nAChRs in the fetus - lots, and in Alzheimer's dementia - not enough; also AChBPs - acetylcholine binding proteins might be protective against jab version S1 subunit.

*I added a link on SARS-CoV-2 spike effects on alpha 7 nAChRs. // Interestingly, a short period of nicotine use in Alzheimer's may lead to improved learning and memory for a longer amount of time.

The nicotinic acetylcholine receptors (nAChRs) develop early in the fetal brain (a majority of the subunits are expressed 7.5-12 weeks post conception) (Alzu’bi, et al., 2020) and in the placenta. (Alwazzan, et al., 2020)

*This post is a continuation of the nAChR topic, see the second half of this post: nAChRs - lengthy; nattokinase, brief; and Katherine Watt and Laura Jeffery interviews. (Substack)

The nicotinic Acetylcholine receptors are activated by acetylcholine or nicotine. Excess nicotine prenatally can have significant impacts on the growth of the developing infant and increase risk of prematurity and small size for gestational age. ADHD or other psychiatric disorders may develop in the child due to hypoxia, low oxygen in the fetal brain. (Alzu’bi, et al., 2020; Beltrán-Castillo, et al., 2023)

“Nicotine, the most addictive and teratogenic substance in tobacco smoke, reaches and crosses the placenta and can be accumulated in the amniotic fluid and distributed by fetal circulation, altering the cholinergic transmission by acting on the nicotinic acetylcholine receptors (nAChRs) expressed from very early gestational stages in the placenta and fetal tissue³.” (Beltrán-Castillo, et al., 2023)

The amount of nAChRs present in the brain peaks towards the end of fetal development (prior to birth) and then the number and function gradually decreases as we age. (Hellström-Lindahl, Court, 2000)

“Nicotinic acetylcholine receptor (nAChRs) proteins and gene transcripts are already present in human prenatal brain and spinal cord at 4-6 weeks gestation, and a clear age-related increase in number of nAChRs was apparent during first trimester. In pons, there was also a parallel increase in the alpha7 mRNA level with age. The highest specific binding of [3H]epibatidine and [3H]cytisine was detected in spinal cord, pons and medulla oblongata, and binding of [125I]alpha-bungarotoxin was highest in spinal cord, medulla oblongata and mesencephalon. From the late fetal stage brain nAChRs have been shown to fall with increasing age.” (Hellström-Lindahl, Court, 2000)

When there is dysfunction - too little or too much activation of the nAChRs during fetal development, the baby may have developmental changes or may die leading to a miscarriage. Nicotine use prenatally would cause too much activation and a paralytic cholinergic blocking snake venom toxin or Conotoxin could cause too little activation of the nAChRs.

“Nicotine acetyl choline receptors are found to be expressed highly in the placental tissues and in products of conception. They may be associated with the sudden perinatal deaths and miscarriages or complications of pregnancy^.” (Alwazzan, et al., 2020)

A paralytic cholinergic blocking toxin would also cause health problems in a developing fetus due to too little nAChR function. If a venomous snake bite occurs in the first trimester of a woman’s pregnancy, spontaneous fetal death (miscarriage) can be a typical result. Snake bites are not infrequent in Asia, India and Africa and can cause harm for a mother and developing baby. Snake venom can contain a variety of toxins including ones that inhibit nAChR function. (Nasu, Ueda, Miyakawa, 2004)

Use of nAChR mimics has been found helpful as a co-treatment for snake bite along with anti-venom. (Albulescu, et al., 2019)

“We next investigated whether nAChR mimics could be used as snakebite therapeutics. We showed that while α7-AChBP alone did not protect against Naja haje (Egyptian cobra) venom lethality in vivo, it significantly prolonged survival times when coadministered with a nonprotective dose of antivenom. Thus, nAChR mimics are capable of neutralizing specific venom toxins and may be useful adjunct therapeutics for improving the safety and affordability of existing snakebite treatments by reducing therapeutic doses. Our findings justify exploring the future development of AChBPs as potential snakebite treatments.” (Albulescu, et al., 2019)

‘AChBPs’: The team used “two recombinant nAChR mimics: the AChBP from Lymnaea stagnalis and a humanized neuronal α7 version (α7-AChBP)” (Albulescu, et al., 2019)

There is more expression of nAChRs in a placental tissue from someone with pre-eclampsia than in normal pregnancy or with gestational diabetes.

