Agmatine suppresses nitric oxide production in microglia

Abe, Kazuho; Abe, Yu; Saito, Hiroshi

doi:10.1016/s0006-8993(00)02517-8

Cited by 86 publications

(58 citation statements)

References 37 publications

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“…In the present study, HI rat pups showed elevations in NO metabolite concentrations in the brain during reperfusion 6 h after hypoxia, and agmatine treatment (100 mg/kg) eliminated this increase in NO metabolites. The results indicate that agmatine suppresses NO production after hypoxia in vivo as is known to occur in vitro (22)(23)(24)(25). Reduction of NO generation may therefore be one mechanism of neuroprotection by agmatine.…”

Section: Discussionmentioning

confidence: 59%

“…On the assumption that 1 g of wet weight of tissue corresponds to 1 mL of water, the endogenous concentration of agmatine in brain can be estimated at 59.2 M. In this case, 100 mg/kg i.p. agmatine treatment yields levels of agmatine within the range reported to suppress microglial NO production (24).…”

Section: Discussionmentioning

confidence: 77%

“…Agmatine is more than an order of magnitude more potent with NOS I and NOS II than with NOS III (23). Also, agmatine significantly suppresses lipopolysaccharide-induced NO production in a concentration-dependent manner in vitro (14, 24), and agmatine also reduces neuronal death caused by microgliaderived NO (24). Agmatine has been reported to irreversibly inactivate neuronal NOS (25).…”

Section: Discussionmentioning

confidence: 99%

“…Agmatine possesses modest affinities for various receptors, including as an inhibitor of the NMDA subclass of glutamate receptors (19 -21). Agmatine also inhibits all isoforms of NOS (22)(23)(24)(25), with highest reported activity (Ki ϭ 29 M) as an irreversible inactivator of neuronal NOS (25). Treatments with agmatine are neuroprotective in vitro (21,22), as well as in gerbil ischemic brain injury, adult rat ischemic brain injury (26), and adult rat spinal cord injury (16,27,28).…”

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Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

2002

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Nitric oxide and excitatory amino acids contribute to hypoxic-ischemic brain injury. Agmatine, an endogenous neurotransmitter or neuromodulator, is an inhibitor of nitric oxide synthase and an antagonist of N-methyl-D-aspartate receptors. Does agmatine reduce brain injury in the rat pup hypoxicischemic model? Seven-day old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Agmatine or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily thereafter for 3 d. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia by a blinded observer. Agmatine treatments significantly reduced weight loss in the right hemisphere from Ϫ30.5 Ϯ 3.6% in vehicle-treated pups (n ϭ 22) to Ϫ15.6 Ϯ 4.4% in the group treated with 50 mg/kg (n ϭ 18, p Ͻ 0.05) and to Ϫ15.0 Ϯ 3.7% in the group treated with 100 mg/kg (n ϭ 18, p Ͻ 0.05), but the group treated with 150 mg/kg showed no reduction. Other pups received agmatine or vehicle at 5 min after reoxygenation, and brain biochemistry was assessed. Levels of endogenous brain agmatine rose 2-to 3-fold owing to hypoxic-ischemic (3 h), whereas pups treated with agmatine (100 mg/kg) showed 50-fold higher brain agmatine levels (3 h). Agmatine (100 mg/kg) blocked a hypoxia-induced increase in brain nitric oxide metabolites at 6 h (vehicle-treated, ϩ60.2 Ϯ 15.2%; agmatine-treated, ϩ4.2 Ϯ 8.4%; p Ͻ 0.05). Agmatine thus reduces brain injury in the neonatal rat hypoxic-ischemic model, probably by blunting the rise in nitric oxide metabolites normally seen after hypoxia. [11][12][13][14], agmatine is a 4-carbon elongated relative of the synthetic neuroprotective agent, aminoguanidine (12). Agmatine has long been known to exist in plants, bacteria, insects, and invertebrates (13). Only recently was it realized that agmatine is synthesized in mammalian brain (11), where agmatine acts as both a neurotransmitter and neuromodulator (12, 14 -18). From distribution studies of arginine decarboxylase in primary cell cultures, agmatine is thought to be synthesized predominantly by astroglia cells, then released and taken up into neurons by active transport (12,14). Agmatine possesses modest affinities for various receptors, including as an inhibitor of the NMDA subclass of glutamate receptors (19 -21). Agmatine also inhibits all isoforms of NOS (22-25), with highest reported activity (Ki ϭ 29 M) as an irreversible inactivator of neuronal NOS (25). Treatments with agmatine are neuroprotective in vitro (21,22), as well as in gerbil ischemic brain injury, adult rat ischemic brain injury (26), and adult rat spinal cord injury (16,27,28). The effects of agmatine in neonatal HI brain injury have not previously been tested, nor has correlation been studied between the neuroprotective properties of agmatine and NO production in the brain. HI brain injury is a serious cause of death and disability in human newborns. The developmental stage of the brain of the 7-d-old rat pup resembles that of newborn humans (29). As descr...

