1. Garlic Accelerates Red Blood Cell Turnover and Splenic Erythropoietic Gene Expression in Mice

2. garic extract induces HO-1

3. inhibit inflammation

PLoS One. 2010; 5(12): e15358.

Garlic Accelerates Red Blood Cell Turnover and Splenic Erythropoietic Gene Expression in Mice: Evidence for Erythropoietin-Independent Erythropoiesis

B邦nyamin Akg邦l, 1 , 2 Kai-Wei Lin, 1 Hui-Mei Ou Yang, 1 , 3 Yen-Hui Chen, 1 , 4 Tzu-Huan Lu, 1 , 3 Chien-Hsiun Chen, 1 , 3 Tateki Kikuchi, 1 , 4 Yuan-Tsong Chen, 1 , 3 and Chen-Pei D. Tu 1 , 5

1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Authority,
2 Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla, Turkey,
3 National Genotyping Center, Academia Sinica, Taipei, Taiwan Authority,
4 Taiwan Mouse Clinic, National Phenotyping Center, Academia Sinica, Taipei, Taiwan Authority,
5 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America,
University of Louisville, United States of America

Garlic (Allium sativum) has been valued in many cultures both for its health effects and as a culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, procirculatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects.

While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood.

We adopted a phenotype-driven approach to investigate the effects of garlic in a mouse model. We examined RBC indices and morphologies, spleen histochemistry, RBC half-lives and gene expression profiles, followed up by qPCR and immunoblot validation. The RBCs of garlic-fed mice register shorter half-lives than the control. But they have normal blood chemistry and RBC indices. Their spleens manifest increased heme oxygenase 1, higher levels of iron and bilirubin, and presumably higher CO, a pleiotropic gasotransmitter. Heat shock genes and those critical for erythropoiesis are elevated in spleens but not in bone marrow. The garlic-fed mice have lower plasma erythropoietin than the controls, however. Chronic exposure to CO of mice on garlic-free diet was sufficient to cause increased RBC indices but again with a lower plasma erythropoietin level than air-treated controls. Furthermore, dietary garlic supplementation and CO treatment showed additive effects on reducing plasma erythropoietin levels in mice. Thus, garlic consumption not only causes increased energy demand from the faster RBC turnover but also increases the production of CO, which in turn stimulates splenic erythropoiesis by an erythropoietin-independent mechanism, thus completing the sequence of feedback regulation for RBC metabolism. Being a pleiotropic gasotransmitter, CO may be a second messenger for garlic's other physiological effects.

For millennia, garlic (Allium sativum) has been valued in many cultures both for its health effects and as a popular culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, pro-circulatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects [1]每[3]. Although the garlic formulation of AGE (aged garlic extract) has a significant anti-oxidant activity on sickle RBC, excessive garlic intake in animals often leads to hemolytic anemia [4]. While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood. Specifically, the possible relationship between erythropoiesis and garlic's health benefits has not been investigated. In light of the uncertainty regarding garlic's active ingredients [1] and the formation of H2S from garlic's organosulfides in isolated aorta sections [5], we wish to address the possibility of a second messenger for garlic's diverse physiological effects.

We have adopted a phenotype-driven approach to investigate the effects of dietary garlic on erythropoiesis in a mouse model. The array of phenotypic findings〞histochemical analyses of spleens, examination of RBC morphologies, measurements of RBC half-lives, immunobloting, and mRNA expression profile analysis〞all affirm that garlic accelerates RBC turnover and enhances splenic erythropoiesis and related gene expression. Our findings point toward a robust model for illuminating garlic's diverse health benefits. We propose that increased CO production by the heme oxygenase pathway stimulates splenic erythropoiesis by an erythropoietin-independent mechanism as a general homeostatic response to the accelerated RBC turnover caused by garlic consumption. Our proposal is supported by the fact that chronic exposure of mice on a garlic-free diet to low doses of CO stimulates erythropoiesis despite a decreased plasma erythropoietin level. We also propose that CO, a pleiotropic gasotransmitter [6]每[9], may also contribute to other physiological effects of garlic, in addition to erythropoietin-independent erythropoiesis.


Heme released from RBC turnover should induce HO-1 heme oxygenase, which would then produce more Fe2+, biliverdin, and CO . For this reason, we determined the HO-1 mRNA, HO-1 protein, and the constitutive HO-2 protein levels in the spleens of control and garlic-fed mice . The maximal induction of HO-1 mRNA (2.3-fold, p<0.05) occurred around week 6 whereas the HO-1 protein level was elevated in garlic-fed spleens throughout the time course (∼2.5-fold at week 15, Fig. 3). In contrast, the constitutive HO-2 protein remained relatively constant (95㊣5% of control, n = 2). Thus, we conclude that increased degradation of heme occurred in garlic-fed mouse spleens, producing elevated levels of iron, bilirubin (Fig. 2 A每F), and presumably, a stoichiometric amount of CO .

Stimulation of erythropoiesis and related genes (Table 1) by garlic-fed mice is most likely mediated by CO, which by itself can increase the RBC counts, hemoglobin contents, and hematocrit in B6 mice (Figure 4A). It was also reported in rat that chronic exposure to CO increased erythropoiesis [36]. In our results (Figure 4B), however, plasma EPO levels of both garlic-fed mice and CO-treated mice on garlic-free (i.e. cellulose-supplemented) diet decreased relative to air-treated mice on cellulose-supplemented diet (control mice). Furthermore, the decrease of EPO showed an additive effect when garlic-fed mice were chronically exposed to CO (Figure 4B), supporting the proposal that garlic-fed mice produced extra CO. Nevertheless, none of these mice were anemic. Therefore, we have strong evidence (e.g. Figs. 3每4, Tables 1每2, GSE10344) for an EPO-independent pathway in the spleen, which might follow a combination of molecular events in three separate reports [27]每[28], [37].

