Capsaicin - dose dependent effect on cognitive health - too much may cause amyloidosis (and increase Alzheimer's risk).

And why pomegranate peel extract is so good against cancer: it is a STAT3 inhibitor. So is capsaicin at high doses, but then it inhibits a good thing too and promotes brain calcification - a bad thing

Too many hot peppers in the diet has been linked to reduced cognitive function in a 15-year open cohort study with 4582 adults. The risk was greater when the person had a lower BMI rather than a high BMI. A larger body size showed a protective effect against capsaicin in the brain. (Shi, et al., 2019) (*Whether the protective effect was due to extra fat or extra muscle mass - we don’t know. A high BMI doesn’t tell us if the higher wt/ht ratio represents a body builder or a plump person).

“The positive association between chili intake and cognitive decline was stronger among those with low BMI than those with high BMI. The longitudinal data indicate that higher chili intake is positively associated with cognitive decline in Chinese adults in both genders.”

High Chili Intake and Cognitive Function among 4582 Adults: An Open Cohort Study over 15 Years, (Shi, et al., 2019) via Nutrition Detective, - Dr. Garrett Smith, @NutriDetect ·2h also: Capsaicin - Technical Fact Sheet http://npic.orst.edu/factsheets/archive/Capsaicintech.html

My reply: Capsaicin Activates Brain TRP Channels. Brave AI, (search.brave.com) Included later.

In checking the search result links, I learned that higher doses of capsaicin, (the generous hot pepper eaters), inhibit factors in the brain that lower doses wouldn’t inhibit. Capsaicin can cause amyloidosis. (Pákáski, et al., 2009)

"These in vivo data indicate that capsaicin is able to interfere with the brain APP metabolism by promoting the amyloidogenic route." - Capsaicin promotes the amyloidogenic route of brain amyloid precursor protein processing. (Pákáski, et al., 2009)

Lower doses of capsaicin may be protective against cognitive decline and inflammation.

Dose-dependently, capsaicin presynaptically can inhibit glutamate release in the hippocampus (of rats). Calcineurin is involved, inhibition of that took away the effect. Lower doses of capsaicin may have a protective effects for brain health. (Lu, et al., 2017) Capsaicin is also an Nrf2 agonist/activator (Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction, May 2024 preprint)

»> So, the dose - how much hot peppers are eaten, would matter. A high concentration of capsaicin can inhibit enzymes that lower doses wouldn’t inhibit - signal transducer and activator of transcription 3 (STAT3) and carbonic anhydrase 2 are inhibited at doses 10 times higher than doses of capsaicin that are needed to activate TRPV1 channels. (Yang and Zheng, 2017)

• What are TRP channels? Portals across a cell membrane for minerals to travel through. Activation of them opens passage for calcium to enter cells where it causes action to take place, like release of endocannabinoids like anandamide from the cell membrane. Anandamide can then signal activation of TRPV1 channels also - it can increase inflammation to have too much release of endocannabinoids from membrane storage.

Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. (Fig. 1 'Capsaicin and TRPV1', image) (Yang and Zheng, 2017)

Might be of interest: "Interestingly, while being a potent activator, capsaicin also exhibits high selectivity for TRPV1 as it does not activate other homologous channels within the TRPV family (Yang et al., 2016). Beyond this family, capsaicin has been implied to inhibit signal transducer and activator of transcription 3 (Bhutani et al., 2007) and carbonic anhydrase 2 (Ye et al., 2015), though the concentrations required for the inhibitory effects are at least 10 times higher than what is required for activating TRPV1." https://pmc.ncbi.nlm.nih.gov/articles/PMC5326624/

This graphic shows where capsaicin molecule fits in the TRPV1 channel in order to activate it. We also see how small a phytonutrient is compared to a membrane channel. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. (Fig. 1 'Capsaicin and TRPV1', image) (Yang and Zheng, 2017)

TRPV1 ligands include:

• capsaicin;

• anandamide (THC equivalent endocannabinoid - making THC a ligand also);

• endovanilloids (the V in the name of this TRP channel group stands for vanilloid);

• oxidative stress chemicals hydrogen peroxide and nitric oxide;

