AGMATINE: A POTENTIAL BIOLOGICAL THERAPEUTIC EFFECT

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Binjhade et al. World Journal of Pharmacy and Pharmaceutical Sciences

AGMATINE: A POTENTIAL BIOLOGICAL THERAPEUTIC EFFECT

Neha R. Binjhade*, Kamlesh J. Wadher and Milind J. Umekar

Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur,

Maharashtra, 441002 India.

ABSTRACT

Agmatine also called as decarboxylated arginine are natural

biosynthetic, product.Its freshly indicated that agmatine synthesized in

mammals. Agmatine has more biological targets and signaling

pathway. Agmatine has a broad therapeutic index which was

applicable from 16 independent research group this gives attention to

the preclinical and clinical evidences, this was highlights challenges

and opportunities. This review is summarized the implication of

agmatine in CNS and current research of agmatine in other systems of

the body like cancer, cognitive disorder, cardio protectant effect. In

cancer there is low effect of agmatine, in cognitive disorder high effect

also the other research is carry on brain function. In cardioprotecton still research is continue.

KEYWORDS: Agmatine, L-arginine, cardiovascular diseases, Anticancer.

1. INTRODUCTION

Nobel laureate Albert Kossel was the first scientist who discovered the agmatine which is

formed by decarboxylation of L-arginine by enzyme decarboxylation therefore its called as

decarboxylated arginine.[1]

Agmatine is cationic polyamine this polyamines have two or more

primary amino group and this polyamines has a more than one functions in body.[2]

Such as

cell proliferation, synthesis of RNA, lymphocytes differentiation, regulation of inflammatory

responses, role of protein kinase A, repair of cells and dynamic of extracellular matrix, cell

adhesion, certain signaling process.[3]

Author Raghunathan has investigated astrocytes store

and synthesize agmatine. its act on strongly in imidazoline receptor and lowerly in α2

adrenergic receptor, in brain.[4]

Agmatine act as anti-tolerance activity against opioid, prevent

inflammatory and also prevent the somatosensory nervous system disorder. Agmatine act as a

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 10, Issue 8, 1100-1115 Review Article ISSN 2278 – 4357

*Corresponding Author

Neha R. Binjhade

Smt. Kishoritai Bhoyar

College of Pharmacy, New

Kamptee, Nagpur

Maharashtra, 441002 India.

Article Received on

11 June 2021,

Revised on 01 July 2021,

Accepted on 21 July 2021

DOI: 10.20959/wjpps20218-19621


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effect of neural plasticity by NMDA antagonist and inhibits nitric oxide pathways in

biodistribution system.[5]

AGMAT is copious mainly human liver and kidney but also located in other part of the body

like tissues, skeletal muscle and brain. This expression may use in hepatitis B virus

infections.[7]

Table 1: Agmatine cell membrane transporter has various developing blockers which

has various therapeutic targets.

Channel’s transporters Targets References

I. Neurotransmitter

receptors and receptor

ionophores

1- Nicotinic.

2- Imidazoline I1 and I2.

3- a2-adrenergic.

4- Glutamate NMDAR.

5- Serotonin 5-HT2A and 5HT-3receptors.

[8-14]

II. Ion channels. 1- ATP-sensitive K+ channels.

2- Voltage-gated Ca2+ channels.

3- Acid-sensing ion channels (ASICs).

[15-17]

III. Membrane

transporters

1- Agmatine specific-selective uptake sites.

2- Organic cation transporters (mostly

OCT2 subtype).

3- Extra neuronal monoamine transporters

(ENT).

4- Polyamine transporters.

5- Mitochondria also have an agmatine

specific-selective transport system.

[18- 21]

IV. NO synthesis

modulations

1- Differential inhibition of all isoforms of

NOS.

2- Induction of eNOS.

[20,22]

V. Polyamine

metabolism

1- Precursor for polyamine synthesis.

2- Inhibition of polyamine transport.

3- Induction of spermidine/spermine

acetyltransferase (SSAT).

4- Induction of antizyme.

[20,23]

VI. Protein ADP-

ribosylation

1- Inhibition of protein arginine ADP-

ribosylation.

