Agmatine modulation of gut-brain axis alleviates dysbiosis-induced depression-like behavior in rats.

Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior.

Agmatine mitigates behavioral abnormalities and neurochemical dysregulation associated with 3-Nitropropionic acid-induced Huntington's disease in rats.

Huntington's disease (HD) is a progressive neurodegenerative condition characterized by a severe motor incoordination, cognitive decline, and psychiatric complications. However, a definitive cure for this devastating disorder remains elusive. Agmatine, a biogenic amine, has gain attention for its reported neuromodulatory and neuroprotective properties. The present study was designed to examine the influence of agmatine on the behavioral, biochemical, and molecular aspects of HD in an animal model. A mitochondrial toxin, 3-nitro propionic acid (3-NP), was used to induce HD phenotype and similar symptoms such as motor incoordination, memory impairment, neuro-inflammation, and depressive-like behavior in rats. Rats were pre-treated with 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9 and then continued on agmatine treatment (5 - 20 µg/rat, i.c.v.) from day-8 to day-27 of the treatment protocol. 3-NP-induced cognitive impairment was associated with declined in agmatine levels within prefrontal cortex, striatum, and hippocampus. Further, the 3-NP-treated rats showed an increase in IL-6 and TNF-α and a reduction in BDNF immunocontent within these brain areas. Agmatine treatment not only improved the 3-NP-induced motor incoordination, depression-like behavior, rota-rod performance, and learning and memory impairment but also normalized the GABA/glutamate, BDNF, IL-6, and TNF-α levels in discrete brain areas. Similarly, various agmatine modulators, which increase the endogenous agmatine levels in the brain, such as L-arginine (biosynthetic precursor), aminoguanidine (diamine oxidase inhibitor), and arcaine (agmatinase inhibitor) also demonstrated similar effects exhibiting the importance of endogenous agmatinergic pathway in the pathogenesis of 3-NP-induced HD like symptoms. The present study proposed the possible role of agmatine in the pathogenesis and treatment of HD associated motor incoordination, and psychiatric and cognitive complications.

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.

Nattokinase prevents ß-amyloid peptide (Aß1-42) induced neuropsychiatric complications, neuroinflammation and BDNF signalling disruption in mice.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular ß-amyloid (Aß) plaques and neuronal damage. Although AD is typically considered a cognitive neurodegenerative disorder, almost all people diagnosed with AD develop neuropsychiatric complications at some stage in their life span. The present study investigated the effect of chronic Nattokinase (NK) administration on ß-Amyloid peptide (Aß1-42) induced neuropsychiatric conditions (depression-like behaviour, anxiety, and memory impairment) in mice. Aß1-42 peptide injected mice demonstrated depression, anxiety, and impairment of cognitive abilities evaluated as increased immobility time in forced swim test (FST), decreased open arm time/entries in elevated plus maze (EPM) and reference and working memory error in radial arm maze (RAM) respectively with elevation in Interleukin-6 (IL-6), Tumour necrosis factor-α (TNF-α), reduction in Interleukin-10 (IL-10) and Brain-derived neurotrophic factor (BDNF) immunocontent within the hippocampus. Chronic administration of NK (50-100 mg/kg, i.p.) from day 8-27, prevented depression-like behaviour, anxiety, and memory impairment and normalized the neurochemical alteration within the hippocampus of mice injected with Aß1-42 peptide. The effect of NK on psychiatric complications, learning, and memory was comparable to peripheral donepezil treatment. This study suggests that NK improves learning, memory impairment, and neuropsychiatric complications possibly through the downregulation of neuroinflammatory pathways and restoring BDNF signalling in AD.

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.

Achyranthes aspera ameliorates stress induced depression in mice by regulating neuroinflammatory cytokines.

