The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes
Purpose In diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good...
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| Veröffentlicht in: | Acta ophthalmologica (Oxford, England) England), 2017-09, Vol.95 (S259), p.n/a |
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| creator | Allen, C. Horton, K. Malhi, N. Batson, J. Bates, D. |
| description | Purpose
In diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good penetration properties to the retina, have been shown to inhibit choroidal neovascularisation in mice as eye drops by decreasing pro‐angiogenic and increasing anti‐angiogenic VEGF isoforms. SRPK1 inhibitors such as SPHINX31 may therefore switch splicing in DR and prevent increased vascular permeability.
Methods
FFA was performed in Norway Brown rats on day 0 and 7, using the Micron IV retinal microscope (Phoenix Research). Animals received twice daily topical eye drops with eye formulation only control buffer (n = 5) or SPHINX31 (200 μg/ml, n = 6). On day 1 animals received a single dose of streptozotocin (50 mg/kg, i.p.) to induce type I diabetes and maintained for 1 week without insulin. The ratio of interstitial to vascular fluorescence was calculated and plotted against time to determine an estimate of permeability.
Results
Retinal permeability (12.67 ± 1.09 × 10−4 cms−1) was shown to significantly increase (p |
| doi_str_mv | 10.1111/j.1755-3768.2017.0F066 |
| format | Article |
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In diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good penetration properties to the retina, have been shown to inhibit choroidal neovascularisation in mice as eye drops by decreasing pro‐angiogenic and increasing anti‐angiogenic VEGF isoforms. SRPK1 inhibitors such as SPHINX31 may therefore switch splicing in DR and prevent increased vascular permeability.
Methods
FFA was performed in Norway Brown rats on day 0 and 7, using the Micron IV retinal microscope (Phoenix Research). Animals received twice daily topical eye drops with eye formulation only control buffer (n = 5) or SPHINX31 (200 μg/ml, n = 6). On day 1 animals received a single dose of streptozotocin (50 mg/kg, i.p.) to induce type I diabetes and maintained for 1 week without insulin. The ratio of interstitial to vascular fluorescence was calculated and plotted against time to determine an estimate of permeability.
Results
Retinal permeability (12.67 ± 1.09 × 10−4 cms−1) was shown to significantly increase (p < 0.01) in diabetics compared to before diabetes (8.85 ± 1.29 × 10−4 cms−1) in the eye formulation control group. Following a weekly regimen of twice daily topical eye drop treatment with SPHINX31 retinal permeability was no greater in the diabetics than (7.92 ± 1.65 × 10−4 cms−1) than before induction of diabetes, (8.15 ± 2.33 × 10−4 cms−1) and in the control group.
Conclusions
SPHINX31 protected the retinal endothelial permeability barrier from diabetes‐associated loss of integrity. SPHINX31 may therefore be a potential alternative and more specific topical therapeutic for DR.</description><identifier>ISSN: 1755-375X</identifier><identifier>EISSN: 1755-3768</identifier><identifier>DOI: 10.1111/j.1755-3768.2017.0F066</identifier><language>eng</language><publisher>Malden: Wiley Subscription Services, Inc</publisher><subject>Angiogenesis ; Animals ; Diabetes ; Diabetes mellitus ; Diabetic retinopathy ; Eye ; Fluorescence ; Inhibitors ; Insulin ; Ischemia ; Isoforms ; Kinases ; Microvasculature ; Permeability ; Protein kinase ; Rats ; Retina ; Retinopathy ; Splicing ; Streptozocin ; Vascular endothelial growth factor</subject><ispartof>Acta ophthalmologica (Oxford, England), 2017-09, Vol.95 (S259), p.n/a</ispartof><rights>2017 The Authors Acta Ophthalmologica © 2017 Acta Ophthalmologica Scandinavica Foundation</rights><rights>Copyright © 2017 Acta Ophthalmologica Scandinavica Foundation</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1755-3768.2017.0F066$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45551,46808</link.rule.ids></links><search><creatorcontrib>Allen, C.</creatorcontrib><creatorcontrib>Horton, K.</creatorcontrib><creatorcontrib>Malhi, N.</creatorcontrib><creatorcontrib>Batson, J.</creatorcontrib><creatorcontrib>Bates, D.</creatorcontrib><title>The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes</title><title>Acta ophthalmologica (Oxford, England)</title><description>Purpose
In diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good penetration properties to the retina, have been shown to inhibit choroidal neovascularisation in mice as eye drops by decreasing pro‐angiogenic and increasing anti‐angiogenic VEGF isoforms. SRPK1 inhibitors such as SPHINX31 may therefore switch splicing in DR and prevent increased vascular permeability.
Methods
FFA was performed in Norway Brown rats on day 0 and 7, using the Micron IV retinal microscope (Phoenix Research). Animals received twice daily topical eye drops with eye formulation only control buffer (n = 5) or SPHINX31 (200 μg/ml, n = 6). On day 1 animals received a single dose of streptozotocin (50 mg/kg, i.p.) to induce type I diabetes and maintained for 1 week without insulin. The ratio of interstitial to vascular fluorescence was calculated and plotted against time to determine an estimate of permeability.
Results
Retinal permeability (12.67 ± 1.09 × 10−4 cms−1) was shown to significantly increase (p < 0.01) in diabetics compared to before diabetes (8.85 ± 1.29 × 10−4 cms−1) in the eye formulation control group. Following a weekly regimen of twice daily topical eye drop treatment with SPHINX31 retinal permeability was no greater in the diabetics than (7.92 ± 1.65 × 10−4 cms−1) than before induction of diabetes, (8.15 ± 2.33 × 10−4 cms−1) and in the control group.
