Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio.

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE-/- mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE-/- mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

Neuroprotective offerings by agmatine.

Agmatine, an endogenous polyamine in CNS, is derived from arginine by dearboxylation. Like polyamines, agmatine has been studied for its neuroprotetive effects. At present, a large body of experimental evidences has been gathered that demonstrate the neuroprotective effects of agmatine. The neuroprotective effects have been observed in various CNS cell lines and animal models against the excitotocity, oxidative damage, corticosteroidid induced neurotoxicity, ischemic/hypoxic or oxygen-glucose deprivation toxicity, spinal cord injury and traumatic brain injury. The studies have been extended to rescue of retinal ganglion cells from toxicities. The mechanistic studies suggest that neuroprotection offered by agmatine can be assigned to its multimolecular biological effects. These include its action as glutamatergic receptor antagonist, α2-adrenoceptor agonist, imidazoline binding site ligand, NOS inhibitor, ADP ribosylation inhibitor, and blocker of ATP-sensitive potassium and voltage-gated calcium channels, anti-apoptotic and antioxidant. Its action as regulator for polyamine synthesis, insulin release assists the neuroprotection. The cumulative evidences of preclinical studies support the possible use of agmatine as an agent for neuronal damage and neurodegenerative diseases. However, it will be hasty to assert and promote agmatine as a novel therapeutic agent for neuroprotection. The review is focused on the role of agmatine in different types and mechanisms of neural injuries. The aspects of concern like dose range, pharmacokinetics of exogenous agmatine, levels of endogenous agmatine during events of injury etc. has to be addressed.

Long-term (5 years), high daily dosage of dietary agmatine--evidence of safety: a case report.

There is presently a great interest in the therapeutic potential of agmatine, decarboxylated arginine, for various diseases. Recent clinical studies have already shown that oral agmatine sulfate given for up to 3 weeks provides a safe and, as compared with current therapeutics, more effective treatment for neuropathic pain. These studies have ushered in the use of dietary agmatine as a nutraceutical. However, in view of information paucity, assessment of long-term safety of oral agmatine treatment is now clearly required. The authors of this report undertook to assess their own health status during ongoing consumption of a high daily dosage of oral agmatine over a period of 4-5 years. A daily dose of 2.67 g agmatine sulfate was encapsulated in gelatin capsules; the regimen consists of six capsules daily, each containing 445 mg, three in the morning and three in the evening after meals. Clinical follow-up consists of periodic physical examinations and laboratory blood and urine analyses. All measurements thus far remain within normal values and good general health status is sustained throughout the study period, up to 5 years. This case study shows for the first time that the recommended high dosage of agmatine may be consumed for at least 5 years without evidence of any adverse effects. These initial findings are highly important as they provide significant evidence for the extended long-term safety of a high daily dosage of dietary agmatine--a cardinal advantage for its utility as a nutraceutical.

Evidence for oral agmatine sulfate safety--a 95-day high dosage pilot study with rats.

Agmatine, decarboxylated arginine, exerts beneficial effects in various experimental disease models. Clinical trials indicate the safety and effectiveness of short-term (up to 21 days) high dose regimens of oral agmatine sulfate, but longer term studies are lacking. This pilot study undertook to assess the safety of a longer term high dosage oral agmatine sulfate in laboratory rats. Adult Wistar rats consumed 5.3 g/l agmatine sulfate in their drinking water for 95 days, a regimen estimated to result in a daily dosage of absorbed agmatine of about 100mg/kg. Animals' body weight, water consumption and blood pressure were periodically measured, and general cage behavior, fur appearance, urination and feces appearance monitored. These parameters were also determined at 20 days after treatment cessation (day 115). On days 95 and 115, animals were euthanized for gross necropsy assessment. Agmatine-treated rats showed slight, but significant reductions in body weight and blood pressure, and reduced water consumption during treatment, which recovered completely within 20 days after treatment cessation. Otherwise, no abnormal behaviors or organ pathologies were observed. These findings are first to suggest apparent safety of sub-chronic high dosage dietary agmatine sulfate in laboratory rats, thus lending further support to the therapeutic applications of agmatine.

Agmatine attenuates acquisition but not the expression of ethanol conditioned place preference in mice: a role for imidazoline receptors.

The present study investigated the effect of agmatine on acquisition and expression of ethanol conditioned place preference (CPP) and its modulation by imidazoline agents. Swiss albino mice were treated intraperitoneally with saline or agmatine (20-40 mg/kg) before injection of ethanol (1.25 mg/kg) during conditioning days or on a test day (20-120 mg/kg), to observe the effect on acquisition or expression of CPP, respectively. Agmatine inhibited the acquisition but not the expression of ethanol CPP. Furthermore, both the I1 receptor antagonist, efaroxan (9 mg/kg) and the I2 receptor antagonist, BU224 (5 mg/kg) attenuated the agmatine-induced inhibition of the ethanol CPP acquisition. In contrast, the I2 receptor agonist, 2-BFI (5 mg/kg) and I1 receptor agonist, moxonidine (0.4 mg/kg) alone, or a combination of their subeffective doses, significantly attenuated the effect of agmatine (20 mg/kg) on acquisition of ethanol CPP. Agmatine or imidazoline agents alone produced neither place preference nor aversion, and at the doses used in the present study did not affect locomotor activity. Thus, agmatine attenuates the acquisition of ethanol CPP at least in part by imidazoline (I1 or I2) receptors. In future studies, agmatine or agents acting at the imidazoline receptors could be explored for their therapeutic potential in ethanol dependence.

Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents.

The effect of agmatine in preclinical behavioral tests of schizophrenia has been examined in rodents. Agmatine at the doses of 40 and 80 mg/kg blocked conditioned avoidance responding, attenuated apomorphine induced climbing, diminished amphetamine and ketamine hyperlocomotor activity and augmented plasma prolactin levels. Pretreatment of animals with 20 mg/kg of agmatine potentiated the inhibitory effect of haloperidol (0.1 mg/kg, ip) and olanzepine (0.5 mg/kg, ip) in conditioned avoidance response test and apomorphine induced climbing. Agmatine alone at the doses tested here did not induce any cataleptic behavior in mice. However significant catalepsy was exhibited when agmatine (80 mg/kg, ip) was injected to mice pretreated with 5-HT1A receptor antagonist, WAY100, 635. These results indicate that agmatine via regulation of brain dopaminergic signaling modulates dopamine mediated behaviors. The alteration in the levels of endogenous agmatine may contribute to the genesis of psychosis and development of drugs that enhance endogenous agmatine content may be better therapeutic approach to treat schizophrenia with low incidences of extra pyramidal side effects.

Amphoteric agmatine containing polyamidoamines as carriers for plasmid DNA in vitro and in vivo delivery.

In this paper we report on the investigation, as DNA nonviral carriers, of three samples of an amphoteric polyamidoamine bearing 4-aminobutylguanidine deriving units, AGMA5, AGMA10, and AGMA20, characterized by different molecular weights (M(w) 5100, 10100, and 20500, respectively). All samples condensed DNA in spherical, positively charged nanoparticles and protected it against enzymatic degradation. AGMA10 and AGMA20 polyplexes had average diameters lower than 100 nm. AGMA5 polyplexes were larger. All polyplexes showed negligible cytotoxicity and were internalized in cells. AGMA10 and AGMA20 performed differently from AGMA5 as nucleic acid carriers in vitro. AGMA10 and AGMA20 effectively promoted transfection, whereas AGMA5 was ineffective. FITC-labeled AGMA10 was prepared and the intracellular trafficking of its DNA polyplex was studied. DNA/AGMA10 polyplex was largely localized inside the nucleus, while AGMA10 concentrated in the perinuclear region. DNA/AGMA10 polyplex intravenously administered to mice promoted gene expression in liver but not in other organs without detectable toxic side effects.

Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial.

Objective. Agmatine, decarboxylated arginine, was shown in preclinical studies to exert efficacious neuroprotection by interacting with multiple molecular targets. This study was designed to ascertain safety and efficacy of dietary agmatine sulfate in herniated lumbar disc-associated radiculopathy. Study Design. First, an open-label dose escalation study was performed to assess the safety and side-effects of agmatine sulfate. In the follow-up study, participants diagnosed with herniated lumbar disc-associated radiculopathy were randomly assigned to receive either placebo or agmatine sulfate in a double-blind fashion. Methods. Participants in the first study were recruited consecutively into four cohorts who took the following escalating regimens: 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. Participants in the follow-up study were assigned to receive either placebo or agmatine sulfate, 2.670 g/day for 14 days. Primary outcome measures were pain using the visual analog scale, the McGill pain questionnaire and the Oswestry disability index, sensorimotor deficits, and health-related quality of life using the 36-item short form (SF-36) questionnaire. Secondary outcomes included other treatment options, and safety and tolerability assessment. Results. Safety parameters were within normal values in all participants of the first study. Three participants in the highest dose cohort had mild-to-moderate diarrhea and mild nausea during treatment, which disappeared upon treatment cessation. No other events were observed. In the follow-up study, 51 participants were randomly enrolled in the agmatine group and 48 in the placebo. Continuous improvement of symptoms occurred in both groups, but was more pronounced in the agmatine (analyzed n = 31) as compared with the placebo group (n = 30). Expressed as percent of baseline values, significantly enhanced improvement in average pain measures and in quality of life scores occurred after treatment in the agmatine group (26.7% and 70.8%, respectively) as compared with placebo (6.0% [P

Agmatine induces anxiolysis in the elevated plus maze task in adult rats.

Agmatine is an endogenous released polyamine recently proposed to be a putative neurotransmitter, however its physiological role is still to be determined. We investigated the hypothesis that agmatine, systemically administered to adult Wistar rats, might exert anxiolytic-like behavior in the elevated plus maze (EPM) and the open field. Agmatine (1, 10, 20, 40 and 100 mg/kg) and saline were administered i.p. 30 min before the EPM and the open field. Administration of agmatine (20 and 40 mg/kg) increased the time spent in the open arms of the EPM, as compared to the saline group, with no effect on locomotion activity in the open field. However, 100 mg/kg of agmatine significantly reduced the number of entries into enclosed arms of the EPM and the total number of crossings in the open field. We suggest that agmatine, in doses of 20 and 40 mg/kg, causes a mild anxiolytic-like behavior and discuss the possibility that this first reported effect could be caused either by the inhibition of nitric oxide synthase, the blockage of NMDA receptors or by the activation of alpha-2-adrenoceptors.