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T. Puthussery, W. R. Taylor, R. M. Duvoisin, E. L. Fletcher; Neuroprotective Effects of a Purinergic Receptor Antagonist in the rd1 Mouse Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2077. doi: https://doi.org/.
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Purinergic receptors have been implicated in neuronal degeneration in the central nervous system, and we have previously demonstrated that high concentrations of ATP can induce extensive and selective degeneration of photoreceptors in the normal rat retina through activation of P2X receptors. This study extends on these findings by evaluating the efficacy of a purinergic antagonist as a neuroprotective agent in the rd1 mouse model of Retinitis Pigmentosa. We also evaluated functional responses of ON bipolar cells in adult rd1 mice to establish whether bipolar cell dysfunction would be prohibitive to successful photoreceptor replacement in late-stage disease.
Mice homozygous for the rd1 mutation were treated at postnatal day 14 with an intravitreal injection of the purinergic antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and a fellow eye sham injection of PBS. Retinal tissue was collected at postnatal day 21, and rod photoreceptor survival was compared in drug and sham-treated eyes by immunohistochemical labelling for rhodopsin. A separate cohort of untreated adult (postnatal day 70) rd1 mice was used for electrophysiological studies using the whole-cell patch-clamp technique. Pharmacologically-simulated light responses were recorded from ON-bipolar cells in retinal slices of rd1 mutants and wild-type mice.
For neuroprotection studies, we found that PPADS treatment resulted in a significant increase in rod photoreceptor survival at P21. The number of surviving rod photoreceptors in PPADS treated eyes was, on average, 30% higher than matched PBS treated controls (P = 0.0112, paired t-test, n =13). Electrophysiological assessment of bipolar cell function in untreated adult rd1 mice revealed profound impairment of ON bipolar cell responses. Only 15% of cells showed any functional response, and these responses were vastly attenuated in comparison to recordings from wild-type retina.
These findings highlight the importance of extracellular ATP in retinal degeneration and provide a potential new avenue for therapeutic intervention in RP. Aberrant bipolar cell function in late-stage degeneration is likely to limit the success of photoreceptor replacement, thereby highlighting the need for early neuroprotective intervention.
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