Firstly, CO can stimulate HSF-1 activation through the MAPK pathway in the lung endothelial cells, resulting in the increased expression of Hsp70 and other heat shock proteins [27]. Our microarray expression profiles, qPCR, and/or immunoblots showed an increase of Hsp70 and Hsp110 (Figure 3 and Table 1) in the spleens of garlic-fed mice.

Secondly, increased Hsp70 can protect the key transcription factor for erythropoiesis, Gata-1, from caspase-3 mediated proteolysis [28]. Stabilization of Gata-1 presumably increased downstream gene transcription for erythropoiesis [30]. Indeed, we have observed an increase of Gata-1 and the downstream gene expression in our mRNA expression profiles and immunobloting results (Figure 3 and Table 1). Thirdly, the CO induced splenic erythropoiesis could be manifested through ERK1, a different subfamily member of the MAPK family, which is a negative regulator of the adult steady-state splenic erythropoiesis [37]. Ablation of ERK1 induces a splenic stress erythropoiesis phenotype, but the mice display no anemia and did not affect EPO levels or EPO/EPO receptor signaling [37]. Thus, CO could directly or indirectly inhibit ERK1 to induce EPO-independent splenic erythropoiesis. The major difference, however, is the lack of acute anemia in our garlic-fed animal model. The details of the proposed CO-mediated, EPO-independent erythropoiesis remain to be elucidated in garlic-fed mice.

The proposed increase of CO from faster RBC turnover by dietary garlic may also have other physiological functions, some of which may be important for garlic's many health benefits. It is widely perceived that garlic's various health effects stem from the synergistic actions among its diverse chemicals [1]每[3]. Our results on the mRNA expression profiles in the garlic-fed mouse spleens (GSE10344) indicate that the collective effects of phytochemicals (and their metabolites) on the expression of genes, for example, against oxidative stress, are very different from those reports using the alleged key derivatives of garlic such as diallyldisulfide, which changes the expression of cytochrome P450's and phase II enzymes at high doses [38]. We did not, to our surprise, observe much induction of mRNAs for detoxification enzymes by either increased iron or phytochemicals (or their metabolites) in the garlic-fed mouse spleens. Only the mRNAs of flavin containing monooxygenase 2, microsomal glutathione S-transferase (GST) 3, and GST Mu5 [39] were induced by dietary garlic (>1.8-fold, p<0.05). This suggests the absence of unusual oxidative stress in the garlic-fed mouse spleens. Such a condition could at least partially be attributable to the higher level of the potent anti-oxidant, bilirubin (and biliverdin), also produced from increased heme degradation [40]. Thus, chemoprevention mediated by induction of cytoprotective enzymes alone is not sufficient to account for the systemic health benefits of garlic [41].

A second mechanism by which garlic may exercise its health effect has been demonstrated in isolated aorta sections through the vaso-relaxation activities of H2S, which is produced from the organosulfur compounds of fresh garlic extracts, especially the allylsulfides [5], [42]. Their conversion to H2S is non-enzymatic and requires cellular GSH, L-cysteine, or protein thiols [42]. As an environment rich in reduced GSH, RBC would naturally convert garlic's organic polysulfides to H2S, which presumably can circulate to the whole body by binding to hemoglobin and other hemoproteins [5], [43]. Besides, the polysulfides may also modify surface and intracellular proteins by reacting with cellular protein thiols, leading to RBC turnover.

Our results point to a more robust biological amplification process that potentially provides a common second messenger for many of garlic's diverse physiological effects. Garlic and other plants of the genus Allium are known for their production of steroid saponins, compounds with hemolytic activities [1], [44]. Therefore, the presence of steroid saponins in garlic is consistent with the dose-response behavior in the Prussian blue stain of the spleen sections (Figure 2H); saponins could cause mild chronic hemolysis without anemia and resulting in accelerated RBC turnover. As the dosage of saponins (garlic) exceeds the rodent's erythropoietic capacity, anemia ensues [4]. It is entirely possible; however, other classes of garlic compounds manifested the phenotype in our study. We propose that accelerated RBC turnover is the crux of the mechanism(s) by which garlic sustains and amplifies its multiple biological effects. At garlic-enhanced rates of turnover, each degraded RBC may release up to ∼6℅108 heme molecules, of which a significant proportion are then converted to CO, to alleviate any heme toxicity [45]. Garlic's anti-platelet, procirculatory, anti-inflammatory, and anti-apoptotic effects parallel those reported for the HO-CO pathway for heme degradation [1], [6]每[9].

In the scheme of RBC turnover, CO can be regarded as a ※feedback§ regulator by stimulating splenic erythropoiesis, which differs from the EPO-dependent process in the bone marrow. In addition to its stimulatory effect on EPO-independent splenic erythropoiesis, CO is a pleiotropic gasotransmitter [6]每[9]. Furthermore, from the perspective of detoxification of garlic's phytochemicals, many of garlic's health benefits could be the manifestation of physiological recovery to achieve systemic homeostasis. This recovery is presumably mediated by a younger population of RBCs, induction of cytoprotective enzymes, H2S produced from garlic's polysulfides, and by CO (the heme oxygenase pathway), which significantly amplifies (up to ∼6℅108-fold) the chemical effects of garlic. The reticuloendothelial system of spleen apparently plays a crucial role in this recovery process. The relationship between the molecular details of CO-mediated pathways for erythropoiesis and of garlic's many health benefits remain to be elucidated.

