Protective Effects Of Agmatine Research Articles

Agmatine prevents the memory impairment and the dysfunction of hippocampal GSK-3β and ERK signaling induced by aluminum nanoparticle in mice.

The growing usage of aluminum nanoparticles (Al-NP) and their exposure may influence body function. Considering the proposed relationship between Al and the pathogenesis of Alzheimer's disease and the concern about the effect of this nanoparticle on brain health and cognitive function, the use of neuroprotective agents might be helpful. According to the reported neuroprotective effects of agmatine, in the present study, the possible protective effect of agmatine was assessed in mice model of Al-NP-induced memory impairment. In addition, due to the roles of hippocampal Glycogen synthase kinase-3 beta (GSK-3β) and ERK signaling in memory and its disorders, these pathways were also investigated. Al-NP (10 mg/kg/p.o.) with/without agmatine (5 or 10 mg/kg/i.p.) was administered to adult male NMRI mice for 5 days. Novel object recognition (NOR) test session was used to assess cognitive function. Following the behavioral assessments, the hippocampi were used to determine the phosphorylated and total levels of GSK-3β and ERK as well as GAPDH using western blot analysis. The results showed that Al-NP impaired NOR memory in mice while agmatine 10 mg/kg prevented the memory deficit induced by Al-NP. Furthermore, Al-NP activated GSK-3β as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3β and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3β and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

The protective and therapeutic effects of agmatine on isoproterenol-induced myocardial injury in rats

Chronic inflammation and oxidative stress can contribute to the development of cardiovascular diseases. Isoproterenol (ISO), a synthetic catecholamine, is used to study the effects of drugs on cardiotoxicity. Agmatine (AGM) is a type of biogenic amine produced through the decarboxylation of arginine. The purpose of the current study was to evaluate the effects of AGM against ISO-induced cardiotoxicity due to the described roles of AGM in cardiovascular disease. Four groups of thirty-two Wistar Albino rats were divided equally as control, ISO, AGM+ISO, and ISO+AGM. ISO was administered intraperitoneally (i.p.) twice at a dose of 150 mg/kg, at 24-hour intervals. Prior to and after ISO injection, 20 mg/kg of AGM was injected i.p. Hemodynamic measurements and serum and tissue biochemical analyses were evaluated at the end of the experiment. The levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) in the tissue were measured. In the ISO group, levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were increased significantly (p<0.05). Co-administration of ISO and AGM significantly reduced CK and LDH levels (p<0.05). MDA levels increased in the ISO-treated group but decreased in the AGM-treated groups (p<0.05). Notably, there was a reduction in the CAT level in the ISO treatment group (p<0.05). CAT was found to be significantly increased (p<0.05) in the groups that received AGM compared to the ISO group. AGM+ISO group had a reduced density of degenerated cardiomyocytes and granulation tissue compared to the ISO group (p<0.05). Although granulation tissue demonstrated a significant reduction in the ISO+AGM group in comparison to the ISO group (p<0.05). In this study, the results indicate that AGM treatment can potentially inhibit ISO-induced myocardial injury and vascular dysfunction by preserving vascular integrity. Notably, the protective effects of AGM on cardiac damage appear to outweigh its therapeutic benefits, as shown by histopathological analysis

Protective Effects of Agmatine Against Corticosterone-Induced Impairment on Hippocampal mTOR Signaling and Cell Death.

