Agmatine Treatment Research Articles

Therapeutic potential of agmatine in the experimental autoimmune encephalomyelitis

Background/Aim. Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS), in which we investigated the neuroprotective effect of agmatine (AGM), known as a primary amine produced via the decarboxylation of L-arginine. Methods. Dark Agouti rats were divided into groups: control (C), Complete Freund`s Adjuvant (CFA), EAE rats decapitated on the 13th day post immunization (dpi) (EAE13) and on the 20th dpi (EAE20), EAE animals given three (EAE+AGM13) and 10 (EAE+AGM20) doses of AGM, and healthy animals ad-ministered three/10 doses of AGM (AGM). Thiobarbituric acid-reacting substances (TBARS), SH groups (SH), total glutathione (GSH), glutathione peroxidase activity (GPx), superoxide dismutase activities (tSOD, MnSOD, CuZ-nSOD) and nitrite/nitrate concentration (NO2+NO3) were assessed in plasma and brain structures [whole encephalitic mass (WEM) and brainstem (BS)]. Results. The obtained results showed that AGM treatment successfully attenuated severe clinical deficits in EAE. Applications of AGM in EAE rats induced normalized TBARS, SH, GSH, GPx and NO in WEM. In BS, AGM expressed less prominent effects, inducing normalized TBARS, GPx and NO, but no effect on SH and GSH. In both brain structures, tSOD activity lowered and normalized at the peak and in the remission phase of the disease, post-AGM treatment. The effect of AGM on the MnSOD in EAE was expressed in WEM/BS only in the remission phase as a reduced activity. Conclusion. Milder clinical form of developed EAE in rats indicates promising therapeutic effect of AGM in MS. The activated antioxidant system and suppressed oxidative/nitrosative stress development may denote a successful blockade of neu-roinflammation initiated by EAE immunization. The study implies the capability of AGM to attenuate oxidative/nitrosative damage at the peak of EAE by modulating antioxidative defense capacity during the time-course of the disease. Thus, AGM may be considered as an agent with a beneficial effect on neuroinflammation in EAE.

Chronic agmatine treatment modulates behavioral deficits induced by chronic unpredictable stress in wistar rats

Aim: Stressful life events modifies brain neuronal structure that impairs normal brain functions and leads to behavioral deficiencies. Agmatine is a well-recognized neurotransmitter and has been reported to be released as a response to several stressful stimuli. Chronic mild stress model induces depressive like behaviors in rats which simulates human depression. Material and Method: 36 Albino Wistar rats were equally divided in controls and CMS exposed groups that further divided into three groups (n=6). Agmatine (100 mg/Kg/day) and mirtazapine (30 mg/Kg/day) were administered to respective animals while controls with 0.9% saline orally. Test rats were exposed to CMS after one hour of drugs administration and behaviors were observed in different paradigms post 24 hours of drugs monitoring for 28 days. Results: Agmatine significantly increased the time spent and entries of stressed rats in light/ dark transition box test and elevated plus maze test while struggling and mobility in forced swim test was also improved in rats treated with agmatine. Conclusion: All the data collected and results obtained clearly validated the antidepressant and anxiolytic activities of agmatine in CMS induced depression in rats. Thus, drug development based on brain agmatine levels may leads to novel approach for stress related mood disorders therapeutics. Keywords: Chronic mild stress; Agmatine; Mirtazapine; Antidepressant; Behaviors

Evidences for agmatine alterations in Aβ1-42induced memory impairment in mice

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aβ1–42) Alzheimer’s disease mouse model. Aβ1–42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aβ1–42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in β-amyloid induced memory impairment in mice.

Comparative Effectiveness of Agmatine and Choline Treatment in Rats with Cognitive Impairment Induced by AlCl3 and Forced Swim Stress

Endogenous agmatine has a significant role in learning and memory processes as a neurotransmitter. Various studies described the physiological role of endogenous agmatine in learning and memory of multiple cognitive tasks suggesting elevated levels of agmatine during the learning process in the rat brain. Dietary intake of choline showed correlation with cognitive functions in human subjects and treatment with choline supplements validated the ability to diminish learning and cognitive impairment dementias. 36 Albino rats were equally divided into three groups previously: a) control-water, b) Test I - AlCl3 (100 mg/Kg body weight), and c) Test II - Forced swim stress (FSS) for 14 days. On the next day of AlCl3 and FSS last administration, animals were allocated into further three groups and received the following treatments: a. water was given orally to the control group, b. Agmatine (100 mg/Kg Body Weight) group, and c. Choline (100 mg/Kg Body Weight) group for the next 14 days. Behaviors were assessed in Light/Dark Box, Open Field, Novel Object Recognition Test (NOR), T Maze Test, and Morris Water Maze Test. Animals administered with agmatine demonstrated increased time spent in bright areas of light/dark box and square crossed while improved spatial memory in Morris water maze and T maze test and enhanced discrimination of novel object in NOR were observed in learning and memory paradigms along with choline. The present study determines that agmatine at the dose of (100 mg/kg body weight) attenuates memory and cognitive impairment in comparison with choline supplements.

Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate

Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.

Effect of agmatine on food intake in mandarin fish (Siniperca chuatsi).

Agmatine, an endogenous biogenic amine, is considered to be a central neurotransmitter. And it plays an important role in mammal feeding behavior. However, there were few studies on the effect of agmatine on feeding behavior in fishes. Here, we investigated the impact of intracerebroventricular (ICV) injections of agmatine (1.25-20nmol/fish) on food intake in mandarin fish (Siniperca chuatsi). At 1-h post-injection, food intake showed a significant decrease in agmatine-treated fishes compared with the saline treated. Furthermore, the food intake in agmatine treatment mostly did not differ from that in saline treatment at 4--24-h post-injection as well as the results of genes expression of neuropeptide Y (NPY), agouti-regulated peptide (AgRP), and anorexigenic melanocortin 4 receptor (MC4R). In accordance with the insulin level increasing in liver, the gene expression of insulin receptor substrate (IRS2) was significantly higher in agmatine treatment compared to saline treatment at 1-h post-injection. Thus, the anorexigenic effect of agmatine is likely to decrease NPY and AgRP expression levels and increase MC4R and IRS2 levels which was coupled with stimulation of insulin secretion. Although these initial findings are limited in dose, the data firstly provides evidence for the anorectic effects of agmatine in fish.

Abstract TP137: Suppression of Microrna Let-7a Expression Promotes Neurogenesis in Arginine Decarboxylase-neural Stem Cells After Ischemia

Introduction: Neural stem cells (NSCs) have been studied as promising novel treatments for central nervous system (CNS) disorders due to the potential of differentiation into neuron. To increase the therapeutic efficiency of NSCs, we have focused on microRNA let-7a ( let-7a ), known as the regulator of diverse cellular mechanisms and agmatine, an endogenous primary amine synthesized from decarboxylation of L-arginine catalyzed by arginine decarboxylase (ADC) and a neurotransmitter reported to affect neuroprotection in CNS. The purpose of this study is to investigate the role of arginine metabolic enzyme which regulated let-7a in neural stem cell differentiation. Methods: Cortical NSCs were isolated from pregnant imprinting control region mice and used for experiments after 2-3 passages. After let-7a mimic and agmatine treatment, we performed by RT-PCR, western blot and immunocytochemistry. To confirm the effects of arginine metabolic enzyme and let-7a in vivo , mice were subjected to distal middle cerebral artery occlusion (dMCAO). Following dMCAO, mice were treated agmatine by intraperitoneal injection, let-7a mimic by osmotic pump and human ADC gene delivery into the NSCs using retroviral vector ( vh ADC)-NSCs via intracranial injection at the corpus callosum. Results: In vitro study suggested that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated the expression of TLX and increased the expression of ERK by negatively regulating let-7a . Also, after dMCAO, we found that vh ADC-NSC and let-7a co-treatment group reduced the infarct volume, increased the expression of DCX, Neurogenin2, Olig2, and attenuated the expression of GFAP. Conclusion: In the present study, we found that agmatine can enhance NSC differentiation into neurons by modulating expression of let-7a . In vivo study showed that vh ADC-NSC and let-7a co-treatment promoted neurogenesis and inhibited glial differentiation in the treatment of neural stem cell transplantation in ischemic condition. Therefore, our study suggests that the therapeutic efficiency of the vh ADC-NSC on neural stem cell differentiation through suppression of let-7a of the CNS diseases.

Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway.

Valproate is a widely used drug against epilepsy and several other neurological disorders although it has deleterious hepatotoxic side effects. The current study was designed to test if agmatine as nitric oxide modulator has protective effects against valproate-induced hepatic injury. Male Swiss albino mice were treated with sodium valproate (SVP) with or without agmatine for 7 days. Serum and liver samples were collected for analysis. Results have revealed that agmatine exerted hepatoprotective effects against SVP-associated hepatic injury. Agmatine ameliorated SVP-induced elevated serum biochemical markers of hepatic damage such as serum transaminases, alkaline phosphatase, γ-glutamyl transferase, and lactate dehydrogenase. Histopathological examination of the liver showed improvement of hepatic lesions in case of agmatine treatment. Furthermore, agmatine attenuated oxidative stress and enhanced antioxidants in liver tissue. Agmatine inhibited the activation of nuclear factor-κB and ameliorated the immunoexpression of inducible nitric oxide synthetase. This was accompanied by decrease in the level of inflammatory markers as nitrite/nitrate, tumor necrosis factor-α, and interleukin-6. These data provide new evidence of the hepatoprotective activity of agmatine against SVP-induced hepatotoxic effects.