Garlic Accelerates Red Blood Cell Turnover and Splenic Erythropoietic Gene Expression in Mice: Evidence for Erythropoietin-Independent Erythropoiesis

Nutr Res. 2016 Feb;
Aged garlic extract enhances heme oxygenase-1 and glutamate-cysteine ligase modifier subunit expression via the nuclear factor erythroid 2-related factor 2-antioxidant response element signaling pathway in human endothelial cells.

Hiramatsu K1, Tsuneyoshi T1, Ogawa T1, Morihara N2.
Author information
1 Central Research Institute, Wakunaga Pharmaceutical Co. Ltd., 1624 Shimokotachi, Kodacho, Akitakata, Hiroshima 739-1195, Japan.
2 Central Research Institute, Wakunaga Pharmaceutical Co. Ltd., 1624 Shimokotachi, Kodacho, Akitakata, Hiroshima 739-1195, Japan.

The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway defends cells against oxidative stress and regulates the cellular redox balance. Activation of this pathway induces a variety of antioxidant enzymes, resulting in the protection of our bodies against oxidative damage. It has been reported that aged garlic extract (AGE), a garlic preparation that is rich in water-soluble cysteinyl moieties, reduces oxidative stress and helps to ameliorate of cardiovascular, renal and hepatic diseases. We hypothesized that AGE enhances the expression of antioxidant enzymes via the Nrf2-ARE pathway in human umbilical vein endothelial cells in culture. Gene expression of antioxidant enzymes was measured using real-time polymerase chain reaction. Nuclear accumulation of Nrf2 and antioxidant enzymes expression were evaluated using western blotting analyses.

We found that AGE promoted the accumulation of Nrf2 into the nucleus in a time- and dose-dependent manner and increased the gene expression and polypeptide level of heme oxygenase-1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM). Moreover, the effect of AGE in elevating the gene expression of HO-1 and GCLM was found to be mediated via Nrf2 activation in human umbilical vein endothelial cells.

Taken together, these observations suggest that AGE induces the expression of HO-1 and GCLM, which are antioxidant enzymes, via activation of the Nrf2-ARE signaling pathway.

Copyright © 2016 Elsevier Inc. All rights reserved.

Aged garlic extract; Antioxidant; GCLM; HO-1; Nrf2-ARE signaling pathway

Biomed Rep. 2020 Mar;
Sulfur-containing amino acids in aged garlic extract inhibit inflammation in human gingival epithelial cells by suppressing intercellular adhesion molecule-1 expression and IL-6 secretion.

Ohtani M1, Nishimura T1.

1Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima 739-1195, Japan.

Aged garlic extract (AGE) contains various biologically active sulfur-containing amino acids, such as S-allylcysteine (SAC), S-1-propenylcysteine (S1PC) and S-allylmercaptocysteine (SAMC). These amino acids have been demonstrated to lower hypertension, improve atherosclerosis and enhance immunity through their anti-inflammatory and antioxidant activities. It was recently reported that the administration of AGE alleviated gingivitis in a clinical trial.

In this study, to gain insight into this effect of AGE, the authors examined whether AGE and the three above-mentioned sulfur compounds influence the effects of tumor necrosis factor-汐 (TNF-汐) in inducing intercellular adhesion molecule-1 (ICAM-1) expression and interleukin-6 (IL-6) secretion in Ca9-22 human gingival epithelial cells.

It was found that S1PC reduced the level of ICAM-1 protein induced by TNF-汐 possibly through post-translational levels without affecting the TNF-汐-induced mRNA expression. However, SAC and SAMC had no effect. It was also confirmed the inhibitory effect of an antimicrobial peptide [human-汕 defensin-3 (h汕D3)] and found that the inhibitory effects of hbD3 and S1PC were synergistic.

On the other hand, the TNF-汐-induced IL-6 secretion was attenuated by SAC and SAMC in a dose-dependent manner, whereas S1PC was ineffective. In addition, SAC and SAMC, but not S1PC inhibited the phosphorylation of the transcription factor nuclear factor 百-light-chain-enhancer of activated B cells (NF-百B), which is involved in the expression of inflammatory molecules, suggesting that the anti-inflammatory effects of SAC and SAMC are mediated, at least partly, by NF-百B.

On the whole, the findings of this study suggest that the three sulfur amino acids in AGE function synergistically in alleviating inflammation in human gingival epithelial cells.

Copyright © 2019, Spandidos Publications.

ICAM-1; IL-6; aged garlic extract; gingival epithelial cells; inflammation; sulfur-containing amino acid

Sulfur-containing amino acids in aged garlic extract inhibit inflammation in human gingival epithelial cells by suppressing intercellular adhesion ... - PubMed - NCBI

Molecules. 2012 Jul 4;17(7):8037-55. doi: 10.3390/molecules17078037.
6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice.

Bak MJ1, Ok S, Jun M, Jeong WS.
1 Department of Food & Life Sciences, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.