Background and aim: Achyranthes aspera Linn. (A. aspera) (family: Amaranthaceae) is highly recognized in ethnomedicine and traditional systems of Indian medicine as a nervine restorative for several psychiatric disorders. Study presented here was designed to appraise the antidepressant-like effects of A. aspera in murine model of chronic unpredictable mild stress (CUMS) induced depression. Experimental procedures-: Rodents were exposed to different stressor in unpredictive manner during CUMS protocol once a day for 4 weeks. Mice were intraperitoneally injected with A. aspera extract (2.5, 5 and 10 mg/kg) or fluoxetine (10 mg/kg) or betaine (20 mg/kg) once daily during day 15-28 of the CUMS protocol. Sucrose preference, motivation and self-care, immobility latency and plasma corticosterone were evaluated after 24 h of last stressor. After behavioral assessments TNF-α, Il-6 and BDNF immunocontent was determined in hippocampus and prefrontal cortex. Results and conclusion: A. aspera extract as well as betaine improved sucrose preference, increased grooming frequency and latency in splash test and ameliorated depression-like condition in CUMS mice in Porsolt test. A. aspera treatment decreased the elevated plasma corticosterone and reversed the effect of CUMS on TNF-α, Il-6 and BDNF immunocontent in mice. The results of the present study suggest A. aspera as a promising indigenous medicine for stress associated neurobehavioral and comorbid complications.

Lumefantrine solid dispersions with piperine for the enhancement of solubility, bioavailability and anti-parasite activity.

Crystallinity and P-glycoprotein (P-gp) mediated efflux of drugs with low aqueous solubility collaboratively contributes to erratic absorption resulting in low/variable bioavailability. Herein, the amorphous solid dispersions (SD) of lumefantrine (LUMF) containing piperine (PIP), a P-gp and CYP3A4 inhibitor, were formulated with Soluplus (Sol), Klucel (Klu) and Lutrol F68 (Lut), polymeric carriers, to improve solubility and bioavailability of LUMF following oral administration. The LUMF-PIP-SD prepared with Sol exhibited higher aqueous solubility of LUMF in concentration dependent manner and LUMF-PIP-Sol demonstrating maximum aqueous LUMF solubility were characterized by DSC, FTIR and XRD. The DSC thermogram and XRD diffractogram of LUMF-PIP-SD confirmed the loss of crystallinity of LUMF ensuing improved dissolution while possible interaction of LUMF with PIP and /or Sol was evident in FTIR spectrum. DSC and dissolution studies confirmed the stability for LUMF-PIP-Sol SD stored for 90 days under stressed conditions of humidity and temperature. An in situ single-pass intestinal perfusion study in rats indicated 2.2-fold increase in intestinal permeation of LUMF co-administered with PIP. Improved bioavailability of LUMF was evidenced by increased AUC0-∞ and Cmax for LUMF in SD compared to alone LUMF or LUMF with PIP. Peter's four-day suppressive test indicated improved antimalarial activity for LUMF-PIP-Sol SD. Overall, the data suggest that the SD of LUMF incorporated with P-gp inhibitor PIP, improves the bioavailability as well as antimalarial efficacy of LUMF.

Chronic agmatine treatment prevents olanzapine-induced obesity and metabolic dysregulation in female rats.

Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with high obesogenic potential. However, the exact mechanism by which it causes its metabolic dysregulation remains poorly understood. In this study, we investigated the effect of agmatine in olanzapine-induced metabolic derangements in Female Sprague-Dawley rats. Repeated olanzapine administration for 28 days increased body weight while treatment with agmatine from days 15 to 28 prevented the body weight gain induced by olanzapine without any alteration in food intake. Repeated agmatine treatment decreased the elevated feeding efficiency and adiposity index, as well as improved dysregulated lipid metabolism induced by olanzapine. Increased activity of fatty acid synthase (FAS) and decreased expression of carnitine palmitoyl transferase-1 (CPT-1) were detected in chronic olanzapine-treated rats. Although agmatine treatment did not alter FAS activity, it increased CPT-1 activity. It is possible that the inhibitory effect of agmatine on weight gain and adiposity might be associated with increased mitochondrial fatty acid oxidation and energy expenditure in olanzapine-treated rats. We suggest that agmatine can be explored for the prevention of obesity complications associated with chronic antipsychotic treatment.

