The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

BACKGROUND: According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. METHODS: In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. RESULTS: The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. CONCLUSION: Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

Agmatine as a novel intervention for Alzheimer's disease: Pathological insights and cognitive benefits.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and a significant societal burden. Despite extensive research and efforts of the multidisciplinary scientific community, to date, there is no cure for this debilitating disease. Moreover, the existing pharmacotherapy for AD only provides symptomatic support and does not modify the course of the illness or halt the disease progression. This is a significant limitation as the underlying pathology of the disease continues to progress leading to the deterioration of cognitive functions over time. In this milieu, there is a growing need for the development of new and more efficacious treatments for AD. Agmatine, a naturally occurring molecule derived from L-arginine, has emerged as a potential therapeutic agent for AD. Besides this, agmatine has been shown to modulate amyloid beta (Aß) production, aggregation, and clearance, key processes implicated in AD pathogenesis. It also exerts neuroprotective effects, modulates neurotransmitter systems, enhances synaptic plasticity, and stimulates neurogenesis. Furthermore, preclinical and clinical studies have provided evidence supporting the cognition-enhancing effects of agmatine in AD. Therefore, this review article explores the promising role of agmatine in AD pathology and cognitive function. However, several limitations and challenges exist, including the need for large-scale clinical trials, optimal dosing, and treatment duration. Future research should focus on mechanistic investigations, biomarker studies, and personalized medicine approaches to fully understand and optimize the therapeutic potential of agmatine. Augmenting the use of agmatine may offer a novel approach to address the unmet medical need in AD and provide cognitive enhancement and disease modification for individuals affected by this disease.

Efficacy of Agmatine Treatment in Experimental Acute Pancreatitis Rat Model.

BACKGROUND/AIMS: Acute pancreatitis which is characterized by pancreatic inflammation can sometimes be difficult to treat because of limited therapeutic options. The purpose of the study was to assess the effects of agmatine in the acute pancreatitis experimental rat model. MATERIALS AND METHODS: An acute pancreatitis model was created with the administration of cerulein in 40 female Sprague-Dawley rats. Agmatine was administered as a protective agent at 5 mg/kg (low dose) and 10 mg/kg (high dose). The rats were divided into 5 groups, each with 8 rats: group 1 (acute pancreatitis); group 2 (acute pancreatitis+low-dose agmatine 5 mg/kg); group 3 (acute pancreatitis+high-dose agmatine 10 mg/kg); group 4 (placebo, acute pancreatitis+saline); and group 5 (sham and saline infusion). All rats were sacrificed 24 hours after the last injection, and the levels of superoxide dismutase, interleukin-1 beta, and tumor necrosis factor-alpha were assessed in blood samples collected via cardiac puncture. Histopathological examination was performed by a pathologist, who was blind to the groups, according to the Schoenberg's pancreatitis scoring index. RESULTS: The amylase (16.67 and 37.89 U/L), glutathione peroxidase (13.62 and 18.44 ng/mL), tumor necrosis factor-α (39.68 and 64 ng/mL), interleukin-1 (484.73 and 561.83 pg/mL), and transforming growth factor-ß (110.52 and 126.34 ng/L) levels were significantly lower and superoxide dismutase (1.29 and 0.98 ng/L) and malondialdehyde (0.99 and 0.96 nmol/mL) levels were significantly higher in group 3 compared to group 1 (P < .05). Moreover glutathione peroxidase, tumor necrosis factor-α, and transforming growth factor-ß levels were lower, and malondialdehyde levels were higher in the group 3 compared to group 2 (P < .05). Although the Schoenberg's pancreatitis scoring index was not significantly different between the high- and low-dose treatment groups, rats who received high-dose treatment had significantly lower scores compared to those with acute pancreatitis group. CONCLUSION: This is the first study that evaluated the efficacy of agmatine in an experimental model of acute pancreatitis. Agmatine, an anti-inflammatory and antioxidant agent, had a protective effect in an experimental rat model of acute pancreatitis.