The rhizome of ginger (Zingiber officinale Roscoe) is known to have several bioactive compounds including gingerols and shogaols which possess beneficial health properties such as anti-inflammatory and chemopreventive effects. Based on recent observations that 6-shogaol may have more potent bioactivity than 6-gingerol, we obtained a 6-shogaol-rich extract from ginger and examined its effects on the nuclear factor E2-related factor2 (Nrf2)/antioxidant response element (ARE) pathway in vitro and in vivo. 6-Shogaol-rich extract was produced by extracting ginger powder with 95% ethanol at 80 ∼C after drying at 80 ∼C (GEE8080). GEE8080 contained over 6-fold more 6-shogaol compared to the room temperature extract (GEE80RT). In HepG2 cells, GEE8080 displayed much stronger inductions of ARE-reporter gene activity and Nrf2 expression than GEE80RT. GEE8080 stimulated phosphorylations of mitogen-activated protein kinases (MAPKs) such as ERK, JNK, and p38. Moreover, the GEE8080-induced expressions of Nrf2 and HO-1 were attenuated by treatments of SB202190 (a p38 specific inhibitor) and LY294002 (an Akt specific inhibitor). In a mouse model, the GEE8080 decreased the diethylnitrosamine (DEN)-mediated elevations of serum aspartate transaminase and alanine transaminase as well as the DEN-induced hepatic lipid peroxidation. Inductions of Nrf2 and HO-1 by GEE8080 were also confirmed in the mice. In addition, the administration of GEE8080 to the mice also restored the DEN-reduced activity and protein expression of hepatic antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase.

In conclusion, GEE8080, a 6-shogaol-rich ginger extract, may enhance antioxidant defense mechanism through the induction of Nrf2 and HO-1 regulated by p38 MAPK and PI3k/Akt pathway in vitro and in vivo.

6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice. - PubMed - NCBI

What You Need To Know About Black Garlic
Also known as ※aged garlic,§ black garlic comes from a process of slow cooking or aging. The result of this is a dark vegetable with a greater concentration of nutrients than conventional garlic.

It is very popular in Asia, especially in Japan, where they use it as a spice to season dishes.

The process of preparing fermented black garlic is simple. Garlic heads are fermented at a specific temperature (around 70∼C) and humidity (between 85 and 90%).

Neither yeast nor bacteria are added. It*s a slow process, but the result is an increasingly popular natural remedy. The flavor of black garlic is slightly sweet, although somewhat acidic. The size of the cloves reduces noticeably, but their curative properties become more concentrated.

Fermented Black Garlic 每 Experience the Healing Power of This Food

Aged Garlic 每 A Tonic Herb
When Garlic is aged, it becomes a ※tonic herb.§ When a herb is tonic this means it can be taken safely for long periods of time without causing disruptions to your system. Better yet, aging leaves all the medicinal and beneficial properties in tact making it just as effective as raw garlic. Aging simply removes the garlic smell and garlic odor. This means no more garlic breath or garlic body odor!

aged garlic

Aged garlic is great for salad toppings, side dishes or all by itself. Its mild flavor makes it easy to eat as a snack or taken daily for protection against viruses and colds. Even kids are willing to give aged garlic a go. This is great news for parents avoiding antibiotic (drug) use on their children. Aged Garlic is without a doubt a MUST for anyone looking for protection against the many bacteria, viruses and pathogens we face today. Some of the benefits of consuming garlic are:

-Natural Antibiotic
-Reduces Blood Pressure
-High Source Of Organic Sulfur (detoxification)
-High Source Of Antioxidants
-Improves Athletic Performance
-Reduces Inflammation
-Cleanses The Blood
-Improves Blood Circulation

How To Make Aged Garlic: The Benefits Of Garlic Without The Odor!

Aged Garlic Extract
September 25, 2009 Written by JP [Font too small?]
The wisdom that comes only after many years of living and learning is generally a desirable by-product of the aging process. On the other hand, many of the physical changes that are a part of the equation are almost always unwelcome. A similar dynamic occurs in the maturation of food. A certain degree of ripeness is necessary in order for most fruits and vegetables to be edible. But if they*re left to ripen for too long, they*ll spoil. However, there are certain instances where prolonged aging of food can yield medicinal properties. One example is the unique aging process that Allium sativum (garlic) sometimes undergoes.

Aged garlic extract (AGE) differs from dietary garlic and most garlic supplements because, as indicated by its name, it is naturally aged for 20 months. During this lengthy period, the garlic changes in a few important ways: 1) the more irritating and pungent properties of the bulb are rendered much milder; 2) a conversion takes place wherein certain phytochemicals that are typically found in raw garlic are transformed into other ※sulfur-containing compounds§. The latter point is significant because these substances (gamma-glutamyl cysteine, S-allyl cysteine, S-allyl mercaptocysteine and S-methyl cysteine) are not normally found in cooked or raw garlic and are believed to be responsible for the unique health benefits ascribed to AGE. In addition, recent research presented in the journal Plant Foods for Human Nutrition explains that AGE contains higher levels of certain antioxidant phenols than cooked or raw garlic. (1)

Potent cardiovascular protection is associated with AGE supplementation in three recent human studies.

Aged Garlic Extract

Garlic is a suspected serotonergic agent,

at least when eaten raw. And two separate studies show this.
Similar to garlic*s ability to lower cholesterol synthesis, its serotonergic activity is generally projected in a good light.

Yet this view has more to do with pharmaceutical profits than with reason#

There are many good reasons to avoid excessive serotonergic activity.

The pro-serotonergic bias of scientists is rampant.
This is likely because so many pharmaceutically-funded studies been published#

And also because an overly-optimistic view is more conducive for receiving pharmaceutical grants.

That is to say: Scientists appear to solicit funding somewhat indirectly 每 as innuendo 每 by writing in an approbative tone that is agreeable to pharmaceutical companies.