[24]

VII. Matrix

metalloproteases

1- Downregulation of Matrix

metalloproteases (MMP) 2 and 9.

[25-27]

VIII. AGE formation. 1- Inhibition of AGE formation. [26,27]


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Table 2: Historical aspect of agmatine.

Years Discover Authores

2016 - Amelioration of compulsive like behavior by Gawali at el.

2015 - Effect against multiple sclerosis. by Ninkovic et

al.

2014 -. Ant Alzheimer effect -by song et al.,

nicotine induced conditioned place

Preference.

by kotgale et al.

2012 - Depression case study, protection against

schizophrenia.

by kotgale et al.

2008-2010 - Clinical trials neuropathy

2009 - Gastric agmatine (acid protection)

2005 - ↓ Diabetic neuropathy – by courteix et al. by courteix et al.

2005 - ↑Nerve regeneration, partial protection

against MPTP induced Dopaminergic

toxicity.

-by Gilad.

2002-2003 - Anxiolytic and anti-depressive. by Zomkowski

et al.

Anticonvulsant. by Bence et al

Anti-inflammatory properties in astrocytes. by Raghunathan

and piletz.

2002 - Learning and memory augmentation. by Arteni et al.

2001 - Antinociception. by Onal and

Soycan

2000 - Neuroprotection against spinal cord. by Gilad

1999 - Cardio protection.

1996-2004 -

1996 -

1995 -

1994 -

Cytostatic (↓tumor proliferation)

Nephroprotection.

Neuroprotection against neurotoxic and

ischemic brain injuries, ↑ Gastric secretion,

Mild hypotensive effect, ↑ Glomerular

filtration rate.

Nos inhibitor, endogenous brain agmatine.

by - Donald J.

Reis

1990 - Neuronal nicotinic antagonist.

1970-1980 - Effect on glucose metabolism.

1962 - ↑ Lymphocytes proliferation

1924-1930 - Glucoprotection. by Oskar

Minkowski

1911 - ↑ Mild blood flow. by Henry H.

Dale

1910 - Discovery of agmatine -by L.K.M.L. Albert

Kossel.

by L.K.M.L.

Albert Kossel.


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Table 3: Various therapeutically application of agmatine.

Clinical indication Comments References.

Neuropathic pain. Effectual orally and is available

as a nutritious food.

[74]

Opioids modulation Lack of extra pyramidal side

effects

[75.76,80]

Cardiovascular effect. Mild hypotensive effects.

Significant implications for other

clinical indications.

[39,40]

Cardio protection. Only hemodynamic recovery

demonstrated.

[41]

Glucoprotection. Mild hypoglycemic effects.

Historical evidence for clinical

trials in diabetes. Significant

implications for other clinical

indications.

[77]

Nephroprotection. May cause enhanced GFR. [78]

Gastroprotection. May modulate gastric acid

damage. But may enhance stress-

induced ulceration.

Glaucoma. Effective by topical application. [61]

Cognitive

enhancements.

Involvement of increased

endogenous agmatine

metabolism. In-vivo studies on

dementia models are lacking.

[28,29]

Anticancer potential. Cytostatic effects without

cytotoxicity

Figure 1: Various receptors of agmatine.


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2. Pain control and prevention of morphine

In nonclinical research express that agmatine prevent in opposition to acetic acid, formalin,

capsaicin, and nociceptive models of pain in vermin and these action are ascribe to the

reticence of NOS, and antagonism of NMDA receptor,[30]

L- arginine nitryl pathway, and also

tone of opiod, serotonergic, alpha 2 adrenergic and imidazoline receptor.[31]

Agmatine

increases morphine activity in dose dependent manner. Morphine given a higher effect when

it given on intrathecally then after interaxial administration. In difference to the enhancing of

morphine analgesia, agmatine effect is disable on GI transit of morphine. There are three

types of opioid receptor, first is delta receptor which is enhancing the action of agmatine, but

other two is kappa 3 opioid receptor (trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)

cyclohexyl] benzene acetamide) and kappa 1 receptor (naloxone benzoyl hydrazone) are not

affecting any dose of agmatine.[32]

