What is agmatine

Agmantine (1-amino-4-guanidinobutane) is a natural metabolite of the amino acid arginine that is known to cross the blood-brain barrier when given orally ¹. Agmantine is formed when L-arginine is decarboxylated by the enzyme arginine decarboxylase (ADC) and is found naturally in ragweed pollen, ergot fungi, octopus muscle, herring sperm, sponges, and the mammalian brain. Agmatine is hydrolyzed to putrescine (one of the main biogenic amines associated with microbial food spoilage) and urea by agmatinase (AGM) or agmatinase-like protein (ALP) (see Figure 3A). The agmatine sulfate salt has been used as a dietary ingredient and now is available as a nutraceutical ². Agmatine is both an experimental and investigational drug. As an investigational drug, it is being studied in a non-blinded prospective case study in the United States looking at patients who have been diagnosed with small fiber peripheral neuropathy between the ages of 18 to 75 years. Recent clinical studies have already shown that oral agmatine sulfate (daily dose of 2.67 g agmatine sulfate) given for up to 3 weeks provides a safe and, as compared with current therapeutics, more effective treatment for neuropathic pain ³. As an experimental drug, agmatine is being studied for several indications such as cardioprotection, diabetes, decreased kidney function, neuroprotection (stroke, severe central nervous system injuries, epilepsy, glaucoma, and neuropathic pain), and psychiatric conditions (depression, anxiety, schizophrenia, and cognition). The exact mechanism of action is still being investigated for all of the potential indications of agmatine.

Agmatine has been directly associated with many important cellular functions, such as the modulation of insulin release from pancreatic cells ⁴, renal sodium excretion ⁵, inhibition of nitric oxide synthase ⁶, neuroprotective effects ⁷, increased tolerance to morphine ⁸, modulation of ethanol anxiolysis ⁹ and regulation of polyamine biosynthesis ¹⁰. Agmatine is considered a neurotransmitter or neuromodulator ¹¹ because it regulates the release of catecholamines and potentiates opioid analgesia ¹². The injection of agmatine produces anticonvulsant, antineurotoxic and antidepressant-like actions in animals ¹³. Agmatine has also been linked to other central nervous system disorders. Specifically, preclinical studies have demonstrated the beneficial effects of agmatine administration on diseases such as depression, anxiety, hypoxic ischemia, nociception, morphine tolerance, memory, Parkinson’s disease, Alzheimer’s disease, traumatic brain injury-related disorders, and epilepsy ¹⁴. The various biological processes on which agmatine is involved suggest that it might require the fine regulation of its cellular concentrations.

Figure 1. Agmatine chemical structure

Figure 2. Agmatine sulfate chemical structure

Figure 3. Agmatine biosynthesis and breakdown

Footnote: (A) Pathway of agmatine biosynthesis and breakdown. (B) Schematic illustration of the Mn2+ binding site of E. coli agmatinase (AGM). The enzyme can accommodate two closely spaced Mn2+ ions in their active sites, using highly conserved amino acid side chains ¹⁵.

Abbreviations: ADC = arginine decarboxylase; ALP = agmatinase-like protein; AGM = agmatinase; Mn2+ = manganese ion.

[Source ¹⁶ ]

Agmatine function

Moinard et al. ¹⁷ have reported that agmatine concentrations in the brain have been found to be comparable to that of typical neurotransmitters, thus suggesting that agmatine might be a neurotransmitter.

A variety of effects have been demonstrated in response to agmatine in vivo and in vitro, but the biological significance of these effects is still under debate, because the concentrations at which the effects were induced were much higher than those present in blood and tissues ¹⁸. However, agmatine is known to have secretagogue properties, such as the modulation of insulin release and glucose metabolism, the stimulation of adrenaline, and noradrenaline secretion. agmatine antagonizes some hyperalgesic states and enhances the dose-related analgesic effect of morphine ¹⁹.

Agmatine appears to influence appetite regulation. The administration of a high dose of agmatine to satiated rats triggered an increase in their caloric intake and their carbohydrate preferences, whereas agmatine does not modulate caloric intake in hungry rats ²⁰. agmatine also plays an important role in polyamines homeostasis: by inhibiting ornithine decarboxylase, agmatine inhibits smooth muscle proliferation ¹⁷.

Agmatine is recognized as an inhibitor of nitric oxide synthase, an enzyme that, starting from arginine, catalyzes the production of nitric oxide (NO), an intercellular messenger implicated in the regulation of various physiological functions in central neurotransmission. It has been suggested that NO (nitric oxide) may be involved in the mechanism of anxiety, therefore NO (nitric oxide) inhibitors, such as agmatine, may be a potential tool for the treatment of anxiety ²¹, even though Krass et al. ²² failed to demonstrate the reported antidepressant and anxiolytic-like activity of agmatine.

However, it is highly probable that agmatine will play a role in the therapeutic treatment of a number of different diseases. In the treatment of cancer, it has been established that agmatine has a antiproliferative effect due to its suppression of polyamine synthesis and cellular polyamine uptake through the induction of antizyme ²³.

It has also been suggested that agmatine could play an important role in the control of ureagenesis, representing a significant contribution to the therapeutic removal of waste toxic nitrogen from the body. Moreover, agmatine could be useful in the treatment of sepsis, because its administration to endotoxemic rats has been shown to prevent the decrease in blood pressure and renal function usually associated with sepsis ¹⁷.

Agmatine is also able to protect brain mitochondria against the drop in energy capacity by the Ca2+-dependant induction of permeability transition in rat brain mitochondria ²⁴. Furthermore, agmatine may also be considered as a regulator of mitochondria cell death. In addition, by increasing the expression of antizyme, a protein that inhibits polyamine biosynthesis and transport, agmatine exhibits a regulatory effect on cell proliferation ²³.

