Showing papers on "Agmatine published in 2023"

Whole-brain mapping of histaminergic projections in mouse brain

Abstract: Significance Complex behavior involves the collaborative processing of multiple brain regions across 3D-space in the whole brain. Histaminergic neurons, which send its fibers to all major brain regions, is believed to regulate many physiological and pathological processes. However, the understanding of the precise 3D structural pattern of histaminergic projections is limited. Here, we reconstructed the whole-brain 3D precise structure of histaminergic projections in the mouse brain from the whole population and individual neuron perspectives, in which we quantitatively analyzed the distribution characteristics of histaminergic somata and fibers. More importantly, the direct evidence of differences between individual histaminergic neuron was provided in this work. Our findings build a solid foundation for future research studies of histaminergic neural circuits and pharmacological targets.

Perspectives on agmatine neurotransmission in acute and chronic stress-related conditions.

Abstract: 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 during 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.

Polyamine-mediated mechanisms contribute to oxidative stress tolerance in Pseudomonas syringae

Abstract: Bacterial phytopathogens living on the surface or within plant tissues may experience oxidative stress because of the triggered plant defense responses. Although it has been suggested that polyamines can defend bacteria from this stress, the mechanism behind this action is not entirely understood. In this study, we investigated the effects of oxidative stress on the polyamine homeostasis of the plant pathogen Pseudomonas syringae and the functions of these compounds in bacterial stress tolerance. We demonstrated that bacteria respond to H2O2 by increasing the external levels of the polyamine putrescine while maintaining the inner concentrations of this compound as well as the analogue amine spermidine. In line with this, adding exogenous putrescine to media increased bacterial tolerance to H2O2. Deletion of arginine decarboxylase (speA) and ornithine decarboxylate (speC), prevented the synthesis of putrescine and augmented susceptibility to H2O2, whereas targeting spermidine synthesis alone through deletion of spermidine synthase (speE) increased the level of extracellular putrescine and enhanced H2O2 tolerance. Further research demonstrated that the increased tolerance of the ΔspeE mutant correlated with higher expression of H2O2-degrading catalases and enhanced outer cell membrane stability. Thus, this work demonstrates previously unrecognized connections between bacterial defense mechanisms against oxidative stress and the polyamine metabolism.

Acid-sensing ion channel 3 is required for agmatine-induced histamine-independent itch in mice

Abstract: Introduction Itch is a common symptom of many skin and systemic diseases. Identifying novel endogenous itch mediators and the downstream signaling pathways involved will contribute to the development of new strategies for the treatment of chronic itch. In the present study, we adopted behavioral testing, patch clamp recording and metabonomics analysis to investigate the role of agmatine in itch and the underlying mechanism. Methods Behavioral analysis was used to evaluate the establishing of acute and chronic itch mice model, and to test the effects of different drugs or agents on mice itch behavior. Western blotting analysis was used to test the effect of agmatine on phosphorylation of ERK (p-ERK) expression in the spinal cord. Patch clamp recording was used to determine the effect agmatine on the excitability of DRG neurons and the role of ASIC3. Finally, the metabonomics analysis was performed to detect the concentration of agmatine in the affected skin under atopic dermatitis or psoriasis conditions. Results We fused a mouse model and found that an intradermal injection of agmatine (an endogenous polyamine) into the nape of the neck or cheek induced histamine-independent scratching behavior in a dose-dependent manner. In addition, the ablation of nociceptive C-fibers by resiniferatoxin (RTX) abolished agmatine-induced scratching behavior. However, agmatine-induced itch was not affected by the pharmacological inhibition of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1); similar results were obtained from TRPV1−/− or TRPA1−/− mice. Furthermore, agmatine-induced itch was significantly suppressed by the administration of acid-sensing ion channel 3 (ASIC3) inhibitors, APETx2 or amiloride. Agmatine also induced the upregulation of p-ERK in the spinal cord; this effect was inhibited by amiloride. Current clamp recording showed that the acute perfusion of agmatine reduced the rheobase and increased the number of evoked action potentials in acute dissociated dorsal root ganglion (DRG) neurons while amiloride reversed agmatine-induced neuronal hyperexcitability. Finally, we identified significantly higher levels of agmatine in the affected skin of a mouse model of atopic dermatitis (AD) when compared to controls, and the scratching behavior of AD mice was significantly attenuated by blocking ASIC3. Discussion Collectively, these results provide evidence that agmatine is a novel mediator of itch and induces itch via the activation of ASIC3. Targeting neuronal ASIC3 signaling may represent a novel strategy for the treatment of itch.

Putrescine Biosynthesis from Agmatine by Arginase (TtARG) in Thermus thermophilus.