Chronic treatment with agmatine, similarly to fluoxetine, may cause antidepressant-like effects mediated, at least in part, by the modulation of hippocampal plasticity. However, the ability of chronic treatment with agmatine to cause antidepressant-like effects associated with the modulation of mammalian target of rapamycin (mTOR) signaling pathway and protection against neuronal death remains to be established. In this study, we investigated the effects of agmatine (0.1mg/kg, p.o.) and the conventional antidepressant fluoxetine (10mg/kg, p.o.) treatment on the levels of phosphorylated mTOR (p-mTOR), neuronal death, and overall volume in the hippocampal dentate gyrus (DG) of mice exposed to chronic corticosterone (20mg/kg, p.o.) treatment for 21days, a model of stress and depressive-like behavior. Chronic corticosterone treatment increased cell death in the sub-granular zone (SGZ) of the DG, as assessed by Fluoro-Jade B labeling. Agmatine, similarly to fluoxetine, was capable of reversing this alteration in the entire DG, an effect more evident in the ventral portion of the hippocampus. Additionally, reduced phosphorylation of mTOR (Ser2448), a pro-survival protein that is active when phosphorylated at Ser2448, was observed in the whole hippocampal DG in corticosterone-treated mice, an effect not observed in agmatine or fluoxetine-treated mice. Chronic exposure to corticosterone caused a significant reduction in overall hippocampal volume, although no alterations were observed between the groups with regards toDG volume. Altogether, the results indicate that agmatine, similar to fluoxetine, was able to counteract corticosterone-induced impairment on mTOR signaling and cell death in hippocampal DG.

Sıçan Primer Nöron Kültüründe Agmatinin Doz-Süre-Etki Profili

Agmatine is a newly found neurotransmitter and its role in important modulations of central nervous systems how the pharmacological importance of agmatine. The aim of this study was to investigate the possible toxic and proliferative effects of agmatine, which is known to have endogenous neuroprotective effect, on primary rat neuron culture. In this context, it has been tried to determine the possible toxic and protective effects of agmatine at 8 different exposure times at 5 different doses. Neuron cultures obtained from brain cortex in the neonatal rats are treated with agmatine at 15 min, 30 min, 1 h, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, doses of 10-2, 10-3, 10-4, 10-5 and 10-6 M. Then, the dose duration effect relationship was determined with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation kit. According to the results of the viability assay, a statistically significant neuroprotective effect was observed in 10-5 and 10-6 M doses, especially in 1 hour and 24 hours exposure periods. In addition, proliferation was observed only at a concentration of 10-4 M for 24 hours. However, no statistically significant difference in toxic effect was observed. Consequently agmatine showed neuroprotective effect in the primary rat neuron culture, especially at the lowest dose and the longest exposure.

Protective effect of agmatine against hyperoxia-induced acute lung injury via regulating lncRNA gadd7

Hyperoxia-induced acute lung injury (HALI) is a kind of iatrogenic pulmonary dysfunction caused by the prolonged exposure to high concentrations of oxygen, which is commonly seen in the treatment of refractory hypoxemia. Agmatine (AGM), a biogenic amine metabolite of l-arginine, induces a variety of physiological and pharmacological effects in the body. In this study, we investigated the protective effect of AGM on hyperoxia-induced lung injury and explored the underlying mechanism. A series of methods were used including flow cytometry, tunnel assay, dual-luciferase reporter assay, qRT-PCR and Western blotting. The results indicate that AGM can protect hyperoxia-induced lung injury. Further studies suggest that AGM decreased the upregulated expression of lncRNA gadd7 caused by hyperoxia and due to the presence of the competitive binding of lncRNA gadd7 and MFN1 to miR-125a, AGM indirectly decreased MFN1 protein expression to inhibit the cells apoptosis. In conclusion, AGM protects hyperoxia-induced lung injury by decreasing the expression of lncRNA gadd7 to regulate MFN1 expression.

The neuroprotective effect of agmatine against amyloid β-induced apoptosis in primary cultured hippocampal cells involving ERK, Akt/GSK-3β, and TNF-α.