The high content of agmatine in the lumen of the gastrointestinal tract may also originate from the bacteria of the physiological gut microflora, as well as from pathogens such as Helicobacter pylori.

After oral administration of radiolabeled agmatine to rats in vivo, radioactivity was retrieved in all organs investigated, as well as in blood and urine indicating that agmatine is absorbed from the stomach and the gut by means of an energy-dependent transport mechanism and distributed to the organs via the blood stream. Moreover, the accumulation of radioactivity in organs and distal gut luminal content decreases with the administration of increasing doses of putrescine ¹⁸.

Because of the low arginine decarboxylase activity in mammalians, only a fraction of agmatine in the tissues of the organism can be due to endogenous de novo synthesis by arginine decarboxylase, while a substantial portion can be of dietary origin ¹⁸.

Agmatine foods

Several food items contain only small amounts of polyamines, such as agmatine, while higher concentrations can be found in fermented foods. Polyamines can also be considered as indicators of freshness in fish and meat products, as they are produced during food storage, thus confirming the main role of microorganisms in their synthesis. In particular, agmatine is present at high levels in alcoholic beverages, such as wine, beer, and especially in sake (114 mg/L) ²⁵, while low levels have been found in fermented non-alcoholic beverages, such as Turkish shalgam ²⁶. This fact could confirm the role of yeasts in agmatine production.

Table ​1. Agmatine content in different foodstuffs (ppm)

Foodstuffs	Mean	Range	N (A)
WINE
Red wines	n.s.	n.d.–22	286
White wines	n.s.	n.d.–6.5	103
BEER	12	0.5–42	211
SAKE	114	n.s.	n.s.
COFFEE
Green coffee	n.d.	n.d.	n.s.
Roasted	n.s.	n.d.–1.2	n.s.
Instant coffee	0.4	0.4–5.3	68
CEREALS AND VEGETABLES
Flour	n.d.	n.d.	5
Bread	3.3	n.d.–4.7	9
Soy sauce	n.d.	n.d.	4
Soybean paste (Doenjang)	473	n.d.–5508	23
Miso	6.1	n.d.–30	5
Sauerkraut brine	4.3	2.2–6.7	6
Fermented cabbage juice	n.d.	n.d.	5
FISH AND DERIVED PRODUCTS
Fresh fish	92	n.d.–401	13
Fish paste	n.d.	n.d.	3
Cooked fish paste	29	n.d.–161	28
MEAT AND MEAT PRODUCTS
Fresh meat	0.8	n.d.–3.1	22
Fermented meat	6.2	n.d.–43	23
Cooked meat	5.4	n.d.–27	20
DAIRY PRODUCTS
Fermented milk (Kefir)	n.d.	n.d.	10
Ripened cheese	1.1	n.d–18	69
Fresh cheese	0.1	n.d.–1.3	13
Grated cheese	1.2	n.d.–14	12

Footnotes: (A) Number of samples examined; n.d. = Not detected; n.s. = Not specified.

[Source ²⁷ ]

Wine

The concentration of biogenic amines in wine has been reported to range from a few mg/L to about 50 mg/L. The type and concentration of amines in wines depends on several factors, such as winemaking processes, time and storage conditions, raw material quality, and microbial contamination during winery operations. Moreover, some amines are normal constituents of grapes, and their level may vary with grape variety and degree of ripening, as well as with soil type and composition. Therefore, geographical characterization based on the biogenic amine content has also been proposed as a criterion to discriminate several types of wines from different countries or regions ²⁸. Biogenic amines usually investigated in wines are cadaverine (CAD), histamine (HIS), 2-phenylethylamine (2-PHE), putrescine (PUT) and tyramine (TYR); agmatine and ethanolamine can be abundant in wines, but they are rarely investigated ²⁷. Low amounts of biogenic amine, as normal constituents of the raw materials, can be released in must from grapes during the winemaking process, and the biogenic amine concentration may increase as a consequence of alcoholic fermentation, yeast autolysis, malolactic fermentation, and wine aging, red wines usually having a richer amine content than white wines. Generally putrescine and agmatine can contribute significantly to the total amine content in alcoholic beverages, while cadaverine, spermine, and spermidine are rare ²⁷. In particular, putrescine is the most abundant biogenic amine in wine, while agmatine is the most prevalent in beer ²⁹.

For agmatine, the concentration has been reported to vary from not detected to 22 mg/L in red wines and from not detected to 6.5 mg/L in white wines, while putrescine has been found in red wines at concentrations ranging from 0.6 to 21 mg/L and from not detected to 9 mg/L in white wines ³⁰. Spermidine and spermine originate from putrescine, which derives from agmatine; the latter is generally recognized as an intermediate in the putrescine formation pathway, starting from arginine, the most abundant amino acid in grape. Putrescine can also derive from decarboxylation of ornithine. However, putrescine levels increase during fermentation from must to alcoholic, to malolactic fermentation, thus supporting the hypothesis that the principal biosynthetic pathway for putrescine formation is via arginine-agmatine rather than via ornithine ³⁰. Moreover, arginine, from which agmatine derives, is present in must at concentrations higher than those found in the finished wine ³⁰. In addition, wines with a low putrescine content have been shown to possess a high level of agmatine and total polyphenols and vice versa ²⁸. The phenolic compounds seem to be a natural way of reducing putrescine formation in wine, because these moieties can protect the cells against oxidative stress ³¹.