Agmatine act on imidazoline receptor and binds to many

targets and examine as an internal ligands.[33]

3. Prevention of opioid addiction

Kolesnikov and colleagues first examine this, agmatine enhancing the effect of opioid

analgesia systemically and protect addiction of morphine in vermin.[34]

As a result, several

studies agmatine gives a decreasing effect of opioid subordination in rodent’s species by

distinct path of administration.[35,36]

4. Multiple sclerosis

Multiple sclerosis is utmost familiar long-standing condition of the varifocal cerebral disorder

in brain. MS diseases a symptom is erythrogenic disseminating injury influence white and

grey matter, perception to be moderate by auto reference T cells. MS comes from a multiple

interactivity of some contexture and hereditary factors. Contexture factors like home in

immature senility, because of Epstein-Barr virus, and smouldering.[37]

Extrinsic agmatine was

probe on multiple sclerosis parameters like oxidative tension in practical model of

autoimmune encephalomyelitis (EAE).This model shows the auspiciously subdue by

agmatine behavior through changes in brain, this may be latest updates of agmatine action.[38]

5. Cardio protection

Agmatine shows the mild effect on heart, it has decreased the heart rate and blood pressure.

This action is shows by resulted activity of both physical and mental structure by regulating

targets, likes imidazoline receptors, nitryl formation, and noradrenaline.[39]

Agmatine shows

the cardio protective effect. This was investigated through rat heart model by given


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agmatine.[40]

Internal l-arginine may be fast decreasing a systolic and diastolic tensions when

given on healthy patients with several types of blood pressure increasing disease. A summary

of L- arginine was explained on review of clinical pharmacology of l-arginine, especially in

CVS, and other uses of L-arginine prepare by Boger and Bode Boger.[8]

Agmatine, an

internal clonidine – replacing substances, have showed to ability for both α 2- adrenergic and

imidazoline receptors.[41]

Figure 2: Metabolism of L-arginine.

Table 3: NO- dependent and independent cardiovascular action of L- arginine.

Actions. References.

1- Nitric oxide dependent

muscular action

1- ↑Dilation of blood vessels.

2- ↓Erythrocytes adhesion.

3- ↓platelet aggregations formation.

4- ↓Smooth muscles cells

proliferation.

5- ↓Superoxide formation.

6-↓Endothelial dysfunction.

[62,63,64,65,66,67]

2- NO-independent vascular

actions.

1-↓ Angiotensin-converting enzyme

activity[24]

2-↓ Thromboxane B2 formation,

fibrin & platelet-fibrin complex[25]

3-↓ Blood viscosity[26]

4-↓ Leukocyte adhesion to non-

[68,69,70,71]


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endothelial matrix[27]

5-↓Low density lipoprotein oxidation [28]

3-Non-specific cardiovascular

effects.

Enhances the synthesis of urea,

creatine, proline, polyamines and

releases of hormones as insulin,

growth hormone, glucagon and

Prolactin.

[73]

6. Glucoprotection

After 1920s agmatine studies demonstrate the protective effect against diabetes. In the course

of 1990s that several agmatine mechanism of action against glycemia are illuminate, such as

(1) quickest insulin injection given[42]

(2) interchange with pancreatic islets cells to improve

the level of insulin release[43,44]

(3) increase adrenal endorphin discharge through imidazoline

receptors activated, most enhancing molecular glucose intake, as express by Cheng and

coworkers.[45,46]

Agmatine treated mild hypoglycemic which is also useful for other disorder

caused by hypoglycemic that is neuropathic pain, Alzheimer disorder, epilepsy. Agmatine

may be important for reducing the diabetes related systemic misfunctions by (1) reducing

advanced glycation ends productions[47]

(2) increasing nerve regeneration and neuropathic

pain decrease in diabetic neuropathy[48]

(3) enhancing rate of glomerular filtration[49]

(4)

increasing metformin effect[50]

and decreasing metformin induction by cation career[51]

Since

this result shows the effect of agmatine treated diabetes, which is useful for other disorders.