β-Amyloid peptide (Aβ), the major element of senile plaques in Alzheimer's disease (AD), has been found to accumulate in brain regions critical for memory and cognition. Deposits of Aβ trigger neurotoxic events which lead to neural apoptotic death. The present study examined whether agmatine, an endogenous polyamine formed by the decarboxylation of L-arginine, possesses a neuroprotective effect against Aβ-induced toxicity. Primary rat hippocampal cells extracted from the brains of 18-19-day-old embryos were exposed to 10µM of Aβ (25-35) in the absence or presence of agmatine at 150 or 250µM. Additionally, the involvement of Akt (Protein Kinae B), GSK-3β (glycogen synthase kinase 3-β), ERK (Extracellular Signal-Regulated Kinase) and TNF-α (Tumor necrosis factor-α) in the agmatine protection against Aβ-induced neurotoxicity was investigated. Agmatine significantly prevented the effect of Aβ exposure on cell viability and caspase-3 assays. Furthermore, agmatine considerably restored Aβ-induced decline of phospho-Akt and phospho-GSK and blocked Aβ-induced increase of phospho-ERK and TNF-alpha. Taken together, these findings might shed light on the protective effect of agmatine as a potential therapeutic agent for AD.

Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats

AimsOxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats. Main methodsFour groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry. Key findingsThe treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well. SignificanceOur findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress.

Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat

The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca2+) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca2+ and cause an increase in activity of calcium pumps, including Ca2+-ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats.Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin.To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats.

Evaluation of the protective effect of agmatine against cisplatin nephrotoxicity with 99mTc-DMSA renal scintigraphy and cystatin-C

Background: The aim of the current study was to investigate whether agmatine (AGM) has a protective effect against cisplatin-induced nephrotoxicity.Materials and methods: Thirty-two rats were randomly divided into four groups: (1) Saline (control); (2) Cisplatin (CDDP; 7.5 mg/kg intraperitoneally); (3) Agmatine (AGM; 10 mg/kg intraperitoneally); (4) Cisplatin plus agmatine (CDDP + AGM). Agmatine was given before and two consecutive days after cisplatin injection. All the animals underwent renal scintigraphy with 99mTc-DMSA. The levels of serum creatinine, cystatin C, and blood urea nitrogen (BUN) were measured in addition to examination of the tissue samples with light microscopy. Acute renal injury was assessed with biochemical analyses, scintigraphic imaging, and histopathological evaluation.Results: In the cisplatin group, the levels of BUN, creatinine, and cystatin C were significantly higher than that of the controls. Histopathological examination showed remarkable damage of tubular and glomerular structures. Additionally, cisplatin caused markedly decreased renal 99mTc-DMSA uptake. AGM administration improved renal functions. Serum creatinine, BUN, and cystatin C levels had a tendency to normalize and, scintigraphic and histopathological findings showed significantly less evidence of renal toxicity than those observed in animals receiving cisplatin alone.Conclusions: Our data indicate that AGM has a protective effect against cisplatin-induced nephrotoxicity. Therefore, it may improve the therapeutic index of cisplatin. In addition, the early renal damage induced by cisplatin and protective effects of AGM against cisplatin nephrotoxicity was accurately demonstrated with 99mTc-DMSA renal scintigraphy.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson’s disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Protective Effects of Agmatine against Chlorpromazine- Induced Toxicity in the Liver of Wistar Rats

SummaryThe metabolic pathways of chlorpromazine (CPZ) toxicity were tracked by assessing oxidative/nitrosative stress markers. The main objective of the study was to test the hypothesis that agmatine (AGM) prevents oxidative/nitrosative stress in the liver of Wistar rats 15 days after administration of CPZ. All tested substances were administered intraperitoneally (i.p.) for 15 consecutive days. The rats were divided into four groups: the control group (C, 0.9 % saline solution), the CPZ group (CPZ, 38.7 mg/kg b.w.), the CPZ+AGM group (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.) and the AGM group (AGM, 75 mg/kg b.w.).Rats were decapitated 15 days after the appropriate treatment. In the CPZ group, CPZ concentration was significantly increased compared to C values (p<0.01), while AGM treatment induced the significant decrease in CPZ concentration in the CPZ+AGM group (p<0.05) and the AGM group (p<0.01). CPZ application to healthy rats did not lead to any changes of lipid peroxidation in the liver compared to the C group, but AGM treatment decreased that parameter compared to the CPZ group (p<0.05). In CPZ liver homogenates, nitrite and nitrate concentrations were increased compared to controls (p<0.001), and AGM treatment diminished that parameter in the CPZ group (p<0.05), as well as in the AGM group (p<0.001). In CPZ animals, glutathione level and catalase activity were decreased in comparison with C values (p<0.01 respectively), but AGM treatment increased the activity of catalase in comparison with CPZ animals (p<0.05 respectively). Western blot analysis supported biochemical findings in all groups. Our results showed that treatment with AGM significantly supressed the oxidative/nitrosative stress parameters and restored antioxidant defense in rat liver.

