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Mamoru Kamoshita, Shunsuke Kubota, Kenya Yuki, Seiji Miyake, Norihiro Nagai, Kazuo Umezawa, Kazuo Tsubota, Yoko Ozawa; AMPK-NF-κB axis modulates visual function during inflammation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6074.
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AMP-activated protein kinase (AMPK) is well known for its role in cellular energy homeostasis. Recently, AMPK activation has been shown to have an anti-inflammatory effect. The aim of this study is to investigate the effect of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMPK on the neural retina during inflammation, using a mouse model of endotoxin-induced uveitis (EIU). Furthermore, in order to evaluate whether NF-κB is involved in the inflammatory disease pathogenesis downstream of AMPK, we used a specific inhibitor of NF-κB, dehydroxymethylepoxyquinomicin (DHMEQ).
The EIU model was induced by an intraperitoneal injection of lipopolysaccharide (LPS). Each animal was given an intraperitoneal injection of AICAR (250mg/kg) or a vehicle 3 hours before the LPS injection. Visual function was analyzed by electroretinogram (ERG). Protein level of rhodopsin in the retina was measured by immunoblot analysis, and the morphological change was analyzed in the retinal sections. Protein level of activated AMPK and phosphorylated NF-κB during the early phase of inflammation, were measured by immunoblot analysis. Moreover, each animal was given an intraperitoneal injection of DHMEQ (10mg/kg) or a vehicle 2 hours before the LPS injection, and ERG, protein level of rhodopsin, morphological change were analyzed.
The activated AMPK was decreased in the retina during inflammation, but its level was preserved by AICAR administration. The visual function demonstrated by ERG showed impaired photoreceptor cell function, and the level of rhodopsin and the length of outer segments in the photoreceptor cells were reduced during inflammation. However, all these changes were avoided by AICAR. In addition, NF-κB activation in the retina during inflammation, which was suppressed by AICAR, was shown to be responsible for reducing rhodopsin level during inflammation by using the NF-κB inhibitor, DHMEQ.
The AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and AICAR played a neuroprotective role during retinal inflammation.
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