Neuroprotection by agmatine: Possible involvement of the gut microbiome?

Agmatine, an endogenous polyamine derived from L-arginine, elicits tremendous multimodal neuromodulant properties. Alterations in agmatinergic signalling are closely linked to the pathogeneses of several brain disorders. Importantly, exogenous agmatine has been shown to act as a potent neuroprotectant in varied pathologies, including brain ageing and associated comorbidities. The antioxidant, anxiolytic, analgesic, antidepressant and memory-enhancing activities of agmatine may derive from its ability to regulate several cellular pathways; including cell metabolism, survival and differentiation, nitric oxide signalling, protein translation, oxidative homeostasis and neurotransmitter signalling. This review briefly discusses mammalian metabolism of agmatine and then proceeds to summarize our current understanding of neuromodulation and neuroprotection mediated by agmatine. Further, the emerging exciting bidirectional links between agmatine and the resident gut microbiome and their implications for brain pathophysiology and ageing are also discussed.

Biodistribution of Agmatine to Brain and Spinal Cord after Systemic Delivery.

Agmatine, an endogenous polyamine, has been shown to reduce chronic pain behaviors in animal models and in patients. This reduction is due to inhibition of the GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAR) in the central nervous system (CNS). The mechanism of action requires central activity, but the extent to which agmatine crosses biologic barriers such as the blood-brain barrier (BBB) and intestinal epithelium is incompletely understood. Determination of agmatine distribution is limited by analytical protocols with low sensitivity and/or inefficient preparation. This study validated a novel bioanalytical protocol using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for quantification of agmatine in rat biologic matrices. These protocols were then used to determine the plasma pharmacokinetics of agmatine and the extent of distribution to the CNS. Precision and accuracy of the protocol met US Food and Drug Administration (FDA) standards in surrogate matrix as well as in corrected concentrations in appropriate matrices. The protocol also adequately withstood stability and dilution conditions. Upon application of this protocol to pharmacokinetic study, intravenous agmatine showed a half-life in plasma ranging between 18.9 and 14.9 minutes. Oral administration led to a prolonged plasma half-life (74.4-117 minutes), suggesting flip-flop kinetics, with bioavailability determined to be 29%-35%. Intravenous administration led to a rapid increase in agmatine concentration in brain but a delayed distribution and lower concentrations in spinal cord. However, half-life of agmatine in both tissues is substantially longer than in plasma. These data suggest that agmatine adequately crosses biologic barriers in rat and that brain and spinal cord pharmacokinetics can be functionally distinct. SIGNIFICANCE STATEMENT: Agmatine has been shown to be an effective nonopioid therapy for chronic pain, a significantly unmet medical necessity. Here, using a novel bioanalytical protocol for quantification of agmatine, we present the plasma pharmacokinetics and the first report of agmatine oral bioavailability as well as variable pharmacokinetics across different central nervous system tissues. These data provide a distributional rationale for the pharmacological effects of agmatine as well as new evidence for kinetic differences between brain and spinal cord.

Cholinergic deficit induced memory retrieval impairment and hippocampal CaMKII-alpha deregulation is counteracted by sub-chronic agmatine treatment in mice.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII-α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII-α signaling. In addition, the effect of sub-chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII-α deregulation was investigated in mice. Adult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII-α and beta actin proteins. The results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII-α. Sub-chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII-α. This study suggests that hippocampal CaMKII-α might play a role in scopolamine induced amnesia and sub-chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII-α protein.

Preventive putative effect of agmatine on cognitive and molecular outcomes in ventral tegmental area of male offspring following physical and psychological prenatal stress.

