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Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK.

Toutounchian JJ, Steinle JJ, Makena PS, Waters CM, Wilson MW, Haik BG, Miller DD, Yates CR - PLoS ONE (2014)

Bottom Line: Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV.Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone.Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.

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KZ-41 reduces ischemic retinopathy/RNV: Avascular area.A–D) representative flat-mounted retinas stained for endothelial cells using isolectin-B4 (red) from eyes harvested at P17: Normoxia, OIR, OIR+V, OIR+KZ-41, respectively. Mice received daily ocular administration of either KZ-41 (100 mg/kg) or vehicle (ocular nanoemulsion) from P12 to P17. Avascular area was determined using software-assisted analysis; shown in white. OIR mice show significant avascular area as compared to normoxia controls (*P<0.001). KZ-41 lowered area percent avascular area by nearly 50% (#P<0.001). Images were acquired at 10x magnification and digitally stitched together to show the entire retinal vasculature. Data represent mean (± SD). N = 5/group.
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pone-0100210-g007: KZ-41 reduces ischemic retinopathy/RNV: Avascular area.A–D) representative flat-mounted retinas stained for endothelial cells using isolectin-B4 (red) from eyes harvested at P17: Normoxia, OIR, OIR+V, OIR+KZ-41, respectively. Mice received daily ocular administration of either KZ-41 (100 mg/kg) or vehicle (ocular nanoemulsion) from P12 to P17. Avascular area was determined using software-assisted analysis; shown in white. OIR mice show significant avascular area as compared to normoxia controls (*P<0.001). KZ-41 lowered area percent avascular area by nearly 50% (#P<0.001). Images were acquired at 10x magnification and digitally stitched together to show the entire retinal vasculature. Data represent mean (± SD). N = 5/group.

Mentions: The most frequently used in vivo model for studying the effect of genomic or pharmacologic manipulation of key signaling proteins on the natural history of proliferative retinopathies (e.g., RR) is the murine oxygen-induced retinopathy (OIR) model [40], [41], [43]. In the murine OIR model, retinal expression of phosphorylated p38MAPK is enhanced [59]. We used the OIR model to test the hypothesis that KZ-41 would prevent RNV driven by oxidative stress and ischemic injury. Mouse pups received daily ocular administration of either KZ-41 (100 mg/kg; treated eye) or vehicle (ophthalmic NE; contralateral eye) from P12 to P17. As shown in Figure 7 (A–D; Normoxia-N17, OIR17-untreated, OIR17+Vehicle, and OIR17+KZ-41), hyperoxia led to significant vaso-obliteration of the central retina of mouse pups (P7–P12). Both untreated and vehicle-treated retinas showed significantly larger avascular areas surrounding the optic disc as compared to normoxia controls (Fig. 7A–C, 20.5±1.8, 18.6±3.1 vs. 4.4±1.1 AV% area, *P<0.001). Significant neovascularization was also noted in both untreated and vehicle-treated retinas when compared to normoxia controls (Fig. 8A–C, 24.7±2.3, 22.3±1.4 vs. 0.76±0.28 NV% area, *P<0.005). Neither total avascularity nor neovascularization differed between untreated and vehicle-treated retinas (Figs. 7B,C and 8B,C; P>0.05). KZ-41 significantly reduced avascularity (8.6 vs. 18.6 AV% area, #P<0.001) and neovascularization (16.5 vs. 22.3 NV% area, #P<0.01) compared to vehicle-control retinas (Figs. 7C,D and 8C,D). These results suggest that KZ-41 reduces the extent of pathological RNV while not affecting normal revascularization under OIR conditions.


Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK.

Toutounchian JJ, Steinle JJ, Makena PS, Waters CM, Wilson MW, Haik BG, Miller DD, Yates CR - PLoS ONE (2014)

KZ-41 reduces ischemic retinopathy/RNV: Avascular area.A–D) representative flat-mounted retinas stained for endothelial cells using isolectin-B4 (red) from eyes harvested at P17: Normoxia, OIR, OIR+V, OIR+KZ-41, respectively. Mice received daily ocular administration of either KZ-41 (100 mg/kg) or vehicle (ocular nanoemulsion) from P12 to P17. Avascular area was determined using software-assisted analysis; shown in white. OIR mice show significant avascular area as compared to normoxia controls (*P<0.001). KZ-41 lowered area percent avascular area by nearly 50% (#P<0.001). Images were acquired at 10x magnification and digitally stitched together to show the entire retinal vasculature. Data represent mean (± SD). N = 5/group.
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pone-0100210-g007: KZ-41 reduces ischemic retinopathy/RNV: Avascular area.A–D) representative flat-mounted retinas stained for endothelial cells using isolectin-B4 (red) from eyes harvested at P17: Normoxia, OIR, OIR+V, OIR+KZ-41, respectively. Mice received daily ocular administration of either KZ-41 (100 mg/kg) or vehicle (ocular nanoemulsion) from P12 to P17. Avascular area was determined using software-assisted analysis; shown in white. OIR mice show significant avascular area as compared to normoxia controls (*P<0.001). KZ-41 lowered area percent avascular area by nearly 50% (#P<0.001). Images were acquired at 10x magnification and digitally stitched together to show the entire retinal vasculature. Data represent mean (± SD). N = 5/group.
Mentions: The most frequently used in vivo model for studying the effect of genomic or pharmacologic manipulation of key signaling proteins on the natural history of proliferative retinopathies (e.g., RR) is the murine oxygen-induced retinopathy (OIR) model [40], [41], [43]. In the murine OIR model, retinal expression of phosphorylated p38MAPK is enhanced [59]. We used the OIR model to test the hypothesis that KZ-41 would prevent RNV driven by oxidative stress and ischemic injury. Mouse pups received daily ocular administration of either KZ-41 (100 mg/kg; treated eye) or vehicle (ophthalmic NE; contralateral eye) from P12 to P17. As shown in Figure 7 (A–D; Normoxia-N17, OIR17-untreated, OIR17+Vehicle, and OIR17+KZ-41), hyperoxia led to significant vaso-obliteration of the central retina of mouse pups (P7–P12). Both untreated and vehicle-treated retinas showed significantly larger avascular areas surrounding the optic disc as compared to normoxia controls (Fig. 7A–C, 20.5±1.8, 18.6±3.1 vs. 4.4±1.1 AV% area, *P<0.001). Significant neovascularization was also noted in both untreated and vehicle-treated retinas when compared to normoxia controls (Fig. 8A–C, 24.7±2.3, 22.3±1.4 vs. 0.76±0.28 NV% area, *P<0.005). Neither total avascularity nor neovascularization differed between untreated and vehicle-treated retinas (Figs. 7B,C and 8B,C; P>0.05). KZ-41 significantly reduced avascularity (8.6 vs. 18.6 AV% area, #P<0.001) and neovascularization (16.5 vs. 22.3 NV% area, #P<0.01) compared to vehicle-control retinas (Figs. 7C,D and 8C,D). These results suggest that KZ-41 reduces the extent of pathological RNV while not affecting normal revascularization under OIR conditions.

Bottom Line: Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV.Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone.Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

ABSTRACT
Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.

Show MeSH
Related in: MedlinePlus