Regulatory mechanisms underlying agmatine homeostasis in humans

Haenisch, Britta; Kügelgen, Ivar von; Bönisch, Heinz; Göthert, M.; Sauerbruch, Tilman; Schepke, Michael; Marklein, G.; Höfling, Katja; Schröder, D; Molderings, Gerhard J.

doi:10.1152/ajpgi.90374.2008

Cited by 42 publications

(24 citation statements)

References 24 publications

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“…However, exogenous drug administration is not always the best approach for real patients. Taken orally, agmatine is readily distributed throughout the body [53, 54] and can even cross the blood–brain barrier [55, 56]. Moreover, its reported half-life in the body is about 2 hrs [57].…”

Section: Discussionmentioning

confidence: 99%

Retroviral expression of human arginine decarboxylase reduces oxidative stress injury in mouse cortical astrocytes

et al. 2014

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BackgroundIn physiologic and pathologic conditions of the central nervous system (CNS), astrocytes are a double-edged sword. They not only support neuronal homeostasis but also contribute to increases in neuronal demise. A large body of experimental evidence has shown that impaired astrocytes play crucial roles in the pathologic process of cerebral ischemia; therefore, astrocytes may represent a breakthrough target for neuroprotective therapeutic strategies. Agmatine, an endogenous polyamine catalyzed from L-arginine by arginine decarboxylase (ADC), is a neuromodulator and it protects neurons/glia against various injuries.ResultsIn this investigation, agmatine-producing mouse cortical astrocytes were developed through transduction of the human ADC gene. Cells were exposed to oxygen-glucose deprivation (OGD) and restored to a normoxic glucose-supplied condition. Intracellular levels of agmatine were measured by high performance liquid chromatography. Cell viability was evaluated by Hoechest/propidium iodide nuclear staining and lactate dehydrogenase assay. Expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase s (MMPs) were assessed by a reverse transcription polymerase chain reaction, Western immunoblots, and immunofluorescence. We confirmed that ADC gene-expressed astrocytes produce a great amount of agmatine. These cells were highly resistant to not only OGD but also restoration, which mimicked ischemia-reperfusion injury in vivo. The neuroprotective effects of ADC seemed to be related to its ability to attenuate expression of iNOS and MMPs.ConclusionOur findings imply that astrocytes can be reinforced against oxidative stress by endogenous agmatine production through ADC gene transduction. The results of this study provide new insights that may lead to novel therapeutic approaches to reduce cerebral ischemic injuries.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-99) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Retroviral expression of human arginine decarboxylase reduces oxidative stress injury in mouse cortical astrocytes

et al. 2014

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“…Both RNA and cDNA concentrations were determined spectrophotometrically (Biorad Spectronanodrop). The primer sequences included sense 5'-ATTGTTCCGTTCTTCTTGACTT-3' and antisense 5'-AGTGTGATGTGAAGGATTATG-3' for ARG1 (148bp), sense 5'-GGTCCCGCTGCCATAAGAG-3' and anti-sense 5'-CGTGGATTCACTATCAGGTTGTTG-3' f o r A R G 2 ( 1 3 7 b p ) , s e n s e 5'-GGATCCAAATGTGGCTGCGTTCAT-3' and antisense 5'-AACAGCCAGCCATCTACCAGTTCT-3' f o r O A T ( 1 7 5 b p ) , s e n s e 5'-GTGGGTGATTGGATGCTCTTTG-3' and anti-sense 5'-AGGCCCTGACATCACATAGTAG-3' for ODC (108bp), sense 5'-GAAATCCCATCACCATCTTCC-3' and anti-sense 5'-GAGCCCCAGCCTTCTCCATG -3 ' f o r G A P D H ( 1 2 0 b p ) , a n d s e n s e 5'-TGGATCAGCAAGCAGGAGTATG-3' and antisense 5'-AAGAAAGGGTGTAACGCAACTAAG-3' for β-actin (98bp) (Bergeron et al, 2007;Wolf et al, 2007;Haenisch et al, 2008;Kitowska et al, 2008;Kim et al, 2012;Mondal et al, 2013). For all analysis, sqPCR assays were performed in a 25 µL system containing PCR master mix, 30ng first-strand cDNA template and 0.4 µM appropriate primers.…”