The effects of agmatine on acute peritoneal inflammatory injury and neutrophil infiltration induced by zymosan in mice

To investigate the protective effect of agmatine (AGM) against peritoneal inflammatory response and neutrophil (PMN) infiltration induced by zymosan (ZYM) in mice. Thirty-six adult male C57BL/6 mice were randomly divided into sham group, model group, and AGM treatment group. Peritonitis model was reproduced by intra-peritoneal injection of 1 mg/mL ZYM (0.5 mL), while equivalent phosphate buffer saline (PBS) was given to sham group. 200 mg/kg AGM was injected into peritoneal cavity after ZYM challenge in AGM treatment group. Six mice in each group were sacrificed at 2 hours and 6 hours, respectively, after reproduction of the model. Blood sample and peritoneal lavage fluid (PLF) were collected. The levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), tumor necrosis factor-α (TNF-α), interleukins-6 (IL-6) in serum and PLF were determined by enzyme linked immunosorbent assay (ELISA). The number of leukocytes and PMN in PLF were determined by hemocytometer and flow cytometry, respectively. Compared with sham group, all serum and PLF levels of KC, MIP-2, TNF-α and IL-6 were greatly elevated at 2 hours after ZYM injection in model group, while AGM treatment could dramatically reduce the levels of the above-mentioned cytokines in serum and PLF as compared with those of the model group [serum KC (ng/L): 990.7±137.9 vs. 2 053.2±262.7, MIP-2 (ng/L): 642.2±124.4 vs. 1 369.7±146.5, TNF-α (ng/L): 608.6±38.1 vs. 1 044.7±101.0, IL-6 (ng/L): 1 058.2±129.1 vs. 1 443.3±190.1; PLF KC (ng/L): 7 462.3±839.6 vs. 12 723.5±1 515.7, MIP-2 (ng/L): 1 570.8±193.4 vs. 3 471.4±384.7, TNF-α (ng/L): 1 115.8±156.7 vs. 1 499.2±231.2, IL-6 (ng/L): 2 646.5±223.2 vs. 3 126.7±291.4; all P < 0.05]. The expressions of KC, MIP-2 and TNF-α at 6 hours were significantly lower than those at 2 hours in model group and AGM treatment group, but IL-6 levels were further increased. The levels of KC and MIP-2 in serum and PLF at 6 hours were decreased to the levels of sham group. At 6 hours after the reproduction of the model, the number of total inflammatory cells and PMN of PLF in the model group was significantly higher than those of the sham group. In contrast, AGM notably lowered the number of inflammatory cells and PMN in peritoneal fluid after ZYM attack [total inflammatory cells (×109/L): 14.7±1.1 vs. 2.0±0.4, 10.1±1.2 vs. 14.7±1.1; PMN (×109/L): 11.37±1.22 vs. 0.18±0.05, 7.69±0.57 vs. 11.37±1.22, all P < 0.05]. AGM can effectively alleviate acute peritoneal inflammatory injury induced by ZYM, mainly through reducing the secretion of inflammatory mediators and chemokines, and inhibiting the infiltration of leukocytes and neutrophils.

Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.

Neuropeptide‐interactions in Gastric Mucosal Defense Initiated Centrally in the Rat.