Beer

Polyamines are natural beer constituents and are present in malt and yeast at higher concentrations then in hops ³², while tyramine, histamine, and cadaverine are considered to be indicators of microbial contamination during brewing ³³. In several beers agmatine is the most abundant amine with concentrations ranging from 0.5 to 42 mg/L ³⁴. Barley variety, malting technology, and fermentation conditions can influence the biogenic amine content in beer both qualitatively and quantitatively. In particular, during wort processing, significant increases of agmatine, and putrescine have been observed, together with the decrease of spermidine and spermine ³⁵.

Coffee

The profile and levels of biogenic amines in green and roasted coffee are different; in particular, the degree of roasting significantly influences the amine profile and levels. Agmatine has been detected in coffee roasted at a high temperature for a long time. In fact, extensive roasting (12 min at 300°C) contributes to agmatine formation (1.2 mg/kg) by decarboxylation of arginine, which is present in green coffee at levels ranging from 2 to 5 g/100 g. Conversely, agmatine was not found in American coffee, which was roasted for 6 min at 300°C. Furthermore, putrescine is the most abundant amine in green coffee (10 mg/kg), while it is not present in roasted coffee ³⁶. Also the processing of instant coffee can influence both the type and level of biogenic amines; instant coffee contains low levels of agmatine (0.4 mg/kg), while the most abundant biogenic amine is serotonin, followed by cadaverine, tyramine and spermidine ³⁷.

Cereals and vegetables

In cereal foods, in particular in flour and bread samples, putrescine is reported to be the most abundant biogenic amine, at even higher levels than 40 mg/kg, while agmatine has been found only in cereal derivates, in particular in different types of bread samples, at concentrations ranging from 3 to 5 mg/kg of dry matter ³⁸. Agmatine is also a natural constituent of the seedlings of the winged bean, while is not found in the common bean nor in soybean ³⁹. Since several varieties of molds, yeasts, and lactic acid bacteria are involved in the fermentation processes occurring in the production of several soybean products, and as the substrate is very rich in proteins, the formation of various amines might be expected during fermentation. Several studies have highlighted that biogenic amines in fermented soybean products are most probably formed by the lactic microflora that remains active during fermentation ⁴⁰. Among many fermented foods that have been consumed for thousands of years in Asian countries, soy sauce, and miso are the most important, and they are obtained by the fermentation of soybean with or without the addition of rice and wheat (in the case of soy sauce) or rice and barley (in the case of miso), using a mix of molds, yeasts, and lactic acid bacteria. In these products agmatine has rarely been detected, whereas putrescine is one of the most abundant amines that can be found ⁴⁰. Conversely, in Doenjang, a traditional Korean soybean paste produced by the fermentation of naturally occurring bacteria and fungi, the presence of agmatine was reported, in concentrations ranging from not detected to over 5500 mg/kg ⁴¹.

Recently Özdestan et al. ⁴² have investigated the biogenic amine content in Kumru, a traditional Turkish fermented cereal food produced from chickpeas. In this case not detectable amounts of agmatine were found in the product, while other biogenic amines, such as putrescine, cadaverine, spermidine, spermine, and histamine were present in all samples.

Fermentation temperature, salt concentration, and starter selection have a significant effect on biogenic amine production in sauerkraut (fermented cabbage). In particular, the agmatine level seems to be dependent on the inoculum concentration of Lactobacillus curvatus. In sauerkraut brine, agmatine was found to be the prevalent amine, reaching a maximum value of 12 mg/L ⁴³. Conversely, other authors have reported that lactic fermented cabbage juices do not contain agmatine, while putrescine, estimated at levels of up to 360 mg/L, is the most abundant amine, with assessed levels up to 360 mg/L; ⁴⁰.

Fish and fish derived products

Spermine and spermidine are usually the main polyamines present in fresh tissues, at concentrations of less than 10 mg/kg. Depending on the fish species, the free amino acids present in the tissues, and the exposure conditions to spoilage bacteria, other amines can originate during storage or processing, reaching harmful levels, as reported for histamine in the case of animals belonging to the mackerel and herring families ⁴⁴. The existence of a synergic relationship between spermine, spermidine, and histamine with potentially negative consequences on health, has been hypothesized ⁴⁵. Therefore, various indexes have been proposed for fish derived products, such as the “biogenic amine index,” corresponding to the sum of the histamine, putrescine, cadaverine, and tyramine content ⁴⁶ or the “quality index,” directly related to the histamine, putrescine, and cadaverine content and inversely related to the amounts of spermine and spermidine ⁴⁷. Moreover, several authors have indicated that agmatine may be used as a freshness index, because immediately after catch agmatine can not be detected or its level is very low, but then in various fish species the agmatine content increases progressively during chilling storage, reaching concentrations of over 300 mg/kg after 7 days of storage ⁴⁸. The formation of biogenic amines, commonly related to fish spoilage (histamine, tyramine, cadaverine and agmatine), was found to be significantly higher in the first stage of ripening in ungutted anchovies than in gutted ones. Conversely, no differences have been observed regarding the content of spermine and spermidine ⁴⁹. In Rihaakuru, a cooked fish paste, the agmatine concentration is extremely variable, ranging from not detected to 161 mg/kg ⁵⁰, whereas in other fermented and non-fermented fish paste, agmatine is not detectable ⁴⁰. Fish storage conditions can help to reduce the processes favoring the formation of biogenic amines. In particular, refrigeration with flaked ice, traditionally applied to fish, significantly reduces agmatine and the formation of other biogenic amines compared with refrigeration at the same temperature, but without ice ⁴⁸. Protective atmosphere packaging is frequently used to prolong the shelf-life of foodstuffs, and effectively reduces biogenic amine concentrations in different fish. In particular, Ruiz-Capillas and Moral ⁵¹ have shown that for tuna a gas mixture containing 60% CO2 is more effective in reducing these moieties than a gas mixture containing 40% CO2. This was particularly true in the case of white muscle of tuna, where after 25 days of storage an atmosphere containing 60% CO2 caused a 10-fold reduction of the agmatine level compared with the control stored in air.