Section: 7031 Modulation Of L-arginine-arginase Metabolic Pathway Enmentioning

confidence: 99%

Modulation of L-Arginine-Arginase Metabolic Pathway Enzymes: Immunocytochemistry and mRNA Expression in Peripheral Blood and Tissue Levels in Head and Neck Squamous Cell Carcinomas in North East India

Srivastava

Ghosh²

2015

Asian Pacific Journal of Cancer Prevention

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Background: Arginine may play important roles in tumor progression by providing ornithine for polyamine biosynthesis, required for cell growth. The aim of this work was to determine the expression of arginine metabolic pathway enzymes in head and neck squamous cell carcinoma (HNSCC) in northeast India. Materials and Methods: The expressions of arginase isoforms (ARG1 and ARG2), ornithine aminotransferase (OAT) and ornithine decarboxylase (ODC) were examined in fifty paired HNSCC and adjacent non-tumor tissues by immunohistochemistry. Immunocytochemistry, semiquantitative reverse transcription sq-PCR and quantitative real-time qPCR were used to assess protein and mRNA expressions in peripheral blood of fifty HNSCC patients and hundred controls. Results: ARG1 and ODC protein and mRNA were strongly expressed in peripheral blood from HNSCC patients. No ARG2 expression was observed. In vivo, expression of ARG1, ARG2 and ODC was significantly higher in tumor than in non-tumor tissues. Most tumors expressed low levels of OAT, with no difference in tissues or blood, compared to controls. The absolute extent of maximal ARG1 upregulation with qPCR showed 6.23 fold increase in HNSCC. Conclusions: These findings strongly suggest that in HNSCCs, the ARG1 pathway is stimulated leading to the formation of polyamines as indicated by higher ODC expression, which promote tumor growth.

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“…Ample preclinical evidence indicates that ingested agmatine sulfate can be absorbed and modulate multiple molecular targets in the body [67]. These include key neurotransmitter receptors, ionic channels, NO synthesis, cell signaling pathways, and AGE-product formation [30][31][32][33][34][35][36][37][38][39][40][41][42][43]45,49,50].…”

Section: Postulated Mechanisms Of Actionmentioning

confidence: 99%

Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial

et al. 2010

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Objective. Agmatine, decarboxylated arginine, was shown in preclinical studies to exert efficacious neuroprotection by interacting with multiple molecular targets. This study was designed to ascertain safety and efficacy of dietary agmatine sulfate in herniated lumbar disc-associated radiculopathy. Study Design. First, an open-label dose escalation study was performed to assess the safety and side-effects of agmatine sulfate. In the follow-up study, participants diagnosed with herniated lumbar disc-associated radiculopathy were randomly assigned to receive either placebo or agmatine sulfate in a double-blind fashion. Methods. Participants in the first study were recruited consecutively into four cohorts who took the following escalating regimens: 1.335 g/day agmatine sulfate for 10 days, 2.670 g/day for 10 days, 3.560 g/day for 10 days, and 3.560 g/day for 21 days. Participants in the follow-up study were assigned to receive either placebo or agmatine sulfate, 2.670 g/day for 14 days. Primary outcome measures were pain using the visual analog scale, the McGill pain questionnaire and the Oswestry disability index, sensorimotor deficits, and health-related quality of life using the 36-item short form (SF-36) questionnaire. Secondary outcomes included other treatment options, and safety and tolerability assessment. Results. Safety parameters were within normal values in all participants of the first study. Three participants in the highest dose cohort had mild-to-moderate diarrhea and mild nausea during treatment, which disappeared upon treatment cessation. No other events were observed. In the follow-up study, 51 participants were randomly enrolled in the agmatine group and 48 in the placebo. Continuous improvement of symptoms occurred in both groups, but was more pronounced in the agmatine (analyzed n = 31) as compared with the placebo group (n = 30). Expressed as percent of baseline values, significantly enhanced improvement in average pain measures and in quality of life scores occurred after treatment in the agmatine group (26.7% and 70.8%, respectively) as compared with placebo (6.0% [P

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Regulatory mechanisms underlying agmatine homeostasis in humans

Cited by 42 publications

References 24 publications

Retroviral expression of human arginine decarboxylase reduces oxidative stress injury in mouse cortical astrocytes

Retroviral expression of human arginine decarboxylase reduces oxidative stress injury in mouse cortical astrocytes

Modulation of L-Arginine-Arginase Metabolic Pathway Enzymes: Immunocytochemistry and mRNA Expression in Peripheral Blood and Tissue Levels in Head and Neck Squamous Cell Carcinomas in North East India

Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial

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