Abstract
Purpose :
Much effort is focused on strategies to rescue structure and function during retinal ischemia/reperfusion injury (RI/RI) in murine models where the macula is absent and retinal vessels have a spoke-and-wheel architecture. We describe the features of a new RI/RI model in NHPs that may facilitate the translation of interventions for humans.
Methods :
We cannulated the right eye of 9 rhesus macaque monkeys (4 female / 5 males; ages 3-6 years) with a needle attached to a normal saline reservoir set at 1.9 m above eye level for 90 minutes, producing sustained intraocular pressure of 140 mmHg. After RI/RI, we performed fundus photography, OCT, ERG, and VEP at various points over 2 months. Terminal experiments involved Brn-3a immunostaining, GFAP staining, and qPCR to assess retinal inflammatory biomarkers. Unpaired t-tests were performed to assess differences in injured and uninjured eyes.
Results :
An insignificant global RNFL thickness increase was noted on day 7 (12±20μm OD vs. 1±1μm OS; P=0.13 vs. OS) which was followed by significant declines starting on day 21 in injured eyes (P<0.001 vs. OS). Compared to baseline, mean central total retinal thickness declined significantly, beginning at day 7 (-44±27μm OD vs. -1±4μm OS; P=0.004), extending to day 63 (-84±22μm OD vs. -2±3μm OS; P<0.0001). On day 7, significant declines in amplitudes of the light-adapted a-wave (7.9±5.1μv), b-wave (21.1±12.5μv), and VEP N2-P2 (17.0±12.7μv) were noted compared to pre-induction (22.7±4.6μv, 63.4±15.0μv, and 39.9±7.4μv for the a-wave, b-wave, and VEP N2-P2, respectively; P≤0.0024) with minimal recovery by day 63 (10.3±5.1μv, 27.1±13.8μv and 22.0±16.9μv for the a-wave, b-wave, and VEP N2-P2, respectively; P≤0.035). Terminal experiments performed at 2 months revealed a 73% decline in total RGC counts (n=3; P=0.0034 vs. OS) and a 5-fold astrocytic activation versus the uninjured eyes (n=3; P=0.007). Marked increases in TNF alpha (26.4-fold), interferon-gamma (40-fold), and interleukin-1beta (10.5-fold) were also noted on qPCR (P≤0.019 vs. OS, 3 injured vs. 6 uninjured eyes).
Conclusions :
The structural and functional insults demonstrated in this nonhuman primate model of RI/RI mimic those encountered in comparable human conditions and may serve as a useful tool to translate promising interventions into viable treatment approaches.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.