7. Glaucoma

Glaucoma is disorders of eye due to injury in the ocular nerve which is main reasons for

vision. In studies of agmatine using rat model it shows that it lesser the intraocular

pressure[52]

Agmatine effective on hypoxia prompt retinal ganglion cell injury In RGC-5 cells

and this is shows by the action of c-Jun N-terminal kinase and nuclear factor kappa light

chain enhancer of activated B cells signaling pathways.[53]

8. Anticancer

Agmatine also used in cell proliferation turn on cell type and its phases of distinction. Since,

considering agmatine may increase proliferation of T cell and phagocytes[55]

and of

endothelium and neurocytes stem cells later cerebral injury[53,54]

it can also inhibit

proliferation of vascular smooth muscle cells, macrophages, astrocytes, fibroblasts and tumor

cells.[164]

There are assorted studies proof Haenisch and Moldering specify that cancer cell

extension is related with moderate of internal agmatine metabolism.[58]

This involves 1- under


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molecular agmatine aggregation paired with decreased agmatine decarboxylase impression

noticed in human colon cancer polyps. 2-decressed impression of agmatinase and diamine

oxidase expose in human leukemia cells.[57]

3- Suppress agmatine decarboxylase impression

by RNA interference in human tumor cell lines conduct to increased proliferation.[58]

and 4-

therapy with internal agmatine aggregation commonly attain in blood apply against

proliferative action in human tumor cell lines[58]

This shows the results of cytotactic effects of

agmatine, incriminating negative regulation of polyamine metabolism on achievable effect

against proliferation targets.[56,57]

This study continuous of agmatine treatment in tumor.

9. Mitochondrial protection

Mitochondria are mainly permitting to nutrients shortage, environmental toxins and oxidative

damage. Agmatine has proved to preventive action on mitochondria at nanomolar

concentration. It also proved to enhanced oxidative stress- prompt mitochondrial

inflammation, feasibly by showing as a free radical scavenger, and protect Ca2+- dependent

initiation of mitochondrial permeability transition by moderate mitochondrial probable and

nuclear factor kappa light chain enhancer of activated B cells activation[ 59- 62] These

causes cell death. Hence, mitochondrial prevention is contemplate necessary in donating to

the common cytoprotective effects of agmatine in several forcibly systems and therefore, to

its therapeutic actions in a range of disorder model.[63]

10. Antiageing and Sexual functions

Antiaging is treated by L- arginine which is a metabolically polyamine of agmatine. It is first

discovered by Hedin in 1895, during studies of mammalian protein. Arginine is necessary for

natural spermatogenesis. Above 50 year before, scientists proved that given a arginine on

arginine deficient patients in diet to men for 9 days its removed the sperms counts by 90 %

and enhanced the percentage of nonmotile sperm.[22]

There are a several results which proven

the improvement of erectile function by L -arginine administration.[23]

Disclosed the

important biased in sexual functions in men with biological erectile dysfunction after oral

administration of 5 g L- arginine for 42 days, but only condition is they decreased the nitric

oxide formation.

Concluding and Future perspective

In this review we presented a basic research data combined with such clinical studies in a trial

to clarify the ability role of agmatine as a neuromodulator and neuroprotective effect.

Substantial proofs have been shows that agmatine is an internal neuromodulator, with notable


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treating effect against CNS disorder. It is also useful in some neurogenerative disorder,

traumatic brain injury, spinal cord injury, hypoxia include neuropsychiatric disorder such as

depression. The action of agmatine is modulation of NMDA receptor, imidazoline receptors,

serotonin receptor, and acetylcholine receptors. This treated the oxidative stress, apoptosis,

inflammation, and variety of intracellular pathways. Agmatine also used in cancer there is a

little effect of agmatine in cancerous cell. Study is still continuing in cancerous cell.

Agmatine used as a cardio protection. L- Arginine is used in cardiac disfuntioning. its treated

in high blood pleasure. Agmatine also used in glaucoma anti ageing and sexual disfuntioning,

mitochondrial protection. Agmatine used as antidiabetes for protection of glucose formation.

There is a vast importance of agmatine. Also the other researchers were continuing the study

in agmatine for extra other advantages of agmatine.

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AGMATINE: A POTENTIAL BIOLOGICAL THERAPEUTIC EFFECT

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