• protons (H+); and

• “high temperature (>43 oC)” and

• EMF radiation/electricity/magnetic fields. (Nazıroğlu and Demirdaş, 2015)

"TRPV1 channel is mostly expressed in small fiber which are pain-transmitting C fibers [31, 35]. As it was mentioned above, vanilloid receptors have important roles in many physiological and pathophysiological functions including pain, anxiety, thermoregulation, and inflammation [31, 36, 37]. TRPV1 channels are activated by numerous agonists. For instance, TRPV1 is activated by painful physical stimuli such as high temperature (>43 oC), protons, or chemicals such as capsaicin, the pungent ingredient of hot chili peppers or endogenous ligands like anandamide, N-arachidonoyl dopamine, or oxidized linoleic acid metabolites that are known as endovanilloids, oxidative stress such as hydrogen peroxide and nitric oxide, neutrophil activity, and electromagnetic radiation such as mobile phone and Wi-Fi frequencies [13, 27, 31, 37, 38]." Psychiatric Disorders and TRP Channels: Focus on Psychotropic Drugs, (Nazıroğlu and Demirdaş, 2015)

Brave AI summary for my Search Prompt:

"Capsaicin Activates TRP Channels in the Brain, Leading to Calcium Release in Hippocampus" (search.brave.com)

Capsaicin, the active compound in chili peppers, has been found to activate transient receptor potential (TRP) channels in the brain, specifically in the hippocampus, leading to an increase in calcium release. This phenomenon is mediated by the TRPV1 receptor, a non-selective cation channel.

Research suggests that capsaicin binds to TRPV1 receptors in the brain, triggering a cascade of events that ultimately leads to the influx of calcium ions into hippocampal neurons. This calcium release plays a crucial role in modulating various neural processes, including synaptic plasticity, neuronal excitability, and neurotransmitter release.

In the hippocampus, TRPV1 receptors are expressed in both excitatory and inhibitory neurons, and their activation can have distinct effects on neural activity. For example, capsaicin-induced TRPV1 activation has been shown to:

• Enhance glutamate release from excitatory neurons, potentially contributing to excitatory synaptic plasticity and learning and memory processes. *An excess of this activity would be damaging to hippocampal cells, which have a lot of glutamate receptors.

• Inhibit GABA release from inhibitory neurons, leading to reduced inhibitory tone and potentially altering neural oscillations and information processing.

The precise mechanisms underlying capsaicin’s effects on TRP channels and calcium release in the hippocampus are still being elucidated. However, it is clear that this activation plays a significant role in modulating brain function and may have implications for our understanding of pain, mood, and cognitive processes.

Key Entities and Descriptions:

👉TRPV1: A non-selective cation channel and the primary receptor for capsaicin in the brain.

👉Hippocampus: A brain region critical for learning, memory, and spatial navigation, where TRPV1 receptors are expressed.

👉Calcium release: An increase in calcium ion influx into hippocampal neurons, mediated by TRPV1 activation, which modulates neural activity and synaptic plasticity.

• Reference links from the results (search.brave.com):

What is STAT3?

Seems like inhibiting STAT3 could be a good thing for cancer patients as it’s activity can promote cancer… but there are no known STAT3 inhibitors in use as medications…. such as pomegranate peel extract… (Brave AI summary/Pom peel extract is a STAT3 inhibitor - and useful against cancer…):

• Signal Transducer and Activator of Transcription Protein 3 (STAT3): An Update on its Direct Inhibitors as Promising Anticancer Agents. (Gelain, et al., 2019) *paywall

• The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies. (Arora, et al., 2018)

“Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.” (Arora, et al., 2018)

What about Carbonic anhydrase 2 (CA2)?

Carbonic anhydrase 2 (CAII or CA2) - lack of it is linked to kidney and bone changes that lead to cerebral calcification. (Leite, et al., 2023)

“Carbonic Anhydrase II Deficiency:

The protons and bicarbonate ions to be transported by the H⁺-ATPase and AE1 in the α-IC are produced by the catalytic activity of carbonic anhydrase II (CAII) within the cytosol, and normal function of this enzyme is necessary both in the kidney and in osteoclasts for normal bone resorption. Because of its dual organ expression, loss of function of this enzyme causes the combination of renal tubular acidosis with osteopetrosis (also known as Guibaud-Vainsel syndrome or marble brain disease *See: (Leite, et al., 2023)) (McMahon et al 2001, Shah et al 2004).”