Meat and meat products

Biogenic amines can be found in processed meat products as a consequence of microbial activity related to fermentation occurring during processing, or to microbial contamination of poor quality raw meat. Therefore, in cooked meat products (non-fermented) biogenic amines may represent a useful indicator for assessing the hygienic quality of the raw meat utilized for preparing these foodstuffs ⁵². Furthermore, the nitrosable secondary amines (agmatine, spermidine, and spermine) can form nitrosamines by reaction with nitrites, chemical agents considered to possess major carcinogenic properties. This is particularly important in some meat products with high polyamine levels and whose production process requires the use of nitrates and nitrites ⁵³. As with fish, also fresh meat normally contains polyamines such as spermine and spermidine, the levels of which may vary slightly in fermented and ripened meat products. In fresh meat agmatine can be found at levels ranging from not detectable to about 3 mg/kg, while in fermented and ripened meat products the agmatine content may range more widely from not detectable to about 43 mg/kg. However, it has been reported that in these products a low formation of putrescine can be related to the presence of high levels of agmatine, the latter being an intermediate metabolite in the putrescine production pathway from arginine. Generally cooked meat products show lower polyamine concentrations than fresh meat ⁵².

Dry-cured “lacón” is a traditional cured meat product made in Spain, following manufacturing processes very similar to those utilized in the production of dry-cured ham. During the manufacture of dry-cured lacón the content of biogenic amine may vary greatly, as is also the case with ham. In addition, higher levels of tryptamine have been found in fresh lacón pieces than in fresh meat, whereas agmatine has not been detected. However, agmatine was generated during the drying-ripening stage, both with and without additives and the values reached in the final product (around 8 mg/kg) were higher than those found in ham ⁵⁴.

The technology applied in meat processing may influence biogenic amine production. For example, sugar omission in the production of slightly fermented sausages is not recommended, because it may cause an increase in agmatine and the accumulation of other biogenic amines during manufacture and storage ⁵². Furthermore, different concentrations of biogenic amines have been found in fresh, fermented, and cooked meat products, either treated with high pressure processing or under protective atmosphere packaging, which were closely related to the type of product and the processing conditions. In general, protective atmosphere packaging has a positive effect in reducing biogenic amine formation in these products. In commercial meat products treated with high pressure processing, higher biogenic amine concentrations, particularly agmatine, have been reported compared with non-treated samples. This negative effect of high pressure processing has also been observed in frankfurters, butifarra, cooked ham, and chorizo; for the latter product, it has been observed how commercially available non-treated samples may contain agmatine concentrations of about 2 mg/kg, while chorizo treated by high pressure processing may show a 20-fold increase in agmatine content ⁵⁵.

Milk and dairy products

In milk, as in other fresh foods derived from animals, spermine and spermidine are the prevalent polyamines, whereas it must be reported that agmatine was not detectable ⁵⁶. Also in industrial kefir, a milk product belonging to the category of mixed lactic acid and ethanol fermented beverages, agmatine was not detectable. The estimated biogenic amine content in kefir, ranging from 2 to 35 mg/L, is generally lower than that found in other fermented foods. Short fermentation time, the use of starter culture, controlled production conditions such as heating at 90–95°C before fermentation and a low microbial count in the raw material are the main reasons for the low biogenic amine content. Higher biogenic amine levels can be expected in artisanal or home-made kefir compared with industrial samples, because of worse hygienic conditions ⁵⁷.

Cheeses represent an ideal environment for the production of amines. The factors influencing the formation, accumulation, and type of amines are: the availability of amino acids, the presence of bacteria capable of decarboxylating amino acids, pH, salt concentration, water availability, temperature and duration of ripening and storage, bacterial density, the presence of cofactors, and amine catabolism. The pH of cheese is appropriate for biogenic amine production, generally between 5.0 and 6.5, depending on the age and type of the products. Cheeses are also rich in pyridoxal phosphate, which is required for amino acid decarboxylase activity. Studies have shown that in cheese the concentration of biogenic amines decreases with increased fat content. This phenomenon has been attributed to changes in the water activity, which inhibits the growth of proteolytic bacteria, causing a reduction of free amino acid concentration in the medium ⁵³. Numerous bacteria, both intentional or adventitious and isolated from cheese, have been reported as biogenic amine producers ⁵⁶. Several outbreaks of histamine poisoning have occurred following the consumption of cheese; also cases of hypertensive crisis and migraine headache have been observed after the ingestion of cheeses with high levels of tryptamine and 2-phenylethylamine. The use of bacteriocin-producing starters can prevent the formation of histamine. Moreover, the addition of microbial isolates that degrade biogenic amines in order to prevent the presence of hazardous levels of amines in the final products has been proposed. Although the type and levels of amines in each kind of cheese may vary considerably, agmatine is a polyamine which is rarely present in cheeses ⁵⁸.

Agmatine benefits

In 1995, Gilad, et al. ⁵⁹ firstly reported the neuroprotective action of agmatine. Henceforward, more and more studies showed neuroprotection of agmatine in stroke, traumatic brain injuries, neurodegenerative disorders, neuropathic pain, epilepsy, and even in mental disorders. Anti-oxidation, anti-apoptosis, anti-inflammation, brain blood barrier (BBB) protection and brain edema prevention are the common mechanisms involved in the neuroprotective effects.

