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Erica L. Fletcher, Kirstan A. Vessey, Andrew I. Jobling; The Role Of P2X7 Receptors In Exacerbating Photoreceptor Death In The Rd1 Mouse Model Of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1843.
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Factors released from dying rods have been suggested to exacerbate photoreceptor death during retinal degeneration and may also play a role in cone death. Adenosine tri-phosphate (ATP) acts as a neurotransmitter by stimulating P2X or P2Y purinoceptors, and has been implicated in neuronal death in other regions of the CNS. The aim of this study was to investigate the role of the P2X7R in the rd1 mouse model of retinal degeneration.
Expression of P2X7R, and the vesicular nucleotide transporter, VNUT, in the inner and outer retina of adult wildtype mice was assessed using laser capture microdissection and RT-PCR. We quantified the expression of P2X7R and one of the enzymes responsible for degradation of ATP, NTPdase1, in retina of rd1 mice and C57Bl6 control mice (n=16 each) at postnatal day 14 (P14) using quantitative PCR. The rd1 mouse line was crossed with a P2X7R null mouse to generate a P2X7Rnull/rd1 mouse. Photoreceptor numbers were quantified, photoreceptor apoptosis (TUNEL) and the inflammatory response was assessed by counting microglia in rd1 (n=6) and P2X7Rnull/rd1 (n=6) mice at P14 and P18. Finally, we injected the non-specific P2X receptor antagonist, TNP-ATP, intravitreally into one eye of P14 rd1 mice and evaluated photoreceptor number at P21 (N=10).
We found that the photoreceptors of the mouse expressed both P2X7R and the VNUT. Both P2X7-R and NTPdase1 mRNA expression were more than doubled in rd1 mice at P14 (p<0.001), implicating a role for this pathway in retinal degeneration. Rd1 mice lacking the P2X7R had 30% more photoreceptors than the control rd1 mice at P14 (p<0.01). In addition, there were around 35% less microglia in the photoreceptor layer of P2X7Rnull/rd1 mice (p<0.01) indicating a reduced inflammatory response in these mice. Treatment with TNP-ATP significantly reduced photoreceptor death in rd1 mice at P21 compared with sham injected rd1 retinae.
These results suggest blockade of the P2X7R may be a useful therapy in slowing photoreceptor death in retinal degeneration. Inhibition of the P2X7R may reduce photoreceptor death by blocking direct neurotoxicity mediated by extracellular ATP and indirect toxicity mediated by the inflammatory response of microglia.
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