Yet independent scientists aren*t so laudatory about serotonin#

And for good reason#

While too little serotonin is certainly associated with depression, too much is associated with plain old stupidity.

※Augmentation of 5-HT [serotonin] neurotransmission has been shown to impair human vigilance performance, i.e. the ability to remain alert for prolonged periods of time#§
Serotonin has a U-shaped curved demarking a fine line between depression on one end, through emotional poise, and towards idiocy at the other extreme.

Although it can be somewhat enjoyable to be happy for no good reason, too much serotonin can turn someone into a basket case.
For example, over-activating the serotonergic system willy-nilly isn*t particularly desirable for:

(1) People going to school

(2) Those who have children going to school

(3) People involved in legal disputes

(4) People who need to concentrate for any reason at all

So it*s certainly worth knowing which foods can influence the brain in this way#

And that*s not so obvious to figure out.

Exactly which foods make a person think unclearly can evade detection by doing just that#

Especially if they also make a person feel ※happy§ by hyperactivating the serotonergic system.

※In fact, there is some indication that some attentional functions 每 selective attention and memory-related executive functions, strategy-driven retrieval from semantic memory 每 may benefit from a reduction of 5-HT neurotransmission.§
Garlic appears to be one of those serotonergic agents#
And maybe that*s why it*s been historically avoided by Chinese monks, Taoists, and Zen masters.

The exact reason for garlic avoidance is often disregarded as ※quaint Ayurvedic bullsh*t§ by people who feel the need to categorize all foods in a polar, black & white manner.

Yet both foods and drugs can certainly have disparate effects 每 some that can be seen as ※good§ and some that can be seen as ※bad.§

Garlic has such a wide spectrum of effects that it refuses to conform to a simplistic classification.
So, even though it*s useful in certain circumstances, and tastes absolutely great, we need to know its side effects to help determine its appropriate use:

Potential Interaction of Aged Garlic Extract with the Central Serotonergic Function: Biochemical Studies.

Around 2003, a group of French biochemists tested aged garlic extract (AGE) against an entire panel of neurotransmitter receptors.

They found that garlic extract interacts with only one receptor, the serotonin receptor 5-HT1B
And it potentiated that one at the lowest concentrations tested.

Scientists believe that the 5-HT1B receptor inhibits the release of dopamine in the frontal cortex#

And maybe that explains one manner in which serotonin inhibits vigilance and focused attention.

※Moreover, the binding of serotonin [3H]5-hydroxytryptophan to [serotonin receptors] was specifically enhanced in a non-competitive manner.§
Dr. Bob Beck is perhaps the only modern scientist who spoke in the past about a negative effect of garlic on the mind.

While occupied in the manufacturing of electroencephalograph machines in the 1970s, Dr. Beck had found a correlation between garlic ingestion and low EEG recordings.

Yet there is little published science on these effects#

Most articles dealing with garlic and behavior are ambiguous rat studies.
It*s not uncommon these days to attribute a ※pro-memory§ function to a compound simply on the basis of electroshock avoidance trials in rodents.

Obviously, such trials are highly open to interpretation#

Judging by the methods used, it would be just as appropriate to call purported ※*pro-memory effects§ actually ※rat modesty effects.§ And perhaps graph them on a ※timid scale.§

A rodent with a less exploratory attitude may be assumed to ※learn§ faster than a curious one, simply on the basis of being more comfortable in captivity.

Since there isn*t that much data to go on in terms of human studies, individuals must rely a bit more on personal experience than with some other things.

Perhaps the most reliable way to gauge garlic*s effects on your mind would be to avoid it entirely for a few days, and then try a dose of two cloves.

※It was interesting to note that the binding of [3H]5-hydroxytryptophan in the presence of 8-OH-DPAT and mesulergine, that mainly corresponds to 5-HT1B receptors, was significantly enhanced in the presence of the lowest concentrations of AGE tested in these assays.§
(That*s just another way of saying it looks like even the lowest concentration of aged garlic extract bumps up the activity of serotonin.)

Garlic compounds are small, lipophilic, and neutral, and are hence widely assumed to penetrate the blood-brain barrier.
Garlic extract potentiated the 5-HT1B receptor over 250% in the concentration range of 10每20 米g/mL (米g = microgram).

So the concentration mentioned above corresponds to 10每20 parts per million (ppm) 每 very small.

This was an extract of the whole herb, and each chemical constituent would necessarily be present in even lower concentrations.

By way of comparison: In rats, a major garlic compound (diallyl disulfide) yielded plasma concentrations of the main metabolite (allyl mercaptan) of nearly 100 ppm.

This was at a dose of 200 米g per kg of body weight per day.

If extrapolated to an adult human weighing in at 70 kilograms (155 lb), this would equate to 14 grams per day.
Concentrations of garlic metabolites remain in the plasma for days, and could potentially build-up over time.

Your average garlic clove weighs anywhere from 4 to 16 grams, depending on size.

Now, garlic is not pure diallyl disulfide.

But the plasma concentration resulting from ingesting 14 gm of diallyl disulfide a day is 5 to 10 times greater than needed to potentiate 5-HT1B receptors by over 250%.

This alone isn*t enough to explain the mental effects of garlic, long-noted by keen observers.

But there is evidence of other mechanisms of serotonergic activity:

Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice.

Using an ethanolic garlic extract and dozens of Swiss albino mice, a team of Indian scientists tested garlic 每 along with four pharmaceuticals 每 for ※antidepressant§ activity.