Agmatine has been shown in preclinical experiments to interact with multiple molecular targets important for nervous system function. These include: 1) modulation of several neurotransmitter receptors and receptor ionophores (e.g., nicotine, NMDA, imidazoline, and alpha 2-adrenoceptors) ⁶⁰; 2) blockade of key ionic channels (e.g., ATP-sensitive K+ channels and voltage-gated Ca++ channels) ⁶¹; 3) inhibition of nitric oxide (NO) synthase and thus, modulation of NO production ⁶²; 4) inhibition of protein ADP-ribosylation ⁶³ and thus, interference with cell signalling; 5) inhibition of matrix metalloproteases ⁶⁴, enzymes implicated in nerve cell death and neuropathic pain ⁶⁵; and 6) inhibition of advanced glycation end (AGE)-product formation, a process involved in the pathology of diabetes and neurodegenerative diseases ⁶⁶.

Agmatine in ischemic stroke

Stroke has been the second most common disease to cause death and disability in adults around the world ⁶⁷. Ischemic stroke, which accounts for about 87% of cases, is the most common subtype of stroke ⁶⁸. Ischemic stroke is the result of insufficient blood and oxygen supply to the brain. The cell in central portion of the ischemic tissue, known as infarct core, is afflicted with irreversible damage and the area around the infarct core, called penumbra, is at risk of infarction and can be reverted ⁶⁹.

Previous studies have proved that the occurrence of stroke promoted the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which could destroy the structure of blood brain barrier, leading to brain edema ⁷⁰. In addition, the disruption of neuro-inflammatory or oxidative stress balance could produce excessive inflammatory cytokines, reactive oxygen species (ROS) and free radicals, which initiate cell death ultimately ⁷¹.

Numerous experimental researches, most of which focused on the salvation of the tissue in the penumbra, had been carried out to explore the optimal neuroprotective drugs for cerebral ischemia ⁷². But the severe side-effects of these drugs posed great limitation on further clinical trials. In contrast, agmatine displayed its safety in both experimental and clinical trials. The sulfate salt of agmatine had been used as a dietary ingredient many years ago and now is available as a nutraceutical ²⁷. Besides, many studies confirmed the neuroprotective role of agmatine in strokes ⁷³.

Kim et al. ⁷⁴ showed the neuroprotective effects of agmatine both in vivo and in vitro through the mechanism of reducing the production of nitric oxide (NO) by competitively inhibiting neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). Meanwhile, agmatine can also activate endothelial nitric oxide synthase (eNOS) in endothelial cells, and thus increase the production of NO, which acts as a vasodilator to increase the blood flow in the ischemic areas ⁷⁵. Feng et al. ⁷⁶ reported that both endogenous and exogenous agmatine can exert their functions on the NOS (nitric oxide synthase) and reduce hypoxic-ischemic brain injury in neonatal rats. Besides, many other studies verified the effects of agmatine on the three kinds of NOS mentioned above in the setting of cerebral ischemia ⁷⁷.

Brain blood barrier (BBB) is extremely important in maintaining homeostasis and microvascular integrity ⁷⁸. However, the cerebral ischemic attack could induce upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which could destroy the integrity of blood brain barrier. Hyun et al. ⁷⁹ and Yang et al. ⁸⁰ both demonstrated that exogenous agmatine could inhibit the expression of MMP-2 and MMP-9 by induction of eNOS in vitro. Moreover, Hyun and his colleagues ⁷⁹ utilized retrovirus to induce the endogenous agmatine, and their findings suggested that endogenous agmatine could reduce the MMP-2 and MMP-9 expression by regulation of eNOS, NO and activation of transcription factor 3(ATF3). In addition to detecting MMP-2 and MMP-9, Ahn and his colleagues ⁸¹ took advantage of dynamic contrast-enhanced MR imaging to evaluate the beneficial effects of agmatine on blood brain barrier stabilization.

Brain edema frequently was observed to be involved in the worsening process of cerebral ischemia and contributed to increasing mortality after attack of stroke. Jae and his colleagues ⁸² explored the mechanism of brain edema and the effects of agmatine. Their findings suggested that the blood brain barrier disruption and the upregulation of aquaporins-1 and -9 (AQPs) were well correlated with brain edema, and these disadvantages can be significantly attenuated by agmatine treatment. Besides, some other studies revealed the effects of agmatine on reducing the expression of AQP-4 and thus attenuated the brain edema as well ⁸³.

Additionally, studies also showed that agmatine contributed to reducing the apoptosis of neuron and cerebral astrogliosis after cerebral ischemia in a rat model ⁸⁴. Jeong et al. ⁸³ found anti-inflammatory character of agmatine in diabetic middle cerebral artery obstruction (MCAO) rats by decreasing the expression of high-mobility group box 1, RAGE, toll-like receptor (TLR)-2,4.

Overall, the agmatine exerted its neuroprotective effect on ischemic stroke both in in vivo and in vitro experimental models ⁸⁵.