Agmatine prevents development of tolerance to anti-nociceptive effect of ethanol in mice.

Drug tolerance is directly correlated with drug abuse and physical dependence. The development of tolerance is manifested as the decline in pharmacological responses of drugs following repeated administration of the constant dose. The present study evaluated the effect of agmatine in ethanol-induced anti-nociception and tolerance in the tail-flick assay in mice. In an acute protocol, ethanol (1 and 2 g/kg, i.p. [intraperitoneally]) and agmatine (20 and 40 µg/mouse, i.c.v. [intracerebroventricularly]) produced significant analgesic effects in mice, as was evident from the increased baseline tail-flick latency when tested 20 minutes after their administration. Agmatine in a per se non-effective dose (5 µg/mouse, i.c.v.), L-arginine (40 µg/mouse, i.c.v.), and arcaine (25 µg/mouse, i.c.v.) significantly potentiated the anti-nociceptive effect of ethanol. Blood ethanol analysis showed no significant differences in blood ethanol concentration between ethanol/saline- and ethanol/agmatine-treated mice, suggesting that the effects of agmatine were not due to any possible effects on the pharmacokinetics of ethanol. In a separate study, mice were injected with ethanol (2 g/kg, i.p., 12%) or saline (1 mL/kg, i.p.) once daily for 9 days. On days 1, 3, 5, 7, and 9 of the experiment, they were subjected to the tail-flick test. Agmatine (5-20 µg/mouse, i.c.v.), L-arginine (40 µg/mouse, i.c.v.), arcaine (25 µg/mouse, i.c.v.), aCSF (2 µL/mouse, i.c.v.), or saline (1 mL/kg, i.p.) was administered daily prior to the first daily ethanol or saline injections, and reaction latencies were determined in the tail-flick assay. Injections of agmatine, L-arginine, and arcaine prevented the development of tolerance to ethanol-induced analgesia. Given that agmatine and its endogenous modulation can prevent tolerance to the anti-nociceptive effects of ethanol, these data suggest it as a possible new therapeutic strategy for the treatment of alcohol use disorder and associated complications.

Possible involvement of agmatine in neuropharmacological actions of metformin in diabetic mice.

The risk of psychiatric and neurological disorders is significantly higher in patients with diabetes mellitus. Diabetic patients are more susceptible to depression, anxiety and memory impairment as compared with non-diabetic individuals. Metformin, a biguanide used for the management of type 2 diabetes mellitus (T2DM), promotes neurogenesis, enhances spatial memory function and protects the brain against oxidative imbalance beyond its effect on glucose metabolism. However, the exact mechanism of its neuropharmacological actions in T2DM is not known. We investigated the role of the agmatinergic system in neuropharmacological actions of metformin in diabetic mice. Diabetes was induced by the streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 28 days, STZ treated mice exhibited memory impairment in radial arm maze, depression-like behavior in forced swim test and anxiety-like behavior in elevated plus maze along with increased expression of pro-inflammatory cytokines like TNF-α, IL-1ß, IL-6, IL-10 also, reduced agmatine and BDNF levels in the hippocampus and prefrontal cortex compared to the control animals. Metformin and agmatine alone or in combination, by once-daily administration during 14-27 day of the protocol significantly reversed the STZ induced high blood glucose levels, memory impairment, depression and anxiety-like behaviors. It also reduced neuro-inflammatory markers and increased agmatine and BDNF levels in the hippocampus and prefrontal cortex. The present study suggests the importance of endogenous agmatine in the neuropharmacological action of metformin in diabetic mice. The data projects agmatine and metformin combination as a potential therapeutic strategy for diabetes associated memory impairment, depression, anxiety, and other comorbidities.