Foregoing the absurd use of a forced-swim test on mice to determine ※antidepressant activity,§ this study actually yielded some important data:

※Garlic extract significantly decreased immobility time in a dose-dependent manner#indicating significant antidepressant-like activity.§
They found a very substantial reduction in monoamine oxidase-A (an enzyme) activity in the brains of mice fed garlic extract#

And that was at only at 100 mg/kg of body weight per day.

This would be only 7 gm per 70 kg in a human, approximating the weight of a medium-to-large garlic clove.
Monoamine oxidase-A (MAO-A) is the isoform responsible for converting serotonin into 5-hydroxyindole acetic acid.

(That is an inert and water-soluble metabolite readily excreted in the urine.)

Low activity of this enzyme translates into higher brain concentrations of serotonin.

Modest doses of garlic extract 每 only 100 mg/kg per day for mice 每 lowered MAO-A by 64%:

Monoamine oxidase-A levels in garlic-fed mice were reduced to only 36% of their original value. This represents a 64% reduction.

A corresponding increase in brain serotonin would be a foregone conclusion.

So in addition to aged garlic extract acting directly on 5-HT1B receptors, ethanolic garlic extract can substantially lower monoamine oxidase activity.

These two effects could synergize: Garlic appears capable of both increasing serotonin and potentiating its response.
Yet garlic is not physically dangerous at these dose levels# And it tastes good#

So doing your own bioassay at home is a relatively straightforward process.

Personally, I think I can feel an effect from garlic now that I*ve been on the lookout for it.

※Garlic extract (100 mg/kg) administered to mice for 14 successive days, significantly decreased brain MAO-A and MAO-B activity, as compared to the control group. MAO inhibition was comparable to [the anti-depressant] imipramine.§
So although garlic is an effective antioxidant, antibiotic, antifungal, antifibrotic, antilipidemic, etc., it could very well also act as an antidepressant.

And, although its antidepressant effects would generally be seen as a good thing by most people, there are circumstances where it should be avoided.

Serotonin makes people happy at the expense of focused attention. And that is certainly a liability in certain occupations and activities.
Yet it is possible to be happy by other means, ones that don*t involve artificially increasing serotonin.

※In fact, some findings suggest that overstimulation of the 5-HT system actually induces memory impairment.§

Garlic 每 good or bad for men? | Daily Medical Discoveries Garlic -- good or bad for men?

Summary of HTR1B
5-hydroxytryptamine receptor 1B (5-HT1B receptor) is a protein that in humans are encoded by the HTR1B gene.

The function of the 5-HT1B receptor differs depending upon its location (R). In the frontal cortex, it is believed to inhibit the release of dopamine (R).

In the basal ganglia and the striatum, serotonin inhibits the release of serotonin and decreases glutamate transmission (R). In the hippocampus, it produces a facilitation in excitatory synaptic transmission (R). Outside the brain, 5-HT1B receptor activation constricts the vessels in the lungs (which cause pulmonary hypertension and a higher heart rate) (R).

The Function of HTR1B
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries.

This is Your Brain on Serotonin
By Jacob Devaney on Thursday April 28th, 2016

Understanding the cocktail of chemicals that fuel our consciousness
As we dive into the complex and beautiful neurochemical cocktail that fuels our brains, serotonin is a bit of an enigma. Research shows that serotonin plays an important role in regulating mood, appetite, sleep, and dreaming. It can have both a sedating or stimulating effect and this is somehow related to the flow of thoughts through your mind. Though neuroscience is in its infancy, we can still gain a lot of personal insight through exploring research being conducted across a number of fields, and comparing it to what we have felt or experienced internally.

So what is serotonin? It is a neurotransmitter, which means its a type of chemical that relays brain signals from one area of the brain to another. Nearly every one of the 40 million brain cells we have, are influenced either directly or indirectly by serotonin. Many researchers believe an imbalance in serotonin levels leads to depression. If there are any biochemical glitches like a shortage of tryptophan, the chemical from which serotonin is made, or a lack of receptor sites able to receive serotonin, or serotonin is unable to reach the receptor sites, then researchers say this can cause depression, as well as Obsessive Compulsive Disorders, anxiety, panic and excess anger.

Serotonin has been in the spotlight for its potential role in combatting conditions such as anxiety and depression, which affect many people. Prescription medications like Prozac, Paxil, and Zoloft are in a class of drugs called selective serotonin re-uptake inhibitors (SSRIs). The theory is that these drugs are able to modify the extracellular level of serotonin in the brain by limiting its reabsorption. It is believed that by increasing the level of serotonin surrounding the presynaptic cell the symptoms of depression will be erased. However, there is much research that now refutes this theory; claiming that anti-depressants are glorified and expensive placebos. We know that serotonin plays some role in moods (and mood disorders including depression) but we are not exactly sure how, to what degree, and why.

Serotonin receptorSerotonin receptor
A study from the laboratory of long-time depression researcher Eva Redei, presented at the Neuroscience 2009 conference appears to topple two strongly held beliefs about depression. One is that stressful life events are a major cause of depression. The other is that an imbalance in neurotransmitters in the brain triggers depressive symptoms. 每 Northwestern University Feinberg School of Medicine
Psychedelic Drugs
LSD has been in the news lately due to the release of recent brain scans of people under its influence. It doesn*t take a research laboratory to tell that LSD has a profound effect on peoples* mood, and perceptions. Just take a look at the numerous artists, like the Beatles, Steve Jobs, Alex Grey, or Dock Ellis who have pitched a no-hitter on LSD. The enhanced focus and hallucinatory, dream-like experiences on this substance are attributed to the fact that LSD suppresses the serotonin system. The result is an induced dream-state while wide awake. MDMA (ecstasy) is another psychedelic that influences mood, by causing the brain to become flooded with serotonin.