Prenatal stress (PS) results from a maternal experience of stressful events during pregnancy, which has been associated with an increased risk of behavioral disorders including substance abuse and anxiety in the offspring. PS is known to result in heightened dopamine release in the ventral tegmental area (VTA), in part through the effects of corticotropin-releasing hormone, which directly excites dopaminergic cells. It has recently been suggested that agmatine plays a role in modulating anxiety-like behaviors. In this study, we investigated whether agmatine could reduce negative cognitive outcomes in male mice prenatally exposed to psychological/physical stress, and whether this could be associated with molecular changes in VTA. Agmatine (37.5 mg/kg) was administrated 30 min prior to PS induction in pregnant Swiss mice. Male offspring were evaluated in a series of behavioral and molecular assays. Findings demonstrated that agmatine reduced the impairment in locomotor activity induced by both psychological and physical PS. Agmatine also decreased heightened conditioned place preference to morphine seen in PS offspring. Moreover, agmatine ameliorated the anxiety-like behavior and drug-seeking behavior induced by PS in the male offspring. Molecular effects were seen in VTA as the enhanced brain-derived neurotrophic factor (BDNF) induced by PS in the VTA was reduced by agmatine. Behavioral tests indicate that agmatine exerts a protective effect on PS-induced impairments in male offspring, which could be due in part to agmatine-associated molecular alterations in the VTA. Taken together, our data suggest that prenatal treatment with agmatine exerts protective effect against negative consequences of PS on the development of affective circuits in the offspring.

Agmatine prevents the memory impairment and the dysfunction of hippocampal GSK-3ß 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-3ß) 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-3ß 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-3ß as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3ß and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3ß and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring.

Physical or psychological stress experienced by a mother during gestation is often associated with serious behavioural and cognitive deficits in newborns. Investigations of protective agents, which could prevent the adverse outcomes of prenatal stress (PS), are warranted. Agmatine is a neurotransmitter putatively involved in the physiological response to stress, and exogenous administration of agmatine has been shown to produce a variety of neuroprotective effects. In this study, we aimed to assess whether prenatal agmatine exposure could ameliorate behavioural and cognitive deficits in female offspring born to prenatally stressed mice. Pregnant Swiss Webster (SW) mice were exposed to physical or psychological stress from the 11th to 17th days of gestation. Agmatine (37.5 mg/kg, i.p.) was administrated 30 min before the induction of stress for seven consecutive days. The pups were assessed using a variety of behavioural tests and molecular assays on postnatal days 40 to 47. Agmatine attenuated impairments in locomotor activity, anxiety-like behaviour, and drug-seeking behaviour associated with both physical and psychological PS. Furthermore, agmatine reduced PS-induced impairments in passive avoidance memory and learning. Neither PS nor agmatine treatment affected the mRNA expression level of hippocampal brain-derived neurotrophic factor (BDNF) or tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). Taken together, our findings highlight the protective effects of prenatally administered agmatine on PS-mediated behavioural and cognitive deficits of the offspring. Future studies are needed to elucidate the underlying mechanisms, which could allow for more targeted prenatal treatments.

Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling.

BACKGROUND: Following central nervous system (CNS) injury, the investigation for neuroinflammation is vital because of its pleiotropic role in both acute injury and long-term recovery. Agmatine (Agm) is well known for its neuroprotective effects and anti-neuroinflammatory properties. However, Agm's mechanism for neuroprotection is still unclear. We screened target proteins that bind to Agm using a protein microarray; the results showed that Agm strongly binds to interferon regulatory factor 2 binding protein (IRF2BP2), which partakes in the inflammatory response. Based on these prior data, we attempted to elucidate the mechanism by which the combination of Agm and IRF2BP2 induces a neuroprotective phenotype of microglia. METHODS: To confirm the relationship between Agm and IRF2BP2 in neuroinflammation, we used microglia cell-line (BV2) and treated with lipopolysaccharide from Escherichia coli 0111:B4 (LPS; 20 ng/mL, 24 h) and interleukin (IL)-4 (20 ng/mL, 24 h). Although Agm bound to IRF2BP2, it failed to enhance IRF2BP2 expression in BV2. Therefore, we shifted our focus onto interferon regulatory factor 2 (IRF2), which is a transcription factor and interacts with IRF2BP2. RESULTS: IRF2 was highly expressed in BV2 after LPS treatment but not after IL-4 treatment. When Agm bound to IRF2BP2 following Agm treatment, the free IRF2 translocated to the nucleus of BV2. The translocated IRF2 activated the transcription of Kruppel-like factor 4 (KLF4), causing KLF4 to be induced in BV2. The expression of KLF4 increased the CD206-positive cells in BV2. CONCLUSIONS: Taken together, unbound IRF2, resulting from the competitive binding of Agm to IRF2BP2, may provide neuroprotection against neuroinflammation via an anti-inflammatory mechanism of microglia involving the expression of KLF4.