Evidences for agmatine alterations in Aß1-42induced 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 (Aß1-42) Alzheimer's disease mouse model. Aß1-42 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 Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.

Involvement of agmatine in antidepressant-like effect of HMG-CoA reductase inhibitors in mice.

3-Hydroxy-3-methyl-glutaryl-co-enzyme-A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 µg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 µg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 µg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.

Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats.

Chronic maternal ethanol exposure leads to poor intelligence, impaired cognition and array of neurological symptoms in offsprings and commonly referred as fetal alcohol spectrum disorder (FASD). Despite high prevalence and severity, the neurochemical basis of FASD remains largely unexplored. The present study evaluated the pharmacological effects of agmatine in cognitive deficits associated with FAS in rat's offsprings prenatally exposed to alcohol. Pregnant rats received ethanol in liquid modified diet during the entire gestational period of 21 days. Offsprings were treated with agmatine (20-80 mg/Kg, i.p.) during early postnatal days (PND: 21-35) and subsequently evaluated for anxiety in elevated plus maze (EPM), depression in forced swim test (FST) and learning and memory in Morris's water maze (MWM) during post adolescent phase. Hippocampal agmatine, BDNF, TNF-α and IL-6 levels were also analyzed in prenatally ethanol exposed pups. Offsprings prenatally exposed to ethanol demonstrated delayed righting reflex, reduced exploratory behavior along with anxiety, depression-like behavior and impaired memory. These behavioral abnormalities were correlated with a significant reduction in hippocampal agmatine and BDNF levels and elevation in TNF-α and IL-6 immunocontent. Chronic agmatine (40 and 80 mg/Kg, i.p.) administration for 15 days (PND: 21-35), improved entries and time spent in open arm of EPM, decreased immobility time in FST. It also reduced latency to reach the platform location; increased the number of entries, time spent in platform quadrant and also number of crossing over platform quadrant when subjected to MWM test in prenatally ethanol exposed offsprings. This study provides functional evidences for the therapeutic potential of agmatine in cognitive impairment and other neurological complications associated with FASD.

Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats.

Epidemiological studies indicated that mood disorders like depression and anxiety are highly prevalent in type-II diabetes mellitus (T2DM). However, the neurobiological mechanisms underlying the relationship between T2DM and depression have yet to be identified. Thus, understanding the neural mechanisms that mediate the co-morbidity of depression and type-II diabetes mellitus may unlock new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in T2DM induced depression using forced swim test (FST) and anxiety in the elevated plus-maze (EPM)in rats. T2DM was induced by the combination of high-fat diet (HFD) and streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 12 weeks, HFD fed and STZ injected rats exhibited depression-like behaviors and anxiety. It was associated with increased expression of pro-inflammatory cytokines like IL-6 and TNF-α, and reduced BDNF immunocontent in the hippocampal tissues. The T2DM-induced depression, anxiety, and neuroinflammatory markers were significantly inhibited by agmatine (10-20 mg/kg, i.p.), by once-daily administration during 9th to 12th week of the protocol. Agmatine levels were significantly reduced in the hippocampus of T2DM rats as compared to the normal fed (NF) control animals. In conclusion, the present study suggests the importance of endogenous agmatine in T2DM induced anxiety and depressive-like behavior in rats. The data projects agmatine as a potential therapeutic target for T2DM-associated depression, anxiety, and comorbidities.

Agmatine reverses memory deficits induced by Aß1-42 peptide in mice: A key role of imidazoline receptors.