Ecstacy and serotonin receptorEcstacy and serotonin receptor
Our bodies produces endogenous DMT (dymethyltryptamine), which is a structural analog of both serotonin and melatonin. DMT attaches to serotonin receptor sites which exist in high concentrations on nerve cells in brain areas. Occurring naturally in the plant kingdom and in mammals, DMT is the psychoactive component of Ayahuasca, the visionary Amazonian brew. Not surprisingly, many have attested to the ability of Ayahuasca to cure depression.

#the brain is where DMT exerts its most interesting effects. There, sites rich in these DMT-sensitive serotonin receptors are involved in mood, perception, and thought. Although the brain denies access to most drugs and chemicals, it takes a particular and remarkable fancy to DMT. It is not stretching the truth to suggest that the brain ※hungers§ for it.§ 每 DMT: The Spirit Molecule by Rick Strassman, M.D. (2001)
Dreaming and sleep
High levels of serotonin are associated with wakefulness, and low levels are associated with sleep. Therefore it comes as no surprise that the REM sleep cycle (during which most of our dreams occur) happens when the serotonin system shuts off during sleep. Melatonin plays a supporting role to serotonin in this function because it prepares the body for darkness and sleep, regulating our circadian rhythm. As you can see, sleep disorders, moods, ability to focus, alertness, and dreams are quite entwined with the level of serotonin in our brains.

Sleep disorderSerotonin levels are related to sleep disorders
The Brain-Gut Connection
Believe it or not, much of the serotonin in our bodies (up to 95%) resides within our gut. The brain and gut communicate back and forth through the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both ends of this network. An amino acid, tryptophan, is converted into 5-HTP in the small intestine. 5-HTP is then converted to serotonin that is later converted into melatonin. (See tryptophan-rich foods listed below)

Gut brain connectionThe brain and gut communicate
So, the question most people are probably asking is: can I increase my serotonin levels, and if so how?

If you have ever experienced a gut feeling then you may have been tuning in to what researchers call the second brain which is the enteric nervous system. This part of the gut consists of sheaths of neurons embedded in the walls of the long tube of our alimentary canal, which runs from our throat to our anus. Not surprisingly, much of our brain processes are affected by mood which are a direct result of our gut health.

Serotonin is a bit of a mystery because excess levels of it in the gut are also associated with diseases like irritable bowel syndrome. A recent Nature Medicine Study done with rats using a drug that inhibited serotonin in the gut appears to have cured osteoporosis. There also seems to be a link to autism yet the research is still in its early stages. People who take SSRI*s (anti depressants that inhibit serotonin) often have digestion issues as a result. So keep eating sauerkraut, and other live cultures like jun or kombucha to keep healthy flora in your digestive tract. The irony is that so many of us focus on our thoughts, meditation, etc. when the issue may be rooted in our digestion.

How to Increase your Serotonin
It is not so simple to determine the perfect amount of serotonin needed because it appears that too much and too little can each have both beneficial and detrimental effects. It does however seem that increasing ones serotonin levels will help with focus, energy, and mood if you are feeling low. Eating foods rich in tryptophan helps the body synthesise 5-HTP, which can then be turned into serotonin. These foods include but are not limited to: nuts, seeds, tofu, cheese, red meat, chicken, turkey, fish, oats, beans, lentils, and eggs. There are 5-HTP supplements available but it is preferable to source nutrients from whole and organic foods.

TryptophanFoods rich in tryptophan
Research shows that serotonin production is a two-way street with mood. By doing things that elevate your mood, you will increase serotonin production which will get you in an even better mood as the cycle feeds on itself. Yoga and exercise have proven to be beneficial in mood elevation, especially when combined with being outdoors. There is evidence which suggests that exposure to bright light increases serotonin, and people often employ full-spectrum lights in the winter to keep from acquiring SAD (Seasonal Affective Disorder).

Exercise and sunlightExercise and sunlight have been linked with increased serotonin production
We humans have inherited quite an awesome and complex physiology. Serotonin is perhaps one of the most mysterious and important of all neurotransmitters and being more aware of its interactions will hopefully bring about improvements in your moods and dreams.

This is Your Brain on Serotonin

Dopamine and serotonin: Brain chemicals explained

Dopamine and serotonin are chemical messengers, or neurotransmitters, that help regulate many bodily functions. They have roles in sleep and memory, as well as metabolism and emotional well-being.

People sometimes refer to dopamine and serotonin as the ※happy hormones§ due to the roles they play in regulating mood and emotion.

They are also involved in several mental health conditions, including low mood and depression.

Dopamine and serotonin are involved in similar bodily processes, but they operate differently. Imbalances of these chemicals can cause different medical conditions that require different treatments.

In this article, we look at the differences between dopamine and serotonin, their relationship, and their links with medical conditions and overall health.

What is dopamine?

Neurons in the brain release dopamine, which carries signals between neurons.

The body uses dopamine to create chemicals called norepinephrine and epinephrine.

Dopamine plays an integral role in the reward system, a group of brain processes that control motivation, desire, and cravings.

Dopamine levels also influence the following bodily functions:

blood flow
urine output
What is serotonin?
Serotonin is another neurotransmitter present in the brain.