Conclusions
SPHINX31 protected the retinal endothelial permeability barrier from diabetes‐associated loss of integrity. SPHINX31 may therefore be a potential alternative and more specific topical therapeutic for DR.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic retinopathy</subject><subject>Eye</subject><subject>Fluorescence</subject><subject>Inhibitors</subject><subject>Insulin</subject><subject>Ischemia</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Microvasculature</subject><subject>Permeability</subject><subject>Protein kinase</subject><subject>Rats</subject><subject>Retina</subject><subject>Retinopathy</subject><subject>Splicing</subject><subject>Streptozocin</subject><subject>Vascular endothelial growth factor</subject><issn>1755-375X</issn><issn>1755-3768</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNo9kFFrwjAUhcPYYM7tL4zAntslTZO2sBeROWUyZfrgW0jaW0yptkuqw3-_VIf35RzuOVwuH0LPlITUz2sV0oTzgCUiDSNCk5BMiBA3aHBd314939yjB-cqQgQVIh4gvd4CXn0vPyk2-63RpmssXi2ns68No7i1cIR953yWW1AOCmyhM3tV4xbsDpQ2telOPsYK26bwXbzzUuOmxIVRGjpwj-iuVLWDp38dovXkfT2eBvPFx2w8mgdtSkUAEYGkKBIVs5yxmFOuU5ZS_32ZqTTnOitzoYFxpUVJNM8hjrJIFJHOBZQZZUP0cjnb2ubnAK6TVXOw_lUnacZEFKeMct96u7R-TQ0n2VqzU_YkKZE9S1nJHpTsocmepTyzlKPF6mzYH-NAaac</recordid><startdate>201709</startdate><enddate>201709</enddate><creator>Allen, C.</creator><creator>Horton, K.</creator><creator>Malhi, N.</creator><creator>Batson, J.</creator><creator>Bates, D.</creator><general>Wiley Subscription Services, Inc</general><scope>7TK</scope></search><sort><creationdate>201709</creationdate><title>The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes</title><author>Allen, C. ; Horton, K. ; Malhi, N. ; Batson, J. ; Bates, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p816-e20e7dd7a43c334515b8381768f9a8c5b9fc6be35ab6f0b5ce42926d2bc6ef913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetic retinopathy</topic><topic>Eye</topic><topic>Fluorescence</topic><topic>Inhibitors</topic><topic>Insulin</topic><topic>Ischemia</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Microvasculature</topic><topic>Permeability</topic><topic>Protein kinase</topic><topic>Rats</topic><topic>Retina</topic><topic>Retinopathy</topic><topic>Splicing</topic><topic>Streptozocin</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Allen, C.</creatorcontrib><creatorcontrib>Horton, K.</creatorcontrib><creatorcontrib>Malhi, N.</creatorcontrib><creatorcontrib>Batson, J.</creatorcontrib><creatorcontrib>Bates, D.</creatorcontrib><collection>Neurosciences Abstracts</collection><jtitle>Acta ophthalmologica (Oxford, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Allen, C.</au><au>Horton, K.</au><au>Malhi, N.</au><au>Batson, J.</au><au>Bates, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes</atitle><jtitle>Acta ophthalmologica (Oxford, England)</jtitle><date>2017-09</date><risdate>2017</risdate><volume>95</volume><issue>S259</issue><epage>n/a</epage><issn>1755-375X</issn><eissn>1755-3768</eissn><abstract>Purpose
In diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good penetration properties to the retina, have been shown to inhibit choroidal neovascularisation in mice as eye drops by decreasing pro‐angiogenic and increasing anti‐angiogenic VEGF isoforms. SRPK1 inhibitors such as SPHINX31 may therefore switch splicing in DR and prevent increased vascular permeability.
Methods
FFA was performed in Norway Brown rats on day 0 and 7, using the Micron IV retinal microscope (Phoenix Research). Animals received twice daily topical eye drops with eye formulation only control buffer (n = 5) or SPHINX31 (200 μg/ml, n = 6). On day 1 animals received a single dose of streptozotocin (50 mg/kg, i.p.) to induce type I diabetes and maintained for 1 week without insulin. The ratio of interstitial to vascular fluorescence was calculated and plotted against time to determine an estimate of permeability.
Results
Retinal permeability (12.67 ± 1.09 × 10−4 cms−1) was shown to significantly increase (p < 0.01) in diabetics compared to before diabetes (8.85 ± 1.29 × 10−4 cms−1) in the eye formulation control group. Following a weekly regimen of twice daily topical eye drop treatment with SPHINX31 retinal permeability was no greater in the diabetics than (7.92 ± 1.65 × 10−4 cms−1) than before induction of diabetes, (8.15 ± 2.33 × 10−4 cms−1) and in the control group.
Conclusions
SPHINX31 protected the retinal endothelial permeability barrier from diabetes‐associated loss of integrity. SPHINX31 may therefore be a potential alternative and more specific topical therapeutic for DR.</abstract><cop>Malden</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1111/j.1755-3768.2017.0F066</doi><tpages>1</tpages></addata></record> |
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| subjects | Angiogenesis Animals Diabetes Diabetes mellitus Diabetic retinopathy Eye Fluorescence Inhibitors Insulin Ischemia Isoforms Kinases Microvasculature Permeability Protein kinase Rats Retina Retinopathy Splicing Streptozocin Vascular endothelial growth factor |
| title | The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes |
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