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Samin Hong, Chan Yun Kim, Yoko Iizuka, Jong Eun Lee, Gong Je Seong; Protective Effects of Agmatine on Hypoxic Microglia through Modulating Nitric Oxide Synthase. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2678.
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© ARVO (1962-2015); The Authors (2016-present)
Microglia are the resident macrophages of CNS and play a crucial role in maintaining homeostasis against various neuronal injuries. However, excessive activation of microglia may destroy healthy neurons as well as damaged neurons. We investigated neuroprotective effects of amgatine on hypoxic microglia using in vitro and in vivo models for transient hypoxia.
For in vitro study, BV2 immortalized murine microglia were incubated with or without agmatine in a closed anaerobic chamber. Cell viability was deternined by lactate dehydrogenase (LDH) assay and generation of nitrite was determined using the Griess reaction. For in vivo study, agmatine was intraperitoneally administered and the left middle cerebral artery (MCA) of Sprague-Dawley rats was occluded for 90 min. After 24 h from occlusion, their forebrains were evaluated to check the immunoreactivity with a microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), and inducible nitric oxide synthase (iNOS).
Agmatine definitely attenuated hypoxia-induced cytotoxicity and nitrite production of BV2 microglia. Cytotoxicity reached more than 80% after transient hypoxia, but it was attenuated to less than 60% when cells were treated with 100 µM agmatine (p<0.001, one-way ANOVA). Regarding nitrite, though transient hypoxia increased its concentration in the culture media to 9.43±0.73 µM, agmatine suppressed it to 3.75±0.42 µM (p<0.001, one-way ANOVA). In animals, agmatine decreased the activities of microglia and iNOS induced by transient occlusion of MCA. Transient occlusion of MCA increased the number of Iba1 and iNOS double positive cells (cortex; 229.25±9.30 cells, striatum; 197.25±7.09 cells) compared to controls (cortex; 105.00±7.00 cells, striatum; 64.00±4.00 cells). Agmatine treatment definitely reduced the number of these cells to 164.00±3.61 cells for cortex and 139.33±2.03 cells for striatum.
Our findings reveal that agmatine may reduce microglial damages caused by transient hypoxia and suggest that agmatine may lead to a novel therapeutic strategy for hypoxic neuronal injuries.
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