• Distal Renal Tubular Acidosis, Fiona E. Karet, in Genetic Diseases of the Kidney, 2009, viewable at ScienceDirect.

Capsaicin can affect brain patterns during sleep but not while awake, in rats:

• Capsaicin Changes the Pattern of Brain Rhythms in Sleeping Rats

Abstract: "The heat and capsaicin sensor TRPV1 ion channels were originally discovered in sensory neurons of dorsal root ganglia, and later found in many other tissues and organs. However, whether TRPV1 channels are present in brain regions other than the hypothalamus has been a subject of debate. Here, we addressed this issue with an unbiased functional test by recording electroencephalograms (EEGs) to examine whether capsaicin injection directly into the rat lateral ventricle could alter brain electrical activity. We observed that EEGs during the sleep stage could be significantly perturbed by capsaicin, whereas EEGs during the awake stage did not show a detectable change. Our results are consistent with TRPV1 expression in selective brain regions whose activities are dominative during the sleep stage." https://www.mdpi.com/1420-3049/28/12/4736

Pomegranate peel tangent (this was in my pomegranate paper) -

Pomegranate Peel Extract Inhibits STAT3 (Brave AI)

Pomegranate peel extract has been found to inhibit the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a key transcription factor involved in various cellular processes, including inflammation, immune response, and cancer.

Mechanisms of Inhibition

Studies have shown that pomegranate peel extract can inhibit STAT3 activity through multiple mechanisms:

1. Downregulation of STAT3 phosphorylation: Pomegranate peel extract has been shown to decrease the phosphorylation of STAT3, thereby reducing its transcriptional activity.

2. Inhibition of JAK/STAT signaling pathway: The extract has been found to inhibit the Janus kinase (JAK)/STAT signaling pathway, which is essential for STAT3 activation.

3. Modulation of miRNA expression: Pomegranate peel extract has been shown to regulate the expression of microRNAs (miRNAs) that target STAT3, leading to its inhibition.

Anti-inflammatory and Anti-cancer Effects

The inhibition of STAT3 by pomegranate peel extract has been linked to its anti-inflammatory and anti-cancer properties. STAT3 is a key regulator of inflammatory responses and is often overactivated in cancer cells. By inhibiting STAT3, pomegranate peel extract may:

1. Reduce inflammation: Inhibit the production of pro-inflammatory cytokines and chemokines, thereby attenuating inflammatory responses.

2. Suppress cancer cell growth: Inhibit the proliferation and survival of cancer cells by blocking STAT3-mediated signaling pathways.

Future Directions

Further research is needed to fully elucidate the mechanisms by which pomegranate peel extract inhibits STAT3 and to explore its potential therapeutic applications in inflammatory and cancer-related diseases. However, the available evidence suggests that pomegranate peel extract may be a promising natural compound for the development of novel therapeutics targeting STAT3.

Links…. (Brave AI summary/pom peel is a STAT3 inhibitor)

Photo by Nick Morrison on Unsplash

Housekeeping note - I have noticed that searching my ‘deNutrients’ archive doesn’t turn up the posts under the Pomegranate or How-To’s for Health sections. You have to go to those tabs to search for those posts, so, I am planning to change everything to deNutrients and get rid of the extra sections, but I haven’t done it yet.

Time… To Do Lists…

Addition: I made this post into my first X post - I subscribed for the full services which includes formatted articles. (x.com/deNutrients)

Anti-inflammatory benefits of smaller doses of capsaicin

Health benefits do exist with use of smaller amounts of capsaicin - or hot peppers in more moderate amounts. Capsaicin is an agonist of the Nrf2 receptor which promotes glutathione production and repair of damaged DNA and other immune supporting benefits.

• See: Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction, May 2024

  (preprint)

Capsaicin/hot pepper can help clear the congestion from a cold because the activation of TRPV1 channels causes thinning of mucus ... and a drippy nose with more open airways. It also has anti-microbial benefits so likely helps fight the cold virus too.