BackgroundSeveral neuropeptides were shown to elicit gastric mucosal protective effect given centrally (intracerebroventricularly /i.c.v./, intracisternally or into discrete brain areas), e.g. TRH, opioid peptides, ghrelin, nociceptin, agmatine, substance P (SP), angiotensin II (Ang II) etc. However, numerous data suggest interactions between neuropeptides or with other endogenous mediators. Aim: To analyse if additional neuropeptides are involved in the gastroprotective effect of Ang II or agmatine (endogenous ligand of imidazoline receptors). Methods: Gastric mucosal lesion was elicited by oral administration of acidified ethanol. The compounds were given i.c.v. 10 min prior to ethanol and the lesions were determined 60 min later. The mucosal somatostatin and CGRP contents were determined by RIA. Results: 1. Both Ang II (0.012‐0.191 nmol) and agmatine (0.88‐4.4.nmol) induced significant reduction of the gastric lesions. 2. Parallel, the dramatic decrease of mucosal CGRP and somatostatin levels of gastric mucosa following ethanol administration was restored by both compounds. 3. The gastroprotective effect of Ang II was inhibited both by candesartan and L 733 060, selective NK1 receptor antagonist. Moreover, the protective effect of agmatine was inhibited both by alpha2/imidazoline I1 receptor antagonists idazoxan/efaroxan and the selective I1 receptor ligand, AGN 192403 as well as the opioid receptor antagonist, naloxone.ConclusionSP and opioid peptides might be involved in the gastroprotive effect of Ang II and agmatine, respectively.Supported by OTKA 75965

Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition.

Neural injury is associated with the development of diabetic retinopathy. Müller cells provide structural and metabolic support for retinal neurons. High glucose concentrations are known to induce Müller cell activity. Agmatine is an endogenous polyamine, which is enzymatically formed in the mammalian brain and has exhibited neuroprotective effects in a number of experimental models. The aims of the present study were to investigate whether agmatine protects Müller cells from glucose-induced damage and to explore the mechanisms underlying this process. Lactate dehydrogenase activity and tumor necrosis factor-α mRNA expression were significantly reduced in Müller cells exposed to a high glucose concentration, following agmatine treatment, compared with cells not treated with agmatine. In addition, agmatine treatment inhibited glucose-induced Müller cell apoptosis, which was associated with the regulation of Bax and Bcl-2 expression. Agmatine treatment suppressed glucose-induced phosphorylation of mitogen-activated protein kinase (MAPK) protein in Müller cells. The present study demonstrated that the protective effects of agmatine on Müller cells were inhibited by N-methyl-D-aspartic acid (NMDA). The results of the present study suggested that agmatine treatment protects Müller cells from high-concentration glucose-induced cell damage. The underlying mechanisms may relate to the anti-inflammatory and antiapoptotic effects of agmatine, as well as to the inhibition of the MAPK pathway, via NMDA receptor suppression. Agmatine may be of use in the development of novel therapeutic approaches for patients with diabetic retinopathy.

Protective effect of agmatine in acute chlorpromazine hepatotoxicity in rats

The present study focused on potentially beneficial effects of agmatine on oxidative stress development in the liver during chlorpromazine treatment in rats. We wanted to examine the role of reactive oxygen species and efficiency of antioxidant protection through the determination of malondylaldehyde and total glutathione concentrations in rat liver homogenate, as well as plasma concentrations of malonylaldehyde and sulfhydryl groups after the treatment. Also, liver tissue sections were examined to follow histological changes. Chlorpromazine was applied intraperitoneally at a single dose of 38.7 mg/kg b.w. The second group was treated with both chlorpromazine (at a single dose of 38.7 mg/kg b.w.) and agmatine (at a single dose of 75 mg/kg b.w.). Agmatine was applied immediately after the chlorpromazine. The control group was treated with 0.9% saline solution in the same manner. Rats were sacrificed by decapitation 24 h after the treatment and biochemical and immunohistochemical examinations were performed. Analysis of data showed that treatment with agmatine significantly attenuated the oxidative stress indicators as evidenced by lowering malonylaldehyde concentrations in the liver and in plasma while not affecting liver concentrations of total glutathione and plasma concentration of sulfhydryl groups. Additionally, histological evaluation revealed the improvement of liver damage in this respect. The presented data indicated that intraperitoneally administered agmatine protects against chlorpromazine-induced liver disease in rats.