Agmatine is a biogenic amine synthesized following decarboxylation of L-arginine by the enzyme arginine decarboxylase and exhibits favourable outcome in neurodegenerative disorders. Present study was designed to examine the relationship between agmatine and the imidazoline receptors in memory deficits induced by Aß1-42 peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aß1-42 peptide (3 µg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aß1-42, TNF-α and IL-6 and BDNF immunocontent analysis within the hippocampus. While the learning and memory impairment was evident in the mice subjected to MWM test following Aß1-42 peptide administration, there was a significant increase in Aß1-42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20 mg/kg); imidazoline I1 receptor agonist, moxonidine and imidazoline I2 receptor agonist, 2-BFI starting from day 8 to 27 post-Aß1-42 injection, significantly prevented the cognitive deficits and normalized the Aß1-42 peptide, IL-6, TNF-α and BDNF immunocontent in hippocampus. On the other hand, pre-treatment with imidazoline I1 receptor antagonist, efaroxan and imidazoline I2 receptor antagonist, BU 224 attenuated the effects of agmatine on learning and memory in MWM, IL-6, TNF-α and BDNF content. In conclusion, the present study provides functional evidence for the involvement of the imidazoline receptors in agmatine induced reversal of Aß1-42 induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.

Involvement of hippocampal agmatine in ß1-42 amyloid induced memory impairment, neuroinflammation and BDNF signaling disruption in mice.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular ß-amyloid (Aß) plaques and neuronal damage. The present study investigated the effect of chronic intra-hippocampal agmatine administration on ß-Amyloid (Aß) induced memory impairment in mice. Aß1-42 peptide injected mice demonstrated impairment of cognitive abilities evaluated as reference memory error and working memory error in radial arm maze (RAM) and decreased exploration time for novel object as well as recognition index in novel object recognition (NOR) test along with elevation in Aß1-42 peptide, ß-Site APP cleaving enzyme 1 (BACE 1), microtubule-associated protein tau (MAPt), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and reduction in neprilysin and brain derived neurotrophic factor (BDNF) immunocontent within hippocampus and prefrontal cortex. Importantly, this was associated with a reduction in the agmatine levels following Aß1-42 peptide administration. Chronic administration of agmatine from day 8-27, prevented the memory impairment in mice and normalized the neurochemical alteration within prefrontal cortex and hippocampus induced by Aß1-42 peptide administration. However, it did not modulate the amyloid precursor protein and BACE expression. This study suggests that agmatine improves learning and memory impairment possibly through the down regulation of neuroinflammatory pathways in AD.

Agmatine ameliorates manifestation of depression-like behavior and hippocampal neuroinflammation in mouse model of Alzheimer's disease.

Extensive clinical and experimental studies established that depression and mood disorders are highly prevalent neuropsychiatric conditions in Alzheimer's disease (AD). However, its neurochemical basis is not clearly understood. Thus, understanding the neural mechanisms involved in mediating the co-morbidity of depression and AD may be crucial in exploring new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in ß-amyloid (Aßß1-42) peptide-induced depression using forced swim test (FST) in mice. Following the 28th days of its administration, Aß1-42 peptide produced depression-like behavior in mice as evidenced by increased immobility time in FST and increased expression of pro-inflammatory cytokines like IL-6 and TNF-α compared to the control animals. The Aß1-42 peptide-induced depression and neuroinflammatory markers were significantly inhibited by agmatine -, moxonidine, 2-BFI and l-arginine by once-daily administration during day 8-27 of the protocol. The antidepressant-like effect of agmatine in Aß1-42 peptide in mice was potentiated by imidazoline receptor I1 agonist, moxonidine and imidazoline receptor I2 agonist 2-BFI at their sub-effective doses. On the other hand, it was completely blocked by imidazoline receptor I1 antagonist, efaroxan and imidazoline receptor I2 antagonist, idazoxan Also, agmatine levels were significantly reduced in brain samples of ß-amyloid injected mice as compared to the control animals. In conclusion, the present study suggests the importance of endogenous agmatinergic system and imidazoline receptors system in ß-amyloid induced a depressive-like behavior in mice. The data projects agmatine as a potential therapeutic target for the AD-associated depression and comorbidities.

