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Saif Ahmad, Nehal Elsherbiny, Ahmed Elsherbini, Sadanand Fulzele, Gregory Liou; Role of Adenosine Kinase in Traumatic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3268.
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© ARVO (1962-2015); The Authors (2016-present)
Our goal is to understand the mechanism of traumatic optic neuropathy (TON) in order to prevent vision loss. Following traumatic insults to the optic nerve, retinal microglial cells are activated through MAP Kinase pathways and increased cytotoxic activity that causes retinal ganglion cell death. Under the stress of TON, extracellular concentration of adenosine is likely to increase due to its increased formation by ecto-5’-nucleotidase (CD73) or decreased metabolism by the intracellular adenosine kinase (AK). The accumulated intracellular adenosine is then released through equilibrative nucleoside transporters. Extracellular adenosine activates an anti-inflammatory pathway through A2A adenosine receptor. However, we do not know whether AK or CD73 contributes more in causing this imbalance. We have demonstrated that hypoxia-induced microglia activation was inhibited by inhibitors of MAP Kinases (ERK and P38) and AK. We have also shown that hypoxia-induced CD73 up-regulation suppressed microglia activation. Based on these findings, we hypothesize that an imbalance in adenosine formation and metabolism in the retinal microglia participated by AK may contribute significantly to retinal complications in the setting of TON.
Mice were anesthetized according to standard protocol and bilateral limbal conjunctival peritomy was performed posteriorly to the optic nerve in each mouse. Compression by forceps was performed on the right optic nerve in each mouse with the left optic nerve serving as a control. Compression was released at 10 seconds and pupillary dilation was noted. Mice were treated with or without an AK inhibitor (AKI), ABT702 (25μg/kg; i. p.), every other day for 7 days. All retinas were then harvested for RNA preparation. Gene expression was determined by Real-Time PCR analysis.
In a series experiments with Real-Time PCR, increased expression of TNF-α, Iba1, and caspase3 were shown in nerve crush model. In subgroup of nerve crush model that was treated with AKI, lower expression was noted. It was also noted that administration of AKI showed no effect in the control.
Our results suggest that TON can be effectively treated with an inhibitor for AK, which ameliorates inflammation by reducing microglial activity. Inhibition of AK potentially amplifies the endogenous therapeutic effects of site- and event-specific accumulation of extracellular adenosine, which is of highly translational impact.
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