Protective effects of agmatine on lipopolysaccharide -induced acute hepatic injury in mice

To observe the effect of agmatine ( AGM) on lipopolysaccharide ( LPS )-induced acute hepatic injury in mice, and to explore its related mechanism. Sixty C57BU6 mice were randomly divided into control group ( n = 20, with intra-peritoneal injection of phosphate buffer saline 10 mg/kg), model group ( n = 20, with intra-peritoneal injection of LPS 10 mg/kg), and AGM group (n=20, with intra-peritoneal injection of LPS 10 mg/kg and AGM 200 mg/kg). Ten mice in each group were sacrificed at 6 hours and 24 hours, respectively, after modeling, blood samples were collected for the determination of tumor necrosis factor-a ( TNF -a) and interleukin ( IL-113 and IL-6) by enzyme linked immunosorbent assay (ELISA) at 6 hours after modeling , and for determination of alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) by automatic biochemistry analyzer at 24 hours after modeling. Hepatic homogenate was also collected for determining the endo nuclear nuclear factor-KB ( NF -KB) p65 by Western blotting at 6 hours after modeling, and for observation of pathological changes at 24 hours after modeling. At 6 hours after modeling, .the mice in model group became lethargic and quiet, and their food and water assumption was reduced, but AGM was found to be able to greatly improve the general status of animals in AGM group. AGM was found to lower the contents of serum TNF-a ( IJ.g/L: 296.3 ± 42.5 vs. 627.2 ± 81.3, t=7.327, P=0.002), IL-113 ( f.Lg/L: 109.1 ± 12.3 vs. 264.2 ± 18.8, t= 11.958, P=0.001), IL-6 ( mg/L: 11.4 ± 1.9 vs. 23.6 ± 2.5, t=6.729, P=0.003), ALT (U!L: 107.9 ± 8.5 vs. 189.9 ± 13.6, t=8.856, P=0.001 ), AST (UIL: 347.4 ± 24.9 vs. 716.8 ± 60.4, t=9.793, P=0.001) and TBil ( f.Lmol!L: 8.3 ± 0.9 vs. 10.6 ± 0.5, t=3.869, P=0.018) in mice with acute hepatic injury induced by LPS. AGM also depressed TNF -a ( ng/g: 287.4 ± 32.5 vs. 461.5 ± 31.4, t=6.673, P= 0.003), IL-113 (pg/g: 146.7 ± 13.5 vs. 351.6 ± 28.7, t=11.190, P=0.001) and intranuclear NF-KB p65 level (NF-KBp65/TBP: 0.515 ± 0.060 vs. 0.853 ± 0.080, t=5.849, P=0.004) in liver tissue. Histological examination demonstrated that AGM significantly reduced liver injury caused by LPS, as manifested in amelioration of hepatocytes swelling, necrosis and neutrophil infiltration. Agmatine can reduce LPS-induced acute hepatic injury in mice via suppressing NF-κB translocation and reduction of the synthesis and release of cytokines.

Protective effects of agmatine against d-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice

Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D-galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 μg/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS-induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-α production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases.