Inhibitory influence of agmatine in ethanol withdrawal-induced depression in rats: Behavioral and neurochemical evidence.

Although ethanol withdrawal depression is one of the prominent reasons for ethanol consumption reinstatement and ethanol dependence, its neurochemical basis is not clearly understood. The present study investigated the role of the agmatinergic system in ethanol withdrawal-induced depression using the forced swim test (FST) in rats. Chronic exposure of animals to ethanol for 21 days and its abrupt withdrawal produced depression-like behavior, as evidenced by increased immobility time in the FST, compared to the pair-fed control animals. The ethanol withdrawal-induced depression was significantly attenuated by agmatine (20-40 µg/rat, i.c.v. [intracerebroventricularly]), moxonidine (50 µg/rat, i.c.v.), 2-BFI (20 µg/rat, i.c.v.), L-arginine (80 µg/rat, i.c.v.), amino-guanidine (25 µg/rat, i.c.v.), and arcaine (50 µg/rat, i.c.v.) by their once-daily administration during the withdrawal phase (Days 21, 22, and 23). The antidepressant effect of agmatine in ethanol-withdrawn rats was potentiated by the imidazoline receptor I1 agonist moxonidine (25 µg/rat, i.c.v.) and the imidazoline receptor I2 agonist, 2-BFI (10 µg/rat, i.c.v.) at their sub-effective doses. On the other hand, it was completely blocked by the imidazoline receptor I1 antagonist, efaroxan (10 µg/rat, i.c.v.) and the imidazoline receptor I2 antagonist, idazoxan (4 µg/rat, i.c.v.). In addition, agmatine levels were significantly reduced in brain samples of ethanol-withdrawn rats as compared to the pair-fed control animals. In conclusion, the present study suggests the importance of the endogenous agmatinergic system and the imidazoline receptors system in ethanol withdrawal-induced depression. The data project agmatine as a potential therapeutic target for the alcohol withdrawal-induced depression.

Agmatine reverses ethanol consumption in rats: Evidences for an interaction with imidazoline receptors.

Alcohol is one of the most widely abused recreational drugs, largely linked with serious health and social concerns. However, the treatment options for alcohol-use disorders have limited efficacy and exhibit a range of adverse drug reactions. Large numbers of preclinical studies have projected a biogenic amine, agmatine as a promising potential treatment option for drug addiction, including alcoholism. In the present study, administration of agmatine (20-40 mg/kg, i.p.) resulted in significant inhibition of ethanol self-administration in the right p-VTA in operant conditioning paradigm. Further, acute intracranial administration of agmatine (20 and 40 µg/rat) significantly reduced the ethanol consumption in the two bottle choice paradigm. Agmatine is degraded to putrescine and guanido-butanoic acid by the enzyme agmatinase and diamine oxidase respectively and inhibition of these enzymes results in augmentation of endogenous agmatine. In the present study, diamine oxidase inhibitor, aminoguanidine and agmatinase inhibitor, arcaine were used to block the agmatine metabolic pathways to increase brain agmatine levels. Drugs that augment endogenous agmatine levels like L-arginine (80 µg/rat, i.c.v.) or arcaine (50 µg/rat, i.c.v.) and aminoguanidine (25 µg/rat, i.c.v.) also reduced the ethanol consumption following their central administration. The pharmacological effect of agmatine on ethanol consumption was potentiated by imidazoline receptor agonists, I1 agonist moxonidine (25 µg/rat, i.c.v.), and imidazoline I2 agonist, 2-BFI (10 µg/rat, i.c.v.) and was blocked by imidazoline I1 antagonist, efaroxan (10 µg/rat, i.c.v.), and I2 antagonist, idazoxan (4 µg/rat, i.c.v.) at their ineffective doses per se. Thus, our result suggests the involvement of imidazoline I1 and I2 receptors in agmatine induced inhibition of ethanol consumption in rats.

Neuroprotective offerings by agmatine.

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