Neuroprotective effect of agmatine in mouse spinal cord injury model: Modulation by imidazoline receptors

Objective: The involvement of imidazoline receptors in the effect of agmatine was studied in locomotor recovery following experimental SCI (ESCI) in mice. Methods: ESCI was induced in mice using compression method. Locomotor function score (0–10) was measured on day 14 following ESCI. Results: Agmatine (2.5, 5, and 10 mg/kg) treatment through intraperitoneal route for 14 days following ESCI, dose-dependently improved the motor function score. Clonidine (0.1 mg/kg; imidazoline I1 receptor agonist) or moxonidine (0.5 mg/kg; I2 receptor agonist) treatment 15 min before agmatine (2.5 mg/kg) daily for 14 days, following ESCI, significantly potentiated the effect of per se agmatine. On the other hand, 15 min before treatment of efaroxan (1 mg/kg; imidazoline I1 receptor antagonist) or idazoxan (3 mg/kg; imidazoline I2 receptor antagonist) significantly blocked the motor function score of agmatine (10 mg/kg). Conclusion: These data suggest that imidazoline receptors may modulate the locomotor recovery following ESCI in agmatine treated mice, perhaps through I1/I2 receptors.

Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.

Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice.

Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism. We investigated the effect of exogenous agmatine on the development of atherosclerosis and changes in lipid profile in apolipoprotein E knockout (apoE-/-) mice. Agmatine caused an approximate 40% decrease of atherosclerotic lesions, as estimated by en face and cross-section methods with an influence on macrophage but not on smooth muscle content in the plaques. Agmatine treatment did not changed gelatinase activity within the plaque area. What is more, the action of agmatine was associated with an increase in the number of high density lipoproteins (HDL) in blood. Real-Time PCR analysis showed that agmatine modulates liver mRNA levels of many factors involved in oxidation of fatty acid and cholesterol biosynthesis. Two-dimensional electrophoresis coupled with mass spectrometry identified 27 differentially expressed mitochondrial proteins upon agmatine treatment in the liver of apoE-/- mice, mostly proteins related to metabolism and apoptosis. In conclusion, prolonged administration of agmatine inhibits atherosclerosis in apoE-/- mice; however, the exact mechanisms linking observed changes and elevations of HDL plasma require further investigation.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals

Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits. The animals were made epileptic employing pentylenetetrazole (35mg/kg i.p. every 48±2h) kindling model of epilepsy and subsequently were treated with vehicle, valproic acid (300mg/kg/day i.p.) and agmatine (2.5, 5, and 10mg/kg)/day/i.p. for 15days. Except naïve, all the groups were challenged with same pentylenetetrazole dose as employed during kindling on days 5, 10, and 15 to evaluate seizure severity. Two hours after seizure severity test, tail suspension test and passive shock avoidance paradigm was employed to evaluate depression and cognitive behavior respectively. Results suggested that epileptic animals were significantly associated with depression and cognitive impairment. Chronic valproate treatment significantly reduced seizure severity, but was found unable to mitigate depression and cognitive deficits. However, agmatine treatment dose dependently ameliorated seizure severity as well as associated depression and cognitive deficits. On 15th day, animals were euthanized and pertinent neurochemical estimations were carried out in cortical and hippocampal areas of the mice brain. Thus, study concluded that agmatine ameliorated seizure severity, depression and cognitive impairment in epileptic animals, possibly via restoring glutamate-GABA neurotransmission and serotonin synthesis with decreased nitrosative stress.

