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Nadeem H. Fatteh, Saif Ahmad, Sadanand T. Fulzele, Mohammad Naime, Sally El-Shafey, Gregory I. Liou; Adenosine Agonist Combating Inflammation In Traumatic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2986.
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Traumatic optic neuropathy (TON) is an irreversible vision-threatening complication often found in head injuries. Following optic nerve trauma, the body’s innate immune cells scavenge the trauma site for debris while releasing cytokines that cause additional damage and cell death beyond that of the initial insult. While neuronal cell loss stemming directly from the initial insult is irreversible, the secondary inflammation from cytokine release may be prevented. The purpose of our study is to further elucidate mechanisms by which exogenous agonists can effect anti-inflammation and ultimately curb the damage from TON before it is irreversible. Under stress or ischemia such as TON, local tissue concentrations of adenosine are likely to increase due to the release of ATP and its conversion to adenosine by ectonucleotidases including CD73. The released adenosine is anti-inflammatory, as seen in other organ systems, by stimulating the adenosine receptor A2AAR. We tested the hypothesis that the A2AAR agonist (CGS21680) is of therapeutic utility in TON.
Standard protocol was used to anesthetize mice followed by unilateral optic nerve crush in each mouse, with contralateral nerve serving as control. Mice were then either left untreated or treated every other day with an A2AAR agonist, CGS21680, and retinas or whole eyes were then harvested after 7 days for RT-PCR, Western blot, analysis of oxidative stress and cell death, and histology.
RT-PCR showed increased mRNA expression of TNF-α, Iba-1, A2AAR, and CD73 in nerve crush model. In subgroup of nerve crush model that was treated with agonist, lower mRNA expression was noted. Mouse retinas with TON demonstrated higher levels of microglial activity, reactive oxygen species, and ganglion cell death as compared with retinas without TON. All the TON-associated retinal damages and microglial activity were reduced by treatment as compared to control.
TON causes retinal ganglion cell injury that may trigger microglial activation followed by pro-inflammatory cytokine release and further cell death. Therefore, curbing microglial activation may be a way to treat TON. Our results suggest that TON can be effectively treated with selective adenosine receptor agonists which ameliorate inflammation by activating A2AAR, thereby reducing adverse effects of microglial cell activity.
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