• Antimicrobial Properties of Capsaicin: Available Data and Future Research Perspectives. (Periferakis, et al., 2023)

• Capsaicin dose in an herbal cold remedy might be 1/8 teaspoon* of cayenne pepper in a glass of fresh squeezed lemon juice in hot water with a spoonful of raw honey, or a spoonful or two of apple cider vinegar in the hot water. * approximately 500-750 mg cayenne powder

• Hot and Sour soup at a Thai or Chinese restaurant was my go to food when I had a cold. The hot chicken broth and ginger and black mushroom would all be supporting healing too. Don't go overboard on the glutamate excessive soy sauce though.

High Dose of capsaicin may be causing too many

Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care purposes.

Reference List

• Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction, May 2024 preprint

• Capsaicin-Induced Impairment of Functional Network Dynamics in Mouse Hippocampus via a TrpV1 Receptor-Independent Pathway: Putative Involvement of Na+/K+-ATPase https://link.springer.com/article/10.1007/s12035-019-01779-3

• Capsaicin upregulates HDAC2 via TRPV1 and impairs neuronal maturation in mice. https://www.nature.com/articles/emm2017289

(Arora, et al., 2018) Arora L, Kumar AP, Arfuso F, Chng WJ, Sethi G. The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies. Cancers (Basel). 2018 Sep 13;10(9):327. doi: 10.3390/cancers10090327. PMID: 30217007; PMCID: PMC6162647. https://pmc.ncbi.nlm.nih.gov/articles/PMC6162647/

(Gelain, et al., 2019) Signal Transducer and Activator of Transcription Protein 3 (STAT3): An Update on its Direct Inhibitors as Promising Anticancer Agents. https://air.unimi.it/handle/2434/592758

(Leite, et al., 2023) Leite LDR, Resende KKM, Rosa LDS, Mazzeu JF, de Oliveira LC, Scher MDCSD, Acevedo AC, Yamaguti PM. Carbonic anhydrase II deficiency syndrome with amelogenesis imperfecta linked to a homozygous CA2 deletion. Intractable Rare Dis Res. 2023 Aug;12(3):202-205. doi: 10.5582/irdr.2023.01033. PMID: 37662627; PMCID: PMC10468405.https://pmc.ncbi.nlm.nih.gov/articles/PMC10468405/

(Lu, et al., 2017) Lu CW, Lin TY, Hsie TY, Huang SK, Wang SJ. Capsaicin presynaptically inhibits glutamate release through the activation of TRPV1 and calcineurin in the hippocampus of rats. Food Funct. 2017 May 24;8(5):1859-1868. doi: 10.1039/c7fo00011a. PMID: 28418433. https://pubmed.ncbi.nlm.nih.gov/28418433/ *paywall

(Nazıroğlu and Demirdaş, 2015) Nazıroğlu M, Demirdaş A. Psychiatric Disorders and TRP Channels: Focus on Psychotropic Drugs. Curr Neuropharmacol. 2015;13(2):248-57. doi: 10.2174/1570159x13666150304001606. PMID: 26411768; PMCID: PMC4598437. https://pmc.ncbi.nlm.nih.gov/articles/PMC4598437/

(Pákáski, et al., 2009) Pákáski, M., Hugyecz, M., Sántha, P., Jancsó, G., Bjelik, A., Domokos, Á., Janka, Z., Kálmán, J., Capsaicin promotes the amyloidogenic route of brain amyloid precursor protein processing, Neurochemistry International, Vol 54, Issue 7, 2009, pp 426-430, ISSN 0197-0186, https://doi.org/10.1016/j.neuint.2009.01.012. https://www.sciencedirect.com/science/article/pii/S0197018609000308

(Periferakis, et al., 2023) Periferakis AT, Periferakis A, Periferakis K, Caruntu A, Badarau IA, Savulescu-Fiedler I, Scheau C, Caruntu C. Antimicrobial Properties of Capsaicin: Available Data and Future Research Perspectives. Nutrients. 2023 Sep 22;15(19):4097. doi: 10.3390/nu15194097. PMID: 37836381; PMCID: PMC10574431. https://pmc.ncbi.nlm.nih.gov/articles/PMC10574431/