Protective effects of agmatine on lipopolysaccharide-injured microglia and inducible nitric oxide synthase activity

AimsProinflammatory factors released from activated microglia contribute to maintaining homeostasis against various noxious stimuli in the central nervous system. If excessive, however, they may initiate a pathologic neuroinflammatory process. In this investigation, we evaluated whether agmatine, a primary polyamine known to protect neurons, reduces lipopolysaccharide (LPS)-induced damage to microglia in vitro and in vivo. Main methodsFor in vitro study, BV2-immortalized murine microglia were exposed to LPS with agmatine treatment. After 24hours, cell viability and the amount of nitrite generated were determined. For in vivo study, LPS was microinjected into the corpus callosum of adult male albino mice. Agmatine was intraperitoneally administered at the time of injury. Brains were evaluated 24hours after LPS microinjection to check for immunoreactivity with a microglial marker of ionized calcium binding adaptor molecule 1 (Iba1) and inducible nitric oxide synthase (iNOS). Using western blot analysis, protein expression of iNOS as well as that of the proinflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, was determined. Key findingsAgmatine significantly reduced the LPS-induced BV2 microglial cytotoxicity from over 80% to less than 60% (p<0.001), as determined by lactate dehydrogenase assay. It suppressed the nitrite production from 16.4±3.14μM to 5.5±1.27μM (p<0.001), as measured using the Griess reaction. Agmatine also decreased the activities of microglia and iNOS induced by LPS microinjection into corpus callosum. SignificanceOur findings reveal that agmatine attenuates LPS-induced microglial damage and suggest that agmatine may serve as a novel therapeutic strategy for neuroinflammatory diseases.

The protective effects of agmatine in zymosan induced acute lung injury in mice

To examine the protective effects of agmatine (AGM) administration on zymosan (ZYM)-induced inflammatory response and acute lung injury (ALI) in mice. 32 adult male C57BL/6 mice were randomly divided into four groups (n=8 each) to receive i. p. administration of:() phosphate buffer saline (PBS, 0. 5 ml); © AGM (200 mg/kg); © ZYM (500 mg/kg)+PBS (0.5 ml),and ® AGM (200 mg/kg)-ZYM (500 mg/kg). Blood samples and peritoneal exudates were collected from the animals 12 hours after drug administration for concentration of tumor necrosis factor-a (TNF-a),interleukin-6 (IL-6) and nitric oxide (NO) by enzyme linked immunosorbent assay (ELISA). Lung tissue samples were also collected at the same time for histological examination, and determination of tissue content of TNF-a, IL-6, myeloperoxidase (MPO) activity and nuclear factor-KB p65 (NF-cB p65) DNA-binding activity. 12 hours after ZYM injection, the treated mice became lethargic, their activity and water consumption were both reduced, AGM greatly improved the general status, activity, and water consumption in treated mice, while attenuated the increase of TNF-a (ng/L: 252. 6+ 32. 1 vs. 421. 7- 76. 7, 295. 7 ± 78. 6vs. 592. 0 ± 84. 3, both P<0. 05) , IL-6 (ng/L: 2 198. 8 281.8 vs. 4 725. 3 615.4, 19 829. 3 ± 3 647. Ovs. 47 751. 3 ± 5 264.8, both P<0. 05) and NO (pmol/L: 33. 2 ± 4. 3 vs. 50. 2 ± 5. 2, 14.0 ± 3. 6 vs. 45.4 ± 5. 2, both P<0. 05) in serum and peritoneal exudates caused by ZYM. AGM also attenuated the increase of TNF-a (ng/L: 245. 7 ± 39. 1 vs. 378. 3 ± 67. 6, P<0. 05), IL-6 (ng/L: 810. 3 ± 175. 6 vs. 1 172. 4 ± 203.3,P <0. 05), MPO activity (ng/mg: 24. 9 4. 4 vs. 37. 3 5.8, P< 0. 05) and NF-iB p65 optical density(absorbance value: 0. 272 + 0. 029 vs. 0. 347 ± 0. 037, P 0.05) in the lung tissue seen in ZYM treated animals. There was no significant difference between normal PBS and AGM treated group in all the indexes examined. Histological examination demonstrated that ZYM treated animals had severe inflammatory reaction in lung tissues (manifested as vasodilatation and neutrophils infiltration) and AGM significantly reduced such injury. AGM can attenuate the ALI and inflammation induced by ZYM in mice.