title: Inhibition of adenosine kinase attenuates inflammation and neurotoxicity in traumatic optic neuropathy.
abstract: 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.
authors.affiliation: Department of Ophthalmology, School of Medicine, Georgia Regents University (GRU), Augusta, GA, USA; Departmet of Biological Sciences, Rabigh College of Science and Arts, King Abdulaziz University, Rabigh, Saudi Arabia. Electronic address: asaif77@yahoo.com.
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Ophthalmology, School of Medicine, Georgia Regents University (GRU), Augusta, GA, USA; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Nehal M
authors.initials: NM
authors.lastname: Elsherbiny
authors.affiliation: Departmet of Biological Sciences, Rabigh College of Science and Arts, King Abdulaziz University, Rabigh, Saudi Arabia.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Bhatia
authors.affiliation: Department of Ophthalmology, School of Medicine, Georgia Regents University (GRU), Augusta, GA, USA.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elsherbini
authors.affiliation: Department of Orthopedics, Georgia Regents University (GRU), Augusta, GA, USA.
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.affiliation: Department of Ophthalmology, School of Medicine, Georgia Regents University (GRU), Augusta, GA, USA. Electronic address: giliou@gru.edu.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
mesh_terms: D000241:Adenosine / Q000627:therapeutic use; D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D009025:Morpholines / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000150:complications* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use; D012160:Retina / Q000187:drug effects / Q000473:pathology
chemical_list: C491049:Aif1 protein, mouse; D000893:Anti-Inflammatory Agents; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D033721:Equilibrative Nucleoside Transporter 1; D007093:Imidazoles; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; C498476:SLC29A1 protein, mouse; C416933:ABT 702; D052248:Nitric Oxide Synthase Type I; D000248:Adenosine Kinase; D000241:Adenosine; C093642:SB 203580
keywords: ABT-702; Adenosine kinase; Inflammation; MAPKinase; Microglia; Traumatic optic neuropathy