Agmatine improves liver function, balance performance, and neuronal damage in a hepatic encephalopathy induced by bile duct ligation.

INTRODUCTION: In the current study, we investigate whether oral administration of agmatine (AGM) could effectively reduce motor and cognitive deficits induced by bile duct ligation (BDL) in an animal model of hepatic encephalopathy (HE) through neuroprotective mechanisms. METHODS: The Wistar rats were divided into four groups: sham, BDL, BDL+ 40 mg/kg AGM, and BDL+ 80 mg/kg AGM. The BDL rats were treated with AGM from 2 weeks after the surgery for 4 consecutive weeks. The open field, rotarod, and wire grip tests were used to assess motor function and muscle strength. The novel object recognition test (NOR) was performed to evaluate learning and memory. Finally, blood samples were collected for the analysis of the liver markers, the animals were sacrificed, and brain tissues were removed; the CA1 regions of the hippocampus and cerebellum were processed to identify apoptosis and neuronal damage rate using caspase-3 immunocytochemistry and Nissl staining. RESULTS: The serological assay results showed that BDL severely impaired the function of the liver. Based on histochemical findings, BDL increased the neuronal damage in CA1 and Purkinje cells, whereas apoptosis was significantly observed only in the cerebellum. AGM treatment prevented the increase of serum liver enzymes, balance deficits, and neuronal damage in the brain areas. Apoptosis partially decreased by AGM, and there were no differences in the performance of animals in different groups in the NOR. CONCLUSIONS: The study suggests AGM as a potential treatment candidate for HE because of its neuroprotective properties and/or its direct effects on liver function.

Analysis of Regulatory Mechanism of AcrB and CpxR on Colistin Susceptibility Based on Transcriptome and Metabolome of Salmonella Typhimurium.

With the increasing and inappropriate use of colistin, the emerging colistin-resistant isolates have been frequently reported during the last few decades. Therefore, new potential targets and adjuvants to reverse colistin resistance are urgently needed. Our previous study has confirmed a marked increase of colistin susceptibility (16-fold compared to the wild-type Salmonella strain) of cpxR overexpression strain JSΔacrBΔcpxR::kan/pcpxR (simplified as JSΔΔ/pR). To searching for potential new drug targets, the transcriptome and metabolome analysis were carried out in this study. We found that the more susceptible strain JSΔΔ/pR displayed striking perturbations at both the transcriptomics and metabolomics levels. The virulence-related genes and colistin resistance-related genes (CRRGs) were significantly downregulated in JSΔΔ/pR. There were significant accumulation of citrate, α-ketoglutaric acid, and agmatine sulfate in JSΔΔ/pR, and exogenous supplement of them could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. Additionally, we also demonstrated that AcrB and CpxR could target the ATP and reactive oxygen species (ROS) generation, but not proton motive force (PMF) production pathway to potentiate antibacterial activity of colistin. Collectively, these findings have revealed several previously unknown mechanisms contributing to increased colistin susceptibility and identified potential targets and adjuvants for potentiating colistin treatment of Salmonella infections. IMPORTANCE Emergence of multidrug-resistant (MDR) Gram-negative (G-) bacteria have led to the reconsideration of colistin as the last-resort therapeutic option for health care-associated infections. Finding new drug targets and strategies against the spread of MDR G- bacteria are global challenges for the life sciences community and public health. In this paper, we demonstrated the more susceptibility strain JSΔΔ/pR displayed striking perturbations at both the transcriptomics and metabolomics levels and revealed several previously unknown regulatory mechanisms of AcrB and CpxR on the colistin susceptibility. Importantly, we found that exogenous supplement of citrate, α-ketoglutaric acid, and agmatine sulfate could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. These results provide a theoretical basis for finding potential new drug targets and adjuvants.