A difference in number of nAChRs was not observed in relation to miscarriage risk with groups of pregnant women with pre-eclampsia or gestational diabetes compared to women with a normal pregnancy. There was, however, increased expression - more nAChRs, in the placental tissue of women with pre-eclampsia compared to the amount in placentas of women with gestational diabetes or those with a normal pregnancy. (Alwazzan, et al., 2020)

“α7-nAChR expression showed no notable differences among different cases of miscarriages irrespective of the mother’s age and gestational age at which the event occurred. However, there were some changes among the normal, [pre-eclampsia] PE, and [gestational diabetes] GD placental groups in the linings of the blood vessels. Changes were restricted to the villi (as opposed to the decidua) lining cells, both cytotrophoblast and syncytiotrophoblast, and were specific to the α7 subunit. PE blood vessel lining was thicker and showed more expression of this receptor in endothelial cells and myofibroblasts in PE and GD groups.” (Alwazzan, et al., 2020)

nAChRs play a role in learning and memory and loss of function is seen in normal aging or more severely in neurocognitive diseases associated with age.

In normal aging minor degeneration leads to reduced plastic synaptic plasticity which equals a slightly worse ability to form new memories and forget old ones. In more severe degeneration of the nAChRs symptoms of Alzheimer’s dementia may be observed. There is also a loss of nAChRs in Parkinson’s disease but occurs earlier in Alzheimer’s while changes in the dopaminergic system occurs early in Parkinson’s disease and is not a significant factor in Alzheimer’s deterioration.

“The cholinergic system is involved in memory and learning, and the impairment of its function due to loss of neurons or loss of their cholinergic phenotype compromises cognition and is regarded as the earliest event in Alzheimer’s disease (AD) etiology.” (Gasiorowska, et al., 2021)

Synaptic plasticity is reduced in Alzheimer’s with fewer nAChRs or reduced activation. The odd but good news: Providing nicotine has been shown to improve learning and memory in human or animal trials, even with only a short treatment period. Possibly the extra few doses of nicotine led to an increase in expression (amount transcribed from the gene) of nicotinic acetylcholine receptors. (Gasiorowska, et al., 2021)

“Healthy aging humans and animals perform worse in hippocampus-related learning and memory tasks as compared with younger adults, and nicotine administration remedies partly or completely this deficit (Zeid et al., 2018). In aging rodents, hippocampal LTP facilitation and immediate improvement of spatial memory is caused by both acute and chronic types of nicotine administration (Levin and Torry, 1996; Srivareerat et al., 2011).

»The acute and chronic nicotine types of administration improve cognitive performance in patients suffering from neurodegenerative disorders. It was found that relatively short-term nicotine patch exposure improved learning and memory in patients with probable AD, and that this improvement persisted throughout the washout period (Wilson et al., 1995).” (Gasiorowska, et al., 2021)

*The Bing search engine suggested I try the new Bing search AI and it found a few of these links and then I kept looking.

The miracle of life, is really a miracle. Good thing to keep in mind. And my condolences to anyone who has lost their baby during these trying times. Photo by Picsea on Unsplash

Addition, a May 2023 article states the spike interaction with alpha7 nAChRs is not binding with it but acting as a coagonist, possibly with nicotine. That doesn’t explain why smokers did better than average at staying out of the hospital. And my own passive exposure symptoms of colitis only got better after I added 10 mg of nicotine to my daily routine.

The research by O’Brien, et al., however focused on risk of nicotine in advance - Did nicotine prior to a SARS-CoV-2 exposure potentiate the effects at nAChRs? (O’Brien, et al., 2023) And their focus is on the original virus version of the chimeric spike and that sequence is different than the CoV ‘vaccine’ version which seemed far worse to me and I had gtten ill in February 2020 with the initial version. I got better quicker from that (3 weeks) than from passive exposure illness in May 2021.

“A structural model of the SARS-CoV-2 glycoprotein shows this neurotoxin-like region, located at the junction between the S1 and S2 segments, is highly exposed to solvent, free of shielding glycans, and accessible to host cellular protein targets (4, 52). Functional and binding studies have shown that the SARS-CoV-2 neurotoxin-like region functions either as a coagonist on α7 nAChRs and does not bind to the α7 nAChR orthosteric site, respectively (53, 54).” (O’Brien, et al., 2023)

Disclaimer: This information is being shared for educational purposes within the guidelines of Fair Use and is not intended to provide individual health guidance. Please seek a health practitioner for individualized health guidance.