However, more than 90% of the body*s total serotonin resides in the enterochromaffin cells in the gut, where it helps regulate the movement of the digestive system.

In addition to aiding digestion, serotonin is involved in regulating:

the sleep-wake cycle
mood and emotions
metabolism and appetite
cognition and concentration
hormonal activity
body temperature
blood clotting

Dopamine vs. serotonin: Similarities, differences, and ...

Aug 19, 2019 ﹞ Serotonin inhibits impulsive behavior, while dopamine enhances impulsivityDopamineand serotonin have opposite effects on appetite; whereas serotonin suppresses it, low levels of dopamine

Garlic and alpha lipoic supplementation enhance the immune ...
Supplementation with mixture of antioxidants (garlic aqueous extract and alpha lipoic acid) cannot counteract this inhibition. Elevation in malondialdehyde (MDA), oxidative stress biomarker, was concomitant to the effect of pesticides mixture on AChE enzyme, all through the treated groups pronounced in weaning treated groups.

Cited by: 3
Publish Year: 2015
Author: Manal Ea Elhalwagy, Nevine S Darwish, Dina A Shokry, Aly Ge Abd El-Aal, Sherif H Abd-Alrahman, Abd-A...
(PDF) Garlic in health and disease - ResearchGate
Garlic powder, aged garlic and garlic oil have demonstrated antiplatelet and anticoagulant effects by interfering with cyclo-oxygenase-mediated thromboxane synthesis.

Evidences for the involvement of monoaminergic and ...
This suggests that garlic extract might produce antidepressant-like effect through interaction with 汐 1-adrenoceptors, dopamine D 2 receptors, serotonergic and GABAergic receptors, thereby increasing the levels of norepinephrine, dopamine, serotonin and decreasing GABA levels in the brain of mice. Garlic extract (100 mg/kg p.o.) administered to mice, for 14 successive days, significantly decreased brain MAO-A #

Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice.
Dhingra D, Kumar V

Indian Journal of Pharmacology, 01 Aug 2008, 40(4):175-179


The present study was undertaken to investigate the effect of the ethanolic extract of Allium sativum L. (Family: Lilliaceae), commonly known as garlic, on depression in mice.


Ethanolic extract of garlic (25, 50 and 100 mg/kg) was administered orally for 14 successive days to young Swiss albino mice of either sex and antidepressant-like activity was evaluated employing tail suspension test (TST) and forced swim test (FST). The efficacy of the extract was compared with standard antidepressant drugs like fluoxetine and imipramine. The mechanism of action of the extract was investigated by co-administration of prazosin (alpha1-adrenoceptor antagonist), sulpiride (selective D2-receptor antagonist), baclofen (GABA(B) agonist) and p-CPA (serotonin antagonist) separately with the extract and by studying the effect of the extract on brain MAO-A and MAO-B levels.

RESULTS: Garlic extract (25, 50 and 100 mg/kg) significantly decreased immobility time in a dose-dependent manner in both TST and FST, indicating significant antidepressant-like activity. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg p.o.) and imipramine (15 mg/kg p.o.) in both TST and FST. The extract did not show any significant effect on the locomotor activity of the mice. Prazosin, sulpiride, baclofen and p-CPA significantly attenuated the extract-induced antidepressant-like effect in TST. Garlic extract (100 mg/kg) administered orally for 14 successive days significantly decreased brain MAO-A and MAO-B levels, as compared to the control group.

CONCLUSION: Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems.

Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice. - Abstract - Europe PMC

A possible emerging role of phytochemicals in improving ...
Aged garlic extract (AGlE, Allium sativum), which contains S-allycisteine, S-allymercaptocysteine, allicin, and diallosulfides, has been reported to exhibit beneficial effects towards cognitive impairments in a novel strain of senescence accelerated mouse (SAM) , , , .

Cited by: 506
Publish Year: 2001
Author: Kuresh A Youdim, James A Joseph
Repeated Administration of Fresh Garlic Increases Memory ...
The effects of aged garlic extract (AGE) on longevity and learning and memory performances were studied in the senescence accelerated mouse (SAM). A solid diet containing 2% #

Modulation of Cytokine Secretion by Garlic Derivatives
Herbal medicines with immunomodulatory activity alter the immune function through the dynamic regulation of molecules such as cytokines and chemokines. Altering cytokine expression and targeting their receptors may offer therapeutic potential. Current pharmacological strategies include cytokine antagonist, agonist, inhibition, and stimulation models. However, in light of the adverse events experienced with cytokine-targeted therapy, it could be useful to consider the use of phytotherapy in the modulation of cytokine expression [47]. Recently, Quintero-Fabi芍n et al. examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes. Incubation of cells for 24 h with 100 米mol/L alliin prior to LPS (100 ng/mL) stimulation for 1 h prevented an increase in the expression of proinflammatory genes IL-6, MCP-1, and Egr-1 and in the protein levels of IL-6 and MCP-1. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, decreased following alliin treatment. Furthermore, gene expression profile by microarray evidences an upregulation of genes involved in immune response and downregulation of genes related with cancer [30]. Indeed SAC, caffeic acid (CA), uracil, diallyl trisulfide (DATS, as known as Allitridin), diallyl sulfide (DAS), and other garlic-derived compounds can inhibit transcription factor NF-百B, a master regulator, inhibiting the transcription of several cytokine genes involved in proinflammatory responses, such as TNF-汐, interleukin-1beta (IL-1汕), IL-6, MCP-1, and IL-12(p70) [25, 48每50].

Immunomodulation and Anti-Inflammatory Effects of Garlic Compounds