Agmatine in traumatic brain injury

Traumatic brain injury (TBI) is a condition of emergency and ranks second to conventional stroke in causing death and disability, which place tremendous burden on the family and society ⁸⁶. It can be divided into primary injury and secondary injury ⁸⁷. A series of pathophysiological changes are involved in the progress of traumatic brain injury, which include brain edema, cellular apoptosis, blood brain barrier disruption, inflammation and so on ⁸⁸. However, there were no ideal therapeutic drugs for the patients suffering from traumatic brain injury so far. Recently, many studies verified the beneficial effects of agmatine in traumatic brain injury. In 1996, Gad and his colleagues ⁸⁹ explored the neuroprotective effects of agmatine in rodent brain injury. Previous researches reported that excessive accumulation of glutamate or NO could lead to cellular ischemia and neurotoxicity ⁹⁰. In a rat model of fluid percussion brain injury, Jinn et al. ⁹¹ found that agmatine could reduce excessive glutamate and NO, and attenuated traumatic brain injury resultantly. Furthermore, they also demonstrated that traumatic brain injury-induced intracranial hypertension, cerebral hypotension, cerebral infarction, motor and proprioception deficits and body weight loss could all be alleviated by agmatine ⁹¹. In 2010, Jinn and his colleagues ⁹² conducted a series of experiments on the neuroprotective effects of agmatine, and found that agmatine could improve the outcome of traumatic brain injury in rats by attenuating neuronal and glial apoptosis, inhibiting gliosis, promoting angiogenesis and neurogenesis. In addition, Jae and his colleagues ⁹³ found that agmatine could reduce brain edema by suppressing the expression of AQP1, 4 and 9. Besides, they also found that agmatine could inhibit cellular apoptosis by inhibiting the phosphorylation of MAPKs and increasing the nuclear translocation of NF-κB after traumatic brain injury. In addition, agmatine had also been proved to play neuroprotective role in rat spinal cord model. It could significantly restore the locomotor function and reduce tissue damage by blocking the N-methyl-D-aspartate (NMDA) receptor and NOS ⁹⁴.

Agmatine in Parkinson’s disease

Parkinson’s disease commonly presented as motor dysfunction, is one of the most common neurodegenerative diseases in the aged ⁹⁵. It was reported that the degeneration of dopaminergic neurons in the substantia nigra pars, which leads to motor dysfunction, is the on-off step in the progression of Parkinson’s disease. Recently, many studies showed that glutamatergic neurotransmission also contributed greatly to the pathogenesis of Parkinson’s disease ⁹⁶.

Excitatory amino acids were assumed to have neurotoxicity and aggravate the condition of patients with Parkinson’s disease ⁷⁴. N-methyl-D-aspartate (NMDA) is the receptor of excitatory amino acid, and its antagonists like memantine, amantadine and agmatine were extensively proved to ameliorate motor function of Parkinson’s disease patients ⁹⁷.

In the experimental model of Parkinson’s disease induced by rotenone, agmatine could significantly decrease the level of oxidative stress in SH-SY5Y cells. Besides, agmatine could also reduce the cellular apoptosis induced by rotenone ⁹⁸. In addition, a recent in vitro study demonstrated that agmatine could prevent redox reaction and cellular injury ⁹⁹.

Gilad and his colleagues ⁷⁸ developed a new mouse Parkinson’s disease model by intranasal administration of 1-methyl-4-phenyl-4-1,2,3,6-tetrahydropyridine (MPTP), and found that agmatine could provide a partial (31%) protection of Parkinson’s disease induced by MPTP. Matheus and his colleagues delivered agmatine to a group of aged mice before the treatment with MPTP. Their results demonstrated that agmatine could prevent the occurrence of motor, cognitive and neurological impairments induced by MPTP ¹⁰⁰.

Agmatine in Alzheimer’s disease

Alzheimer’s disease commonly accompanied with progressive cognitive dysfunction, is also one of the most common neurodegenerative diseases in the aged. Its pathological hallmarks are extracellular deposition of amyloid-beta peptide, and presence of neurofibrillary tangles in the neuron ¹⁰¹ which are mainly distributed in the hippocampus, cerebral cortex and basal ganglia ¹⁰². Currently, the accumulation of amyloid-beta peptide, abnormal phosphorylation of Tau peptide, oxidative stress and radical injury has been recognized as the main pathophysiologic mechanism of Alzheimer’s disease ¹⁰³. Agmatine showed its neuroprotective role in oxidative stress, radical injury and other pathological process. For example, Baranov et al. ¹⁰⁴ revealed that agmatine could exert its anti-oxidative effect by activating many kinds of antioxidants including glutathione. Besides, agmatine could decrease the level of free radical and inhibit the accumulation of amyloid-beta peptide ¹⁰⁵.

N-methyl-D-aspartate (NMDA) is the receptor of the excitatory amino acid and its dysfunction can lead to the apoptosis of neuron ⁷⁴. It was reported that the level of endogenous agmatine rose sharply on the setting of brain injury ⁹¹ and exerted its neuroprotective effect by competitively inhibiting the NMDA receptor and activity of excitatory amino acid ⁷¹. In the Alzheimer’s disease patients, accumulation of amyloid-beta peptide in neuron increased the level of excitatory amino acid, which then produced neurotoxicity. Agmatine was reported to postpone apoptosis of neuron by inhibiting the neurotoxicity of excitatory amino acids ¹⁰⁶. Except for its effect on neurotoxicity, amyloid-beta peptide could also down-regulate the insulin receptor which widely exists in the central nervous system. However, retaining the insulin receptor and its ligand is quite important in the treatment of Alzheimer’s disease ¹⁰⁷. Somang and his colleagues demonstrated that agmatine could promote the secretion of insulin and protect the insulin receptor via binding with the imidazoline receptors ¹⁰⁸. This process could then reduce the accumulation of amyloid-beta peptide and inhibit the abnormal phosphorylation of Tau peptide, which ultimately ameliorate the cognition and memory injury of Alzheimer’s disease patients ¹⁰⁹.