The effect of maternal separation stress-induced depression on ovarian reserve in Sprague Dawley Rats: The possible role of imipramine and agmatine through a mTOR signal pathway.

PURPOSE: To examine the possible role of impramine and agmatine through a mTOR signal pathway on rat ovary after maternal separation stress-induced depression. METHODS: Sprague Dawley neonatal female rats were divided into control, maternal separation (MS), MS+imipramine, and MS+agmatine groups. Rats were subjected to MS for 4 hours daily from postnatal day (PND) 2 to PND 21 and pups were exposed to social isolation (SI) on PND23 for 37 days for model establishment treated with imipramine (30 mg/kg; ip) or agmatine (40 mg/kg; ip) for 15 days. In order to examine behavioral changes rats were all subjected to locomotor activity and forced swimming tests (FST). Ovaries were isolated for morphological evaluation, follicle counting and mTOR signal pathway protein expression levels were detected. RESULTS: Increased number of primordial follicles and diminished ovarian reserve in the MS groups were detected. Imipramine treatment caused diminished ovarian reserve and atretic follicle; however, agmatine treatment provided the maintenance of ovarian follicular reserve after MS. mTOR signal pathway may have an important role during rat ovarian follicular development in model of MS. CONCLUSIONS: Our findings suggest that agmatine may help to protect ovarian reserve during follicular development by controlling cell growth.

Agmatine prevents the manifestation of impulsive burying and depression-like behaviour in progesterone withdrawn female rats.

Premenstrual dysphoric disorder (PMDD) is characterized by various physical and affective symptoms, including anxiety, irritability, anhedonia, social withdrawal, and depression. The present study investigated the role of the agmatinergic system in animal model of progesterone withdrawal in female rats. Chronic progesterone exposure of female rats for 21 days and its abrupt withdrawal showed enhanced marble burying, increased immobility time, and reduced no. of entries in open arm as compared to control animals. The progesterone withdrawal-induced enhanced marble burying anxiety and immobility time was significantly attenuated by agmatine (5-20 mg/kg, i.p.), and its endogenous modulators like L-arginine (100 mg/kg, i.p.), amino-guanidine (25 mg/kg, i.p.) and arcaine (50 mg/kg, i.p.) by their once-daily administration from day 14-day 21 of the protocol. We have also analysed the levels of agmatine, progesterone, and inflammatory cytokines in the hippocampal region of progesterone withdrawn rats. There was a significant decline in agmatine and progesterone levels and an elevation in cytokine levels in the hippocampal region of progesterone withdrawn rats compared to the control animals. In conclusion, the present studies suggest the importance of the endogenous agmatinergic system in progesterone withdrawal-induced anxiety-like and depression-like behaviour. The data also projects agmatine as a potential therapeutic target for the premenstrual dysphoric disorder.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine.

INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats.

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress.

Agmatine is an endogenous polyamine produced from l-arginine and degraded by agmatinase (AGMAT). Studies in humans and animals have shown that agmatine has neuroprotective, anxiolytic, and antidepressant-like actions. However, little is known about the role of AGMAT in the action of agmatine or in the pathophysiology of psychiatric disorders. Therefore, this study aimed to investigate the role of AGMAT in the pathophysiology of MDD. In this study, we observed that AGMAT expression increased in the ventral hippocampus rather than in the medial prefrontal cortex in the chronic restraint stress (CRS) animal model of depression. Furthermore, we found that AGMAT overexpression in the ventral hippocampus elicited depressive- and anxiety-like behaviors, whereas knockdown of AGMAT exhibited antidepressant and anxiolytic effects in CRS animals. Field and whole-cell recordings of hippocampal CA1 revealed that AGMAT blockage increased Schaffer collateral-CA1 excitatory synaptic transmission, which was expressed both pre- and post-synaptically and was probably due to the inhibition of AGMAT-expressing local interneurons. Therefore, our results suggest that dysregulation of AGMAT is involved in the pathophysiology of depression and is a potential target for designing more effective antidepressants with fewer adverse effects to offer a better therapy for depression.