Abstract: In the three domains of life, three biosynthetic pathways are known for putrescine. The first route is conversion of ornithine to putrescine by ornithine decarboxylase (ODC: SpeC), the second route is the conversion of arginine to agmatine by arginine decarboxylase (ADC: SpeA), followed by the conversion of agmatine to putrescine by agmatine ureohydrolase (AUH: SpeB), and the third route is the conversion of agmatine to N-carbamoylputrescine by agmatine deiminase (agmatine iminohydrolase, AIH), followed by the conversion of N-carbamoylputrescine to putrescine by N-carbamoylputrescine amidohydrolase (NCPAH). An extreme thermophile, Thermus thermophilus produces putrescine, although this bacterium lacks homologs for putrescine synthesizing pathways such as ODC, AUH, AIH and NCPAH. To identify genes involved in putrescine biosynthesis in T. thermophilus, putrescine biosynthesis was examined by disruption of a predicted gene for agmatinase (agmatine ureohydrolase), or by using purified enzyme. It was found that arginase (TTHA1496) showed an agmatinase activity utilizing agmatine as a substrate. These results indicate that this bacterium can use arginase for putrescine biosynthesis. Arginase is a major contributor to putrescine biosynthesis under physiological conditions. The presence of an alternative pathway for converting agmatine into putrescine is functionally important for polyamine metabolism supporting survival at extreme environments.

Agmatine as a Novel Treatment Option for Neuropathies: Experimental Evidences

Abstract: N-methyl-D-aspartate receptor (NMDAR) antagonist, a subclass of glutamate receptors or nitric oxide synthase (NOS) inhibitors, prevents neuronal plasticity. However, neural plasticity plays a major role in the pain caused by inflammation and neuropathy, providing clinical opportunities for the use of NOS inhibitors and NMDAR antagonists in the treatment of chronic pain. The neuromodulator agmatine has both NOS inhibitory and NMDAR antagonistic activity, and it controls a range of neurotransmitters and signaling pathways in the brain and spinal cord. The effects of agmatine on pain modulation are described and explored in this article, along with a potential mechanism of action for these effects. We specifically offer evidence to support further clinical and pre-clinical trials looking into agmatine as a novel therapeutic agent for neuropathic pain.

Modulating Substrate Specificity of Rhizobium sp. Histamine Dehydrogenase through Protein Engineering for Food Quality Applications

Abstract: Histamine is a biogenic amine found in fish-derived and fermented food products with physiological relevance since its concentration is proportional to food spoilage and health risk for sensitive consumers. There are various analytical methods for histamine quantification from food samples; however, a simple and quick enzymatic detection and quantification method is highly desirable. Histamine dehydrogenase (HDH) is a candidate for enzymatic histamine detection; however, other biogenic amines can change its activity or produce false positive results with an observed substrate inhibition at higher concentrations. In this work, we studied the effect of site saturation mutagenesis in Rhizobium sp. Histamine Dehydrogenase (Rsp HDH) in nine amino acid positions selected through structural alignment analysis, substrate docking, and proximity to the proposed histamine-binding site. The resulting libraries were screened for histamine and agmatine activity. Variants from two libraries (positions 72 and 110) showed improved histamine/agmatine activity ratio, decreased substrate inhibition, and maintained thermal resistance. In addition, activity characterization of the identified Phe72Thr and Asn110Val HDH variants showed a clear substrate inhibition curve for histamine and modified kinetic parameters. The observed maximum velocity (Vmax) increased for variant Phe72Thr at the cost of an increased value for the Michaelis–Menten constant (Km) for histamine. The increased Km value, decreased substrate inhibition, and biogenic amine interference observed for variant Phe72Thr support a tradeoff between substrate affinity and substrate inhibition in the catalytic mechanism of HDHs. Considering this tradeoff for future enzyme engineering of HDH could lead to breakthroughs in performance increases and understanding of this enzyme class.

Putrescine Detected in Strains of Staphylococcus aureus

Abstract: Most forms of life, including the archaea, bacteria, and eukaryotes synthesize the polyamine putrescine. Although putrescine is widely distributed, several Gram-positive bacteria, including Staphylococcus aureus (S. aureus), appear to be the exceptions. We report here that strains of S. aureus can produce the polyamine putrescine, as well as the derivative N-acetyl-putrescine. Three strains of S. aureus from the American Type Culture Collection (ATCC), one strain listed in the National Center for Biotechnology Information (NCBI) database, whose genomic sequence is well defined, and well as eight strains from S. aureus-induced brain abscesses of individual patients from multiple geographic locations were evaluated. Each strain was grown in complete chemically defined medium (CDM) under stringent conditions, after which the partially purified conditioned medium (CM) was analyzed by mass spectroscopy (MS), and the data were reported as the ratio of experimental results to controls. We confirmed the synthesis of putrescine by S. aureus by using 13C/15N-labeled arginine as a tracer. We found that agmatine, N-acetyl-putrescine, ornithine, citrulline, proline, and NH3 were all labeled with heavy isotope derived from 13C/15N-labeled arginine. None of the strains examined produced spermine or spermidine, but strains from either ATCC or human brain abscesses produced putrescine and/or its derivative N-acetyl-putrescine.