Agmatine in epilepsy

Epilepsy is a chronic process characterized by recurrent paroxysmal seizures ¹¹⁰. Epileptogenesis resulted from synchronization and propagation of excessive excitability, which spread from hyper-excitable neurons and glial cells to the normal non-epileptogenic tissue ¹¹¹. The glutamatergic receptors and NMDA receptor were reported to be involved in the initiation of some kinds of epilepsies ¹¹². Besides, epileptic seizures could increase the production of NO, and pre-treatment with NOS inhibitors could give precaution against some types of seizure ¹¹³. As aforementioned, the agmatine could act as an antagonist of NAMD receptor, thus several studies had been carried out to test the neuroprotective effects of agmatine in experiment animals with epilepsies. Their results demonstrated that agmatine could reduce both the incidence and intensity of epilepsy and also exert anticonvulsant effect ¹¹⁴. Additionally, agmatine could inhibit the activation of NOS and reduce the production of NO. It was reported that both the NOS inhibitor and exogenous agmatine had neuroprotective effects on epilepsy ¹¹⁵. Except for the anticonvulsant effect, agmatine could also strengthen the anticonvulsant effect of some other drugs, such as phenobarbital, valproate and lithium chloride ¹¹⁶. Overall, agmatine proved to have neuroprotective effects in epileptic patients.

In the meanwhile, several other studies ¹¹⁷, ¹¹⁸ contradicted this inference, Abe et al. ¹¹⁷ reported that agmatine (200-800μM) could induce the release of glutamate, which could lead to neuronal death. Besides, Luszczki and his colleagues ¹¹⁸ also suggested that the synergistic effect of agmatine in anticonvulsant is also uncertain, which meant that further researches of agmatine in epilepsy are needed before it can be extensively clinically used.

Agmatine in mental disorders

Mental disorder is a group of systemic diseases characterized by a variety of physical and mental discomfort, such as depression, anxiety, addiction, schizophrenia and so on ¹¹⁹. Agmatine has been long-term studied for its neuroprotective effects in mentor diseases. Many studies reported that agmatine exerts its antidepressant-like action by inhibiting the NMDA receptors or interacting with 5-HT1A/1B and 5-HT2 receptors ¹²⁰. Besides, agmatine could suppress the expression of NOS, NMDA receptors or imidazoline receptors, and alleviate drug addiction induced by opioid, morphine, ethanol or psychostimulants ¹²¹. Additionally, agmatine may have beneficial effects on anxiety, schizophrenia and some other mentor diseases in experimental model ¹²².

Anti-apoptotic effects of agmatine

Apoptosis is one type of cell death characterized by energy dependence and programmed cell death ¹²³. Apoptosis is of vital importance to normal physiological metabolism, growth and development, keeping hemostasis by scavenging the aging or damaged cells, shaping of organs or regulating immune system by removal of defective and excessive cells ¹²⁴. However, uncontrolled apoptosis may result in various pathological processes of different diseases, like cancers, Alzheimer’s disease and stroke ¹²⁵. El-Sherbeeny et al. ¹²⁶ demonstrated that agmatine could protect rat liver from nicotine-induced damage by inhibiting the production of proapoptotic protein Bax. In vitro, Mary and his colleagues ¹²⁷ identified the anti-apoptotic effects of agmatine to the Ha-Ras-transformed murine NIH-3T3 cell line by reducing the expression of Bax and caspase-3. In addition, agmatine was also observed to be involved in the modulation of programmed cell death in rats and inhibit the proliferation of human mast cell leukemia cells (HMC-1) and HL-60 cells ¹²⁸. Many researches have demonstrated the anti-apoptotic effect of agmatine in various neurological disorders. For example, Kim and his colleagues ⁹⁵ demonstrated that agmatine could reduce cellular apoptosis in traumatic brain injury of rats by inhibiting phosphorylation of MAPKs and increasing nuclear translocation of NF-kappaB. In addition, Zarifkar ¹²⁹ reported that inhibition of caspase-3 expression by agmatine could also prevent hippocampal apoptosis and spatial memory impairment induced by lipopolysaccharide (LPS). Besides, in rat model of Alzheimer’s disease, agmatine reduced cellular apoptosis through inhibiting the expression of caspase-3 and Bax, and improved the level of Bcl2, PI3K, Nrf2, and gamma-glutamyl cysteine ¹⁰⁹.

Several in vitro studies reported the protection of agmatine on the human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). Agmatine exerted its anti-apoptotic effects by increasing the amount of phosphorylated Akt /Akt, inhibiting the GSK-3β activity and decreasing the expression of apoptotic markers, such as caspase 3, Bax and cytochrome c.

Overall, the anti-apoptotic effect of agmatine had been well demonstrated in neurological diseases.

Agmatine anti-inflammatory effects

Inflammation is a complex immune response of organisms to the injury. Under normal conditions, inflammation could help to scavenge the necrotic cells or tissues, and initiate the tissue repair process ¹³⁰. However, excessive activation of immune responses is harmful to the organisms and can cause injury ¹³¹. Agmatine exerted its anti-inflammatory effect in many ways. For example, in vivo, Taksande ¹³² demonstrated that agmatine could attenuate the symptom of arthritis by reducing the level of inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukins (IL)-6. Meanwhile, an in vitro study showed that agmatine could inhibit the production of pro-inflammatory cytokines, such as IL-6, TNF-α and CCL2, and reduce the cell death ¹³³.