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

2002

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“…The kidney is unusual in displaying high constitutive ADC activity, and may be a principal contributor of systemic agmatine (Lortie et al 1996). Agmatine has the capacity to regulate nitric oxide (NO) synthase activity (Galea et al 1996;Abe et al 2000;Satriano et al 2001a) and has been ascribed roles in association with neurotransmitter receptors (Li et al 1994), modulation of opioid analgesia (Kolesnikov et al 1996), and as an ADP-ribose acceptor (Murayama et al 1993). It is structurally analogous to polyamines (putrescine, spermidine and spermine) and can regulate intracellular polyamine content (Satriano et al 1998).…”

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confidence: 99%

Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Eto

Isome

Sano

et al. 2006

Tohoku J. Exp. Med.

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Polyamines play an essential role in the growth and differentiation of mammalian cells. The depletion of intracellular polyamines results in the suppression of growth. Proliferation of glomerular mesangial cells (MC) is the most common pathologic change in many forms of glomerulonephritis. Agmatine is a metabolite of arginine via arginine decarboxylase (ADC), highly expressed in the kidney, and unique in its capacity to suppress intracellular polyamine levels required for proliferation. As agmatine enters mammalian cells via the polyamine transport system, its antiproliferative effects may preferentially target cells with increased proliferative kinetics. In the present study, we evaluated the antiproliferative effects of agmatine on human MC in vitro. MC proliferation was stimulated with 20% fetal bovine serum (FBS) or platelet-derived growth factor (PDGF-BB, 20 ng/ml). Cell proliferation was measured using the (4.3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) proliferation assay. Intracellular polyamine levels were assayed by high performance liquid chromatography, and cell death was assessed by cellular DNA fragmentation enzyme-linked immunosorbent assay. The MTT proliferation assay showed that agmatine significantly suppressed proliferation of human MC treated with 20% FBS or 5% FBS + PDGF as compared to human MC treated with 5% FBS. Polyamine levels were markedly lower in cells treated with agmatine, and proliferation was rescued by administration of putrescine. The fragmented DNA was hardly detected in agmatine-treated human MC. In summary, human MC stimulated to increase their proliferative kinetics are significantly more sensitive to the antiproliferative effects of agmatine than normally cultured cells. Suppressed proliferation of the agmatine-treated human MC is not due to increased cell death. These results suggest that agmatine is a promising drug candidate for the treatment of human mesangial proliferative glomerulonephritis.

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Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

Ahmed

Aljuhani

Al‐Hujaili

et al. 2018

J Biochem & Molecular Tox

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Valproate is a widely used drug against epilepsy and several other neurological disorders although it has deleterious hepatotoxic side effects. The current study was designed to test if agmatine as nitric oxide modulator has protective effects against valproate‐induced hepatic injury. Male Swiss albino mice were treated with sodium valproate (SVP) with or without agmatine for 7 days. Serum and liver samples were collected for analysis. Results have revealed that agmatine exerted hepatoprotective effects against SVP‐associated hepatic injury. Agmatine ameliorated SVP‐induced elevated serum biochemical markers of hepatic damage such as serum transaminases, alkaline phosphatase, γ‐glutamyl transferase, and lactate dehydrogenase. Histopathological examination of the liver showed improvement of hepatic lesions in case of agmatine treatment. Furthermore, agmatine attenuated oxidative stress and enhanced antioxidants in liver tissue. Agmatine inhibited the activation of nuclear factor‐κB and ameliorated the immunoexpression of inducible nitric oxide synthetase. This was accompanied by decrease in the level of inflammatory markers as nitrite/nitrate, tumor necrosis factor‐α, and interleukin‐6. These data provide new evidence of the hepatoprotective activity of agmatine against SVP‐induced hepatotoxic effects.

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Agmatine suppresses nitric oxide production in microglia

Cited by 86 publications

References 37 publications

Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

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