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Alfred S. Lewin, Haoyu Mao, Hong Li, Soojung S. Gibson, Xiaoping Qi, Michael E. Boulton, Carl Romano; 8-OH DPAT-Mediated Neuroprotection in a Mouse Model of Atrophic Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):941.
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We have previously shown that a) the generic 5-HT1A agonist, 8OH DPAT, can reduce oxidative stress and lipofuscin accumulation in cultured RPE cells (Thampi et al, ARVO 2010) and b) systemic or topical administration of 5-HT1A agonists protected the rat retina from exposure to blue light (Collier et al. IOVS 10-6304). The aim of this study was to determine if 8-OH DPAT was able to protect against retinal degeneration in the SOD2 knockdown mouse model of dry age related macular degeneration (AMD).
C57Bl/6 mice were injected in one eye with an AAV1 virus expressing a ribozyme specific for SOD2 mRNA, which encodes MnSOD. Expression was driven by the RPE-specific VMD2 promoter. The other eye was injected with AAV1 expressing mCherry. Mice were randomly assigned to 3 groups and received daily subcutaneous injections of sterile saline or of 0.5 mg/kg or 5 mg/kg 8-OH DPAT (in sterile saline) daily. At monthly intervals, full field scotopic electroretinography (ERG) amplitudes were measured in all mice, and ONL thickness was assessed by spectral domain optical coherence tomography (SD-OCT).
Injection of the AAV-SOD2 ribozyme (Rz) led to a progressive reduction in maximum a-and b-wave amplitudes over the first 3 months of the study. The drug was well tolerated by mice at both dosages. 8-OH DPAT led to a 40% increase in the a-wave amplitude and a 45% increase in b-wave amplitude over a 3 month period (p<0.05) compared to saline treated mice, but the drug had no impact on the control injected eyes. Three months after administration AAV-SOD2-Rz, drug treatment led to a small (10%) but statistically significant (p<0.006) increase in ONL thickness measured by OCT. Morphological analyses confirmed our findings.
Systemic treatment with the 5HT1A agonist, 8-OH DPAT, reduced the impact of oxidative stress in the RPE and preserved retinal function and structure over a prolonged period in a mouse model of dry AMD. 5HT1A agonists therefore may have utility in the treatment of dry AMD.
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