Perspectives on Agmatine Neurotransmission in Acute and Chronic Stressrelated Conditions.

Adaptive responses to stressful stimuli in the environment are believed to restore homeostasis after stressful events. Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases glucocorticoids (GCs) into the bloodstream. Recently, agmatine, an endogenous monoamine was discovered to have the potential as a pharmacotherapy for stress. Agmatine is released in response to certain stress conditions, especially those involving GCs, and participates in establishing homeostasis disturbed by stress following GC activation. The therapeutic potential of agmatine for the management of psychological diseases involving stress and depression is promising based on a significant amount of literature. When exogenously applied, agmatine leads to reductions in levels of GCs and counteracts stress-related morphologic, synaptic, and molecular changes. However, the exact mechanism of action by which agmatine modifies the effects resulting from stress hormone secretion is not fully understood. This review aims to present the most possible mechanisms by which agmatine reduces the harmful effects of chronic and acute stress. Several studies suggest chronic stress exposure and repeated corticosteroid treatment lower agmatine levels, contributing to stress-related symptoms. Agmatine acts as an antistress agent by activating mTOR signaling, inhibiting NMDA receptors, suppressing iNOS, and maintaining bodyweight by activating α-2adrenergic receptors. Exogenous administration that restores agmatine levels may provide protection against stress-induced changes by reducing GCs release, stimulating anti-inflammatory processes, and releasing neuroprotective factors, which are not found in all therapies currently being used to treat stress-related disorders. The administration of exogenous agmatine should also be considered a therapeutic element that is capable of triggering a neural protective response that counters the effects of chronic stress. When combined with existing treatment strategies, this may have synergistic beneficial effects.

Agmatine reduces alcohol drinking and produces antinociceptive effects in rodent models of alcohol use disorder.

Alcohol use disorder (AUD) is a chronic, relapsing disorder characterized by an escalation of drinking and the emergence of negative affective states over time. Within this framework, alcohol may be used in excessive amounts to alleviate withdrawal-related symptoms, such as hyperalgesia. Future effective therapeutics for AUD may need to exhibit the ability to reduce drinking as well as to alleviate co-morbid conditions such as pain, and to take mechanistic sex differences into consideration. Agmatine is an endogenous neuromodulator that has been previously implicated in the regulation of reward and pain processing. In the current set of studies, we examined the ability of agmatine to reduce escalated ethanol drinking in complementary models of AUD where adult male and female mice and rats were made dependent via chronic, intermittent ethanol vapor exposure (CIE). We also examined the ability of agmatine to modify thermal and mechanical sensitivity in alcohol-dependent male and female rats. Agmatine reduced alcohol drinking in a dose-dependent fashion, with somewhat greater selectivity in alcohol-dependent female mice (versus non-dependent female mice), but equivalent efficacy across male mice and both groups of male and female rats. In mice and female rats, this efficacy did not extend to sucrose drinking, indicating some selectivity for ethanol reinforcement. Female rats made dependent on alcohol demonstrated significant hyperalgesia symptoms, and agmatine produced dose-dependent antinociceptive effects across both sexes. While additional mechanistic studies into agmatine are necessary, these findings support the broad-based efficacy of agmatine to treat co-morbid excessive drinking and pain symptoms in the context of AUD.

Long-term reversal of chronic pain behavior in rodents through elevation of spinal agmatine.

Chronic pain remains a significant burden worldwide, and treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-d-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral (AAV) vector carrying the gene for arginine decarboxylase (ADC) prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-human ADC (hADC) vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options.