Oral targeting of protein kinase C receptor: promising route for diabetic retinopathy?

Area of Science:

• Biochemistry
• Ophthalmology
• Pharmacology

Background:

• Hyperglycemia in diabetes elevates diacylglycerol, activating protein kinase C (PKC) in vascular tissues.
• PKC activation and increased vascular endothelial growth factor (VEGF) contribute to diabetic microvascular complications in the retina, including vascular permeability, inflammation, fluid leakage, and ischemia.

Purpose of the Study:

• To explore the role of PKC and VEGF in diabetic retinopathy.
• To evaluate the therapeutic potential of targeting specific PKC isomers, particularly PKC βII, for diabetic vascular disease.

Main Methods:

• Review of existing literature on PKC, VEGF, and diabetic retinopathy.
• Discussion of therapeutic strategies including PKC isomer-selective inhibitors and VEGF traps.
• Analysis of Ruboxistaurin, a PKC βII inhibitor, in Phase III trials for diabetic retