Inhibition of adenosine kinase attenuates inflammation and neurotoxicity in traumatic optic neuropathy
| Autor: | Gregory I. Liou, Nehal M. Elsherbiny, Saif Ahmad, Kanchan Bhatia, Ahmed Elsherbini, Sadanand Fulzele |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Lipopolysaccharides
Male Adenosine Pyridines Morpholines Immunology Anti-Inflammatory Agents Nitric Oxide Synthase Type I Adenosine kinase Pharmacology Retinal ganglion Retina Equilibrative Nucleoside Transporter 1 Mice chemistry.chemical_compound Adenosine A1 receptor medicine Animals Immunology and Allergy Enzyme Inhibitors Adenosine Kinase Cells Cultured Inflammation biology Nitrotyrosine Calcium-Binding Proteins Microfilament Proteins Imidazoles Purinergic signalling Adenosine A3 receptor Adenosine receptor Mice Inbred C57BL Disease Models Animal Oxidative Stress Pyrimidines Neurology chemistry Optic Nerve Injuries biology.protein Neurotoxicity Syndromes Microglia Neurology (clinical) medicine.drug |
| Zdroj: | Journal of Neuroimmunology. 277:96-104 |
| ISSN: | 0165-5728 |
| DOI: | 10.1016/j.jneuroim.2014.10.006 |
| Popis: | Traumatic optic neuropathy (TON) is associated with apoptosis of retinal ganglion cells. Local productions of reactive oxygen species and inflammatory mediators from activated microglial cells have been hypothesized to underlie apoptotic processes. We previously demonstrated that the anti-inflammatory effect of adenosine, through A2A receptor activation had profound protective influence against retinal injury in traumatic optic neuropathy. This protective effect is limited due to rapid cellular re-uptake of adenosine by equilibrative nucleotside transporter-1 (ENT1) or break down by adenosine kinase (AK), the key enzyme in adenosine clearance pathway. Further, the use of adenosine receptors agonists are limited by systemic side effects. Therefore, we seek to investigate the potential role of amplifying the endogenous ambient level of adenosine by pharmacological inhibition of AK. We tested our hypothesis by comparing TON-induced retinal injury in mice with and without ABT-702 treatment, a selective AK inhibitor (AKI). The retinal-protective effect of ABT-702 was demonstrated by significant reduction of Iba-1, ENT1, TNF-α, IL-6, and iNOS/nNOS protein or mRNA expression in TON as revealed by western blot and real time PCR. TON-induced superoxide anion generation and nitrotyrosine expression were reduced in ABT-702 treated mice retinal sections as determined by immunoflourescence. In addition, ABT-702 attenuated p-ERK1/2 and p-P38 activation in LPS induced activated mouse microglia cells. The results of the present investigation suggested that ABT-702 had a protective role against marked TON-induced retinal inflammation and damage by augmenting the endogenous therapeutic effects of site- and event-specific accumulation of extracellular adenosine. |
| Databáze: | OpenAIRE |
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