Small Molecule Kinase Inhibitors Prevent Blood Vessel Degeneration in Diabetic Retinopathy

A class of low molecular weight 2-amino-4-phenyl-thiophene compounds were identified that inhibits the activity of the enzyme atypical protein kinase C (aPKC) and preserves the blood-retinal barrier (BRB) in retinal diseases such as diabetic retinopathy or uveitis, and the blood-brain barrier (BBB) in the presence of brain tumors.

Diabetic retinopathy is the result of microvascular retinal changes. Hyperglycemia-induced intramural pericyte death and thickening of the basement membrane lead to incompetence of the vascular walls. These damages change the formation of the blood-retinal barrier and also make the retinal blood vessels become more permeable. Pericytes provide a variety of functions such as capillary blood flow regulation, clearance, and phagocytosis of cellular debris, and regulating blood–brain barrier permeability. A lack of pericytes in the central nervous system can cause a breakdown of the blood–brain barrier and lead to other degenerative changes in the brain.

Proinflammatory cytokines and growth factors such as vascular endothelial growth factor (VEGF) contribute to the loss of the BRB and subsequent bleeding into the retina. VEGF signaling requires conventional PKC (PKC-beta) activity. However, PKC-beta inhibition only partially prevents VEGF-induced endothelial permeability and does not affect proinflammatory cytokine-induced permeability suggesting the involvement of alternative signaling pathways.

In a paper published in the June 22, 2012, online edition of the Biochemical Journal investigators at the University of Michigan Kellogg Eye Center (Ann Arbor, USA) provided evidence for the involvement of atypical protein kinase C (aPKC) signaling in VEGF-induced endothelial permeability. In addition, the investigators employed an in vitro kinase assay to screen a chemical library for novel small molecule inhibitors of aPKC.

They reported finding a class of 2-amino-4-phenyl-thiophene derivatives that blocked VEGF-induced tight junction internalization and prevented VEGF induction of retinal endothelial permeability in both primary cell cultures and in rodent retina.

“This is a great leap forward,” said senior author Dr. David A. Antonetti, professor of ophthalmology and visual sciences at the University of Michigan. “We have identified an important target in regulating blood vessel leakage in the eye and we have a therapy that works in animal models. Our research is in the early stages of development. We still have a long way to go to demonstrate effectiveness of this compound in humans to create a new therapy, but the results are very promising.”

“In diabetic retinopathy and a host of other retinal diseases, increases in VEGF and inflammatory factors - some of the same factors that contribute to the response to an infection - cause blood vessels in the eye to leak which, in turn, results in a buildup of fluid in the neural tissue of the retina,” said Dr. Antonetti. “This insidious form of modified inflammation can eventually lead to blindness.”

Related Links:
University of Michigan Kellogg Eye Center