Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib

Nimish K. Acharya, Xin Qi, Eric L. Goldwaser, George A. Godsey, Hao Wu, Mary C. Kosciuk, Theresa A. Freeman, Colin H. Macphee, Robert L. Wilensky, Venkateswar Venkataraman, Robert Nagele

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood-retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood-retina barrier permeability that may be linked to altered expression of blood-retina barrier-associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.

Original languageEnglish (US)
Pages (from-to)200-213
Number of pages14
JournalDiabetes and Vascular Disease Research
Volume14
Issue number3
DOIs
StatePublished - Jan 1 2017

Fingerprint

Retina
Permeability
Swine
Pathology
Hypercholesterolemia
Diabetes Mellitus
Diabetic Retinopathy
Blood Vessels
Immunoglobulin G
1-Alkyl-2-acetylglycerophosphocholine Esterase
Occludin
Tight Junction Proteins
Eye Diseases
Pyramidal Cells
Glial Fibrillary Acidic Protein
Macular Degeneration
Blood-Brain Barrier
Amyloid
Ganglia
Cerebral Cortex

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Acharya, Nimish K. ; Qi, Xin ; Goldwaser, Eric L. ; Godsey, George A. ; Wu, Hao ; Kosciuk, Mary C. ; Freeman, Theresa A. ; Macphee, Colin H. ; Wilensky, Robert L. ; Venkataraman, Venkateswar ; Nagele, Robert. / Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model : Beneficial effects of the LpPLA2 inhibitor Darapladib. In: Diabetes and Vascular Disease Research. 2017 ; Vol. 14, No. 3. pp. 200-213.
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abstract = "Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood-retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in M{\"u}ller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood-retina barrier permeability that may be linked to altered expression of blood-retina barrier-associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.",
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Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model : Beneficial effects of the LpPLA2 inhibitor Darapladib. / Acharya, Nimish K.; Qi, Xin; Goldwaser, Eric L.; Godsey, George A.; Wu, Hao; Kosciuk, Mary C.; Freeman, Theresa A.; Macphee, Colin H.; Wilensky, Robert L.; Venkataraman, Venkateswar; Nagele, Robert.

In: Diabetes and Vascular Disease Research, Vol. 14, No. 3, 01.01.2017, p. 200-213.

Research output: Contribution to journalArticle

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AU - Qi, Xin

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AU - Nagele, Robert

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