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Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved May 6, 2016 (received for review November 4, 2015)
Significance
The role of sigma 1 receptor (Sig1R) in rescuing cone photoreceptor function was investigated in Pde6βrd10 (rd10) mice, a model of severe retinal degeneration. Sig1R, a putative molecular chaperone, is implicated in several human neurodegenerative diseases. We administered (+)-pentazocine, a high-affinity Sig1R ligand, to rd10 mice, which lose rod and subsequently cone photoreceptor cells (PRC) within the first few weeks of life, rendering them completely blind. Regular administration of (+)-pentazocine rescued cone PRC responses, which were markedly preserved and were similar to those in wild-type mice. To our knowledge, this is the first demonstration of significant preservation of retinal function as a consequence of Sig1R activation. The data are highly relevant to potential therapeutic interventions in human retinal disease.
Abstract
Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6βrd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R−/− mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.
Footnotes
- ↵1To whom correspondence should be addressed. Email: sbsmith{at}augusta.edu.
Author contributions: J.W., A.S., and S.B.S. designed research; J.W., A.S., and P.R. performed research; J.W., A.S., and S.B.S. analyzed data; and S.B.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1521749113/-/DCSupplemental.
Sig1R activation preserves retinal cone function
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