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

Kotagale, Nandkishor R.; Rahangdale, Sandip R.; Borkar, Anjali; Singh, None Dr. K. B.; Ikhar, Abhilasha; Takale, Nikita; Umekar, Milind J.; Taksande, Brijesh G.

doi:10.1016/j.ejphar.2021.174255

Cited by 16 publications

(8 citation statements)

References 67 publications

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“…Further research is necessary to elucidate the mechanism of this upregulation. In the frontal cortex, STZ induced an elevated expression of Il1b, which is confirmed by other STZ studies [28,86].…”

Section: Evaluation Of Neuroinflammationsupporting

confidence: 86%

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

McCready,

Gilley,

Kusumo

et al. 2023

Neuroimmunomodulation

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Introduction: Among chronically ill populations, affective disorders remain underdiagnosed and undertreated. A high degree of comorbidity exists between diabetes and affective disorders, particularly depression and anxiety. The mechanisms underlying stress-induced affective dysregulation are likely distinct from that induced by diabetes. A direct comparison between stress- and hyperglycemia-induced affective dysregulation could provide insight into distinct mechanistic targets for depression/anxiety associated with these different conditions. Methods: To this end, the present study used male C57BL/6J mice to compare the independent and combined behavioral and neuroinflammatory effects of two models: (1) unpredictable chronic mild stress and (2) pharmacologically induced hyperglycemia. Results: Streptozotocin-induced hyperglycemia was associated with a set of behavioral changes reflective of the neurovegetative symptoms of depression (i.e., reduced open field activity, reduced grooming, increase immobility in the forced swim task, and decreased marble burying), increased hippocampal Bdnf and Tnf expression, and elevations in frontal cortex Il1b expression. Our chronic stress protocol produced alterations in anxiety-like behavior and decreased frontal cortex Il1b expression. Discussion: While the combination of chronic stress and hyperglycemia produced limited additive effects, their combination exacerbated total symptom burden. Overall, the data indicate that stress and hyperglycemia induce different symptom profiles via distinct mechanisms.

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Section: Evaluation Of Neuroinflammationsupporting

confidence: 86%

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

McCready,

Gilley,

Kusumo

et al. 2023

Neuroimmunomodulation

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“…In this study, we found increased TBARS levels by sucrose consump- to improve anxiety-related disturbances in different models, such as during methamphetamine 68,69 or ethanol withdrawal, 70 in streptozotocin-induced diabetic mice, 71 and in mice exposed to highfat diets. 72,73 The results of this study indicate that metformin is neuroprotective in the prediabetic state, consistent with a growing number of emerging studies in the preclinical and clinical literature demonstrating the benefits of metformin in different neurocognitive and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 59%

“…In this line, the decrease in serum TG and oxidative stress by metformin treatment is probably associated with reverting anxiety disorders to control levels. Accordingly, metformin has previously been shown to improve anxiety‐related disturbances in different models, such as during methamphetamine 68,69 or ethanol withdrawal, 70 in streptozotocin‐induced diabetic mice, 71 and in mice exposed to high‐fat diets 72,73 …”

Section: Discussionmentioning

confidence: 99%

Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Rey,

Coirini,

Marchena

et al. 2023

J Neuroendocrinology

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Excessive consumption of sugary drinks negatively impacts the developing brain, producing long‐lasting behavioral and metabolic disorders. Here, we study whether treatment with the antihyperglycemic agent metformin prevents some of the anxiety and memory alterations produced by chronic sucrose consumption. Male Sprague–Dawley rats had unrestricted access to water (control group) and a bottle containing a 10% sucrose solution (sucrose group, SUC) for 35 days. In parallel, a group of animals from SUC received metformin (25 mg/kg or 50 mg/kg, orally; MET 25 and MET 50 groups, respectively). After 2 weeks of metformin treatment, the animals weighed less than controls. SUC and MET 50 groups compensated for the caloric intake from the sugary solution by consuming less chow. In contrast, total energy intake in MET 25 was higher than the rest of the groups, but they still weighed less than control and SUC groups, suggesting that at this concentration, metformin delays body growth. The animals were then tested for the open field (OF), elevated plus maze (EPM) and novel object location (NOL) tests. In the OF, SUC animals spent more time in the central zone of the arena, evidenced by an increased number of entries and the distance traveled there. In the EPM, SUC animals spent more time in the open arms and less time in the central square. Metformin treatment prevented the decreased anxiety observed in SUC animals in the OF and EPM. In the NOL test, SUC animals showed less interest in novelty and metformin treatment did not improve this alteration. The preference for open spaces in the OF and EPM were associated with increased serum triglycerides (TG) and malondialdehyde levels in the medial prefrontal cortex (mPFC) and the hippocampus (HIP), while poor memory performance was associated with high basal blood glucose levels. In conclusion, the decreased anxiety‐like behavior produced by chronic sucrose consumption was prevented by metformin treatment, through a mechanism that probably involves normalization of TG levels and decreased oxidative stress in mPFC and HIP.

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“…Agmatine was found to be a mediator in the neuropharmacological and lifespan extension effects of metformin. [ 26,27 ] Furthermore, agmatine has hypoglycemic effects, [ 28 ] and can regulate insulin secretion via inhibiting an ATP‐sensitive potassium (K ATP ) channel in a dose‐dependent manner [ 29 ] and activate I 2 ‐imidazoline receptors. [ 30 ] Therefore, pCAA can be a carrier of agmatine and possess these similar effects by increasing agmatine concentration in vivo.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of Barley Phenolamide by Mice and the Human Gut Microbiota and Quantitative Analysis of the Major Metabolites in Mice

Wang

Sang

2022

Molecular Nutrition Food Res

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Scope: This study investigates the metabolism of p-coumaroylagmatine (pCAA), one of the phenolamides in barley, in mice, and by human gut microbiota, and measures the concentrations of its main metabolites in mice. Methods and results: Nine major metabolites are identified from fecal and urinary samples collected from pCAA treated mice via analysis of their LC chromatograms and tandem mass spectra compared to the commercial and synthesized standards. These nine metabolites are generated through four different biotransformation pathways: double bond reduction, amide bond hydrolyzation, cleavage of guanidine, and oxidation of guanidine. Furthermore, interindividual differences in the formation of dihydro-pCAA (M3), high and low metabolizers, are observed in human in vitro intestinal microbial conversion. Moreover, significant amount of pCAA is detected in mice (29.33 ± 1.58 μmol g −1 in feces and 2020.44 ± 130.07 μM in urine), and the concentrations of agmatine (M1) are increased to 177.6 times and 3.2 times in mouse feces and urine, respectively. Conclusion: This study demonstrates that pCAA is metabolized in mice and by human gut microbiota to generate potential bioactive metabolites through four major metabolic pathways. pCAA and its metabolites have the potential to be used as the exposure biomarkers to reflect the intake of whole grain barley.

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

Cited by 16 publications

References 67 publications

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Biotransformation of Barley Phenolamide by Mice and the Human Gut Microbiota and Quantitative Analysis of the Major Metabolites in Mice

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