernicke-Korsakoff syndrome following aggressive thiamine treatment (2010). Thiamine has long been established as deficient in diabetics. One recent study in 2020 Thiamine Level in Type 1 and Type 2 Diabetes Mellitus Patients: A Comparative Study Focusing on Hematological and Biochemical Evaluations found serum thiamine levels to be "significantly" lower in both type 1 and type 2 diabetic patients than in controls.

Of course, you don't want to go overboard with acetylcholinesterase inhibitors and tip into a cholinergic crisis, which is why I don't mess with things like Huperzine A or any isolated potentially dangerous choline or thiamine supplement. I have boiled eggs on my salads and add a half a scoop of organic sunflower lecithin powder into my protein shake. I do drink saffron rooibos, anise hyssop, artemisia annua and tulsi teas. Sunflower seed protein and unfortified nutritional yeast are good sources of thiamine. I was reading a great deal about thiamine and TTFD in particular and in the end I don't think these supplements are safe for long term use. If you clean your body up, you don't need high dose supplements. Taurine can come from goji berries and sustainable fish like sardines. I recently bought Goji Berry Sea Moss Gel for some extra natural taurine. Sustainable fish is also good for boosting GAD65. Everything you need is already provided, a birthright.

I gratefully read a lot of this illuminating literature the research community is putting forth and it does connect some of the puzzle together for me (which is wonderful because I always have some fire lit under me that I have to put out), but I just don't think our lives are meant to be spent doing damage control from what we've been putting into our bodies since (for some) early childhood: processed sugar in processed foods and processed drinks. It would be so lovely if we could just get back to living in a world without diabetes.

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