Reference List

(Albulescu, et al., 2019) Albulescu LO, Kazandjian T, Slagboom J, Bruyneel B, Ainsworth S, Alsolaiss J, Wagstaff SC, Whiteley G, Harrison RA, Ulens C, Kool J, Casewell NR. A Decoy-Receptor Approach Using Nicotinic Acetylcholine Receptor Mimics Reveals Their Potential as Novel Therapeutics Against Neurotoxic Snakebite. Front Pharmacol. 2019 Jul 30;10:848. doi: 10.3389/fphar.2019.00848. PMID: 31417406; PMCID: PMC6683245. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683245/

(Alwazzan, et al., 2020) Immunohistochemical Expression of the Alpha Nicotinic Acetylcholine Receptor 7 in the Human Normal, Diabetic, and Preeclamptic Placenta and Products of Conception, Front. Physiol., 25 Nov 2020, Sec. Autonomic Neuroscience, Vol 11, 2020, https://doi.org/10.3389/fphys.2020.607239 https://www.frontiersin.org/articles/10.3389/fphys.2020.607239/full

(Alzu’bi, et al., 2020) Alzu’bi, A., Middleham, W., Shoaib, M., Clowry, G.J., Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain, Front. Mol. Neurosci., 21 May 2020, Sec. Neuroplasticity and Development, Vol 13, 2020, https://doi.org/10.3389/fnmol.2020.00072 https://www.frontiersin.org/articles/10.3389/fnmol.2020.00072/full “An RNAseq study of human fetal cerebral cortex demonstrated that 9 out of 16 genes for human nicotinic acetylcholine (ACh) receptor subunits are selectively expressed between 7.5 and 12 post-conceptional weeks (PCW)¹.” (Alzu’bi, et al., 2020)

(Beltrán-Castillo, et al., 2023) Beltrán-Castillo, S., Bravo, K., Eugenín, J. (2023). Impact of Prenatal Nicotine Exposure on Placental Function and Respiratory Neural Network Development. In: Gonzalez-Ortiz, M. (eds) Advances in Maternal-Fetal Biomedicine. Advances in Experimental Medicine and Biology, vol 1428. Springer, Cham. https://doi.org/10.1007/978-3-031-32554-0_10 https://link.springer.com/chapter/10.1007/978-3-031-32554-0_10

(Cetin, et al., 2020) The Structure, Function, and Physiology of the Fetal and Adult Acetylcholine Receptor in Muscle, https://www.frontiersin.org/articles/10.3389/fnmol.2020.581097/full “The muscle-type nicotinic acetylcholine receptor (AChR) is a key molecular component located at the postsynaptic muscle membrane responsible for the generation of the endplate potential (EPP), which usually exceeds the threshold potential necessary to activate voltage-gated sodium channels and triggers a muscle action potential.” (Cetin, et al., 2020)

(Gasiorowska, et al., 2021) Gasiorowska A, Wydrych M, Drapich P, Zadrozny M, Steczkowska M, Niewiadomski W, Niewiadomska G. The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain. Front Aging Neurosci. 2021 Jul 13;13:654931. doi: 10.3389/fnagi.2021.654931. PMID: 34326765; PMCID: PMC8315271. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315271/

(Hellström-Lindahl, Court, 2000) Hellström-Lindahl E, Court JA. Nicotinic acetylcholine receptors during prenatal development and brain pathology in human aging. Behav Brain Res. 2000 Aug;113(1-2):159-68. doi: 10.1016/s0166-4328(00)00210-2. PMID: 10942042. https://pubmed.ncbi.nlm.nih.gov/10942042/

(Nasu, Ueda, Miyakawa, 2004) Nasu K, Ueda T, Miyakawa I. Intrauterine fetal death caused by pit viper venom poisoning in early pregnancy. Gynecol Obstet Invest. 2004;57(2):114-6. doi: 10.1159/000075676. Epub 2003 Dec 19. PMID: 14691344. https://pubmed.ncbi.nlm.nih.gov/14691344/

(O’Brien, et al., 2023) O'Brien BCV, Weber L, Hueffer K, Weltzin MM. SARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors. J Biol Chem. 2023 May;299(5):104707. doi: 10.1016/j.jbc.2023.104707. Epub 2023 Apr 13. PMID: 37061001; PMCID: PMC10101490. https://www.jbc.org/article/S0021-9258(23)01735-0/fulltext