Inflammatory neurodegeneration also plays a key role in the pathogenesis of neurological diseases, including acute diseases (stroke or traumatic injury) and chronic neurodegenerative diseases (Alzheimer’s disease or Parkinson’s disease) ¹³¹. Sahin ¹³⁴ showed that agmatine could attenuate sub-chronic stress by down-regulating the gene expression of nod-like receptor protein 3 (NLRP3) inflammasome components (NLRP3, NF-kappaB, PYCARD, caspase-1, IL-1β and IL-18) and reducing the level of pro-inflammatory cytokines. Besides, agmatine could also revert the change of anti-inflammatory cytokines, such as IL-4 and IL-10. In addition, the anti-inflammatory effect of agmatine was also proved in many other neurological diseases, such as transient brain ischemia, depression, traumatic brain injury and micro-opioid receptor tolerance, by regulating the expression of inflammatory cytokines ¹³⁵.

Agmatine anti-oxidant effects

Oxidative stress, which is mainly caused by overbalance of pro-oxidant/anti-oxidant system in cells, takes part in the pathogenesis of many diseases ¹³⁶. Various agents including agmatine had been demonstrated to decrease oxidative stress and protect organisms from injury. Iizuka ¹³⁷ reported that agmatine could protect the retinal ganglion cells from H2O2-induced injury through the alpha 2-adrenergic receptor signaling pathway. Bratislav ¹³⁸ found that agmatine could exert its anti-oxidative effect by protecting antioxidant defense system and restoring the antioxidant capacity in liver tissue. Besides, several studies had demonstrated the anti-oxidative effect of agmatine in the setting of neurological diseases. Gawali and his colleagues ¹³⁹ reported that agmatine could ameliorate depressive-like behavior by reducing the oxidative/nitrosative stress evoked by LPS in hippocampus and prefrontal cortex, and this effect may be achieved via preventing lipid peroxidation and regulating the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase ¹⁴⁰. In addition, agmatine has also been proved to exert anti-oxidative stress in stroke and traumatic brain injury by reducing the generation of reactive oxygen species (ROS) and free radicals ⁷⁷.

Blood brain barrier protection and brain edema prevention

Blood brain barrier is a continuous, non-fenestrated system which regulates the movement of many particles and cells, such as ion, toxicant and inflammatory cells. Any factors disrupting the blood brain barrier would deteriorate the condition of neurological diseases, including stoke, traumatic brain injury and neurodegenerative diseases ¹⁴¹. The most common complication of blood brain barrier disturbance was the vasogenic brain edema, which was reported to be related to the early expression of matrix metalloproteinases-2,9 after brain injury ¹⁴². Agmatine was reported to have significant effect in inhibiting the expression of matrix metalloproteinases ⁷⁹. Therefore, regulation of agmatine on the expression of matrix metalloproteinases may be the potential mechanism of blood brain barrier protection and vasogenic brain edema attenuation.

In addition, another type of brain edema that commonly occurs during brain injury is cytotoxic brain edema. One of the most frequent and elaborated mechanisms of cytotoxic edema is the dysfunction of aquaporin (AQP) in the brain. The aquaporin are a group of water channel proteins which regulate the movement of water molecule between plasma membrane. AQP1, 4 and 9 were clearly identified in the brain tissue. AQP1, 4 were reported to be involved in cerebrospinal fluid formation and their dysfunction could also contribute to brain edema ¹⁴³. Several studies demonstrated that the mechanism of agmatine in preventing cytotoxic edema is to suppress the expression of aquaporin (AQP)-1, 4, and 9. The changes had been demonstrated in many types of neurological diseases, such as traumatic brain injury, stroke or degenerative diseases ¹⁴⁴.

Although the effect of agmatine in reducing the brain edema had been well demonstrated, its therapeutic effect was doubted by some researchers and more studies should be launched ¹⁴⁵.

Agmatine dosage

At this time there is not enough scientific information to determine an appropriate range of doses for agmatine.

Agmatine side effects

No adverse effect of 5 years daily agmatine intake of 2.67 g agmatine sulfate/day for humans ³ and 21 days of 3.560 g agmatine sulfate/day for humans ². Gilad and his colleagues ³ assessed long-term safety of oral agmatine treatment by consuming a 2.67 g agmatine sulfate daily dosage of oral agmatine over a period of 4-5 years. All measurements remained within normal values and no discomfort was observed during the follow-up period ³.

In a randomized, double-blind, placebo-controlled trial of agmatine sulfate (1.335 g/day agmatine sulfate for 10 days, 2.670 g/day for 10 days, 3.560 g/day for 10 days, and 3.560 g/day for 21 days) in patients with herniated lumbar disc-associated radiculopathy ¹⁴⁶, three participants reported discomfort as a result of mild-to-moderate diarrhea and nausea that appeared 2–3 days after taking the high dose (3.560 g/day) of agmatine sulfate. These symptoms disappeared within 1–2 days after treatment cessation. Only one participant, however, chose to discontinue for that reason. None of the affected participants required any treatment related to the side-effects. In summary, only 2 of the 34 participants failed to complete the study, one as a result of free will discontinuation and the other as a result of mild-to-moderate adverse effects. These mild side-effects were initially predicted for two reasons: One, sulfate salts (e.g., magnesium sulfate [Epsom salt] and sodium sulfate [Glauber’s salt]) are long known to stimulate peristaltic action and are used therapeutically as purgative or cathartic agents; and two, guanidine group-containing dietary ingredients, arginine and creatine, are also known to cause mild diarrhea and nausea at high doses ¹⁴⁶. Additionally, these mild side effects were expected based on previous experience with a group of nine people, who elected, on their own cognizance, to take agmatine sulfate on a continuous basis for a year. Three individuals developed transient mild diarrhea and gas which began 1–3 days after treatment initiation and subsided within several days thereafter ¹⁴⁶.

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