Agmatine, telomerase and trace minerals levels in patients with obstructive sleep apnea syndrome

Abstract: Obstructive sleep apnea syndrome (OSAS) is a disease characterized by repetitive, partially or complete upper airway obstructions resulting in hypoxia and bioelectrical wakefulness reactions along with sleep. There is a limited and different information on the biochemical pathways that may determine harmful effects in OSAS patients with different disease severity. Hence, we aimed to estimate the plasma levels of polyamine agmatine, which has many effects on the central nervous system, telomerase and trace minerals in patients with OSAS. The study included 90 volunteer patients diagnosed with OSAS and divided into three groups of 30 people each according to the apnea-hypopnea index (AHI) score: mild, moderate and severe. Nocturnal blood oxygen saturation percentage (SpO2) and body mass index (BMI) were measured. Plasma agmatine level was defined by ultra-high-pressure liquid chromatography (UHPLC), plasma trace elements (Cu, Co, Mg, Mo, Zn, Se) level by inductively coupled plasma mass spectrometer (ICP-MS) and serum telomerase level by enzyme-linked immunosorbent assay (ELISA) method. It was found that SpO2 value decreased as the disease progressed and showed a negative correlation with BMI, Co and Se plasma levels. The levels of agmatine and telomerase were shown to lower in patients with severe OSAS group compared to other groups. Keywords: agmatine, sleep apnea syndrome, SpO2, telomerase, trace minerals

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

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

Potential of Agmatine as a New Neuroprotective Molecule in Brain Disorders

Abstract: Agmatine, a cationic endogenous polyamine in the central nervous system, is obtained from the decarboxylation of arginine. Agmatine exerts neuroprotective properties, according to a growing body of experimental data. This review aims to describe the present understanding of the involvement of agmatine in the central nervous system and highlight its potential as a new pharmacological therapy as a neuroprotective agent. A few molecular pathways for agmatine’s neuroprotective properties are also highlighted. Several studies have shown that agmatine has neuroprotective properties in a variety of neurological conditions, including stroke and traumatic brain damage. The prevention of brain edema, blood-brain barrier protection, anti-oxidation, anti-apoptosis, and anti-inflammation is some of the proposed neuroprotective mechanisms of agmatine. Agmatine is extremely effective in treating neurological diseases, as evidenced by its safety and low occurrence of side effects. However, the majority of the studies on agmatine that is now accessible were conducted using different experimental models; further, clinical trials are required before agmatine may be used extensively in clinical settings.

Polyamine-mediated mechanisms contribute to oxidative stress tolerance in Pseudomonas syringae.

Abstract: Abstract Bacterial phytopathogens thriving in the surface or the interior of plants may experience oxidative stress because of the activation of plant defense responses. Polyamines have been proposed to participate in the protection of bacteria against this stress, but the mechanisms behind their functions are mostly unclear. In this study, we sought to understand the effects of oxidative stress on the polyamine homeostasis of the plant pathogen Pseudomonas syringae and decipher the functions of these compounds in stress tolerance. We showed that bacteria react to H 2 O 2 by raising the extracellular amount of the polyamine putrescine while the intracellular levels of this compound as well as the analogue spermidine remained unchanged. Consistent with this, supplementation of media with exogenous putrescine enhanced bacterial tolerance to H 2 O 2 . Deletion of arginine decarboxylase ( speA ) and ornithine decarboxylate ( speC ), prevented the synthesis of putrescine and augmented susceptibility to H 2 O 2 , whereas targeting spermidine synthesis alone through deletion of spermidine synthase ( speE ) increased the level of extracellular putrescine and enhanced H 2 O 2 tolerance. Further research demonstrated that the increased tolerance of the ΔspeE mutant correlated both with increased expression of H 2 O 2 -degrading catalases and enhanced outer cell membrane stability. Thus, this work demonstrates previously unidentified links between the metabolism of polyamines and the defense against oxidative stress in bacteria.

Levilactobacillus brevis with High Production of Putrescine Isolated from Blue Cheese and Its Application

Abstract: Polyamine intake has been reported to help extend the lifespan of animals. Fermented foods contain high concentrations of polyamines, produced by fermenting bacteria. Therefore, the bacteria, isolated from fermented foods that produce large amounts of polyamines, are potentially used as a source of polyamines for humans. In this study, the strain Levilactobacillus brevis FB215, which has the ability to accumulate approximately 200 µM of putrescine in the culture supernatant, was isolated from fermented foods, specifically the Blue Stilton cheese. Furthermore, L. brevis FB215 synthesized putrescine from agmatine and ornithine, which are known polyamine precursors. When cultured in the extract of Sakekasu, a byproduct obtained during the brewing of Japanese rice wine containing high levels of both agmatine and ornithine, L. brevis FB215 grew to OD600 = 1.7 after 83 h of cultivation and accumulated high concentrations (~1 mM) of putrescine in the culture supernatant. The fermentation product also did not contain histamine or tyramine. The Sakekasu-derived ingredient fermented by the food-derived lactic acid bacteria developed in this study could contribute to increasing polyamine intake in humans.