Effects of agmatine on cognitive functions during vascular dementia in biological aging through eNOS and BDNF expression

Objective: Biological aging has been recognized to cause impairment of memory and the development of vascular dementia. Based on our previous work, agmatine has been shown to have a beneficial effect and might have therapeutic potential on cognitive functions, including learning and memory. The aim of the present study was to examine the possible effect of agmatine on biological aging-induced vascular endothelial dysfunction and associated dementia in rats.Methods: We used three different age groups (4-month-olds, 18-month-olds and 24-month-olds; n = 12 in each group) of control and agmatine-treated rats. Control animals received physiological saline for 8 weeks. Agmatine sulfate (40 mg/kg, twice daily) was given to the agmatine groups orally for 8 weeks. Herein, we investigated the effects of agmatine on systolic blood pressure (SBP), nitric oxide (NO)-mediated endothelium-dependent and -independent vasorelaxant responses in thoracic aorta, cognitive performance (passive avoidance test; PAT, and Morris water maze test; MWMT), endothelial nitric oxide synthase (eNOS) expression and both hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression in aged rats.Results: We found cognitive decline, endothelial dysfunction and reduced eNOS and BDNF expression in aged rats. All these changes may result from aging-induced vascular dementia. We also found that chronic treatment with agmatine may improve amygdala-dependent emotional and spatial learning and memorial performance, and endothelial function, and may regulate eNOS and BDNF protein expression in aged rats.Conclusion: Results of the current study point out that chronic agmatine treatment may prevent endothelial dysfunction associated with vascular dementia through eNOS and BDNF expression in aged rats.

Agmatine attenuates chronic unpredictable mild stress-induced anxiety, depression-like behaviours and cognitive impairment by modulating nitrergic signalling pathway

Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28days. Agmatine (20 and 40mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15mg/kg, i.p.) and l-arginine (400mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in Morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15mg/kg) potentiated the effect of agmatine whereas l-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative–nitrergic stress, CORT and BDNF levels.

Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF-α and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-α and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-α and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines.

Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling

The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.

Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways.

Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD.

The Anti-inflammatory Effects of Agmatine on Transient Focal Cerebral Ischemia in Diabetic Rats.

In the previous study, we observed agmatine (AGM) posttreatment immediately after 30 minutes of suture occlusion of the middle cerebral artery (MCAO) reduced the infarct size and neurological deficit in diabetic rats. The aim of the present study was to investigate the anti-inflammatory effect of AGM to reduce cerebral ischemic damage in diabetic rats. Normoglycemic (n=20) and streptozotocin-induced diabetic rats (n=40) were subjected to 30 minutes of MCAO followed by reperfusion. Twenty diabetic rats were treated with AGM (100 mg/kg, intraperitoneal) immediately after 30 minutes of MCAO. Modified neurological examinations and rotarod exercises were performed to evaluate motor function. Western blot and immunohistochemical analysis were performed to determine the expression of inflammatory cytokines in ischemic brain tissue. Real-time polymerase chain reaction was performed to measure the mRNA expression of high-mobility group box 1, receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, and TLR4 RESULTS AND CONCLUSIONS:: AGM posttreatment improved the neurobehavioral activity and motor function of diabetic MCAO rats at 24 and 72 hours after reperfusion. Immunohistochemical analysis showed that AGM treatment significantly decreased the expression of inflammatory cytokines in diabetic MCAO rats at 24 and 72 hours after reperfusion (P<0.01). Western blotting and real-time polymerase chain reaction results indicated that AGM treatment significantly decreased the expression of high-mobility group box 1, RAGE, TLR2, and TLR4 in diabetic rats at 24 hours after reperfusion (P<0.05). This neuroprotective effect of AGM after MCAO was associated with modulation of the postischemic neuronal inflammation cascade.

Agmatine Modulation of Noradrenergic Neurotransmission in Isolated Rat Blood Vessels.

Agmatine, a vasoactive metabolite of L-arginine, is widely distributed in mammalian tissues including blood vessels. Agmatine binding to imidazoline and α₂-adrenoceptors induces a variety of physiological and pharmacological effects. We investigated the effect of agmatine on contractile responses of the rat pulmonary artery and portal vein induced by electrical stimulation of perivascular nerves and by exogenous adrenergic substances. Experiments were performed on isolated segments of rat main pulmonary artery and its extralobular branches, and portal vein suspended in organ bath containing modified Krebs bicarbonate solution and connected to a force-displacement transducer for isometric tension recording. Electrical field stimulation (EFS) produced tetrodotoxin-sensitive contractile responses of pulmonary artery and portal vein. Besides the well known vasorelaxant actions, we found that agmatine also produced a concentration-dependent inhibition of neurogenic contractions induced by EFS in pulmonary arteries; however, the agmatine treatment did not influence the responses to exogenous noradrenaline. The inhibitory effect on EFS-induced contractions was not abolished by the α₂-adrenoceptor antagonist rauwolscine. In portal vein, in contrast, agmatine increased spontaneous mechanical contractions and enhanced the contractions induced by EFS. The results suggest that agmatine can significantly influence vascular function of pulmonary arteries and portal veins by modulating sympathetically mediated vascular contractions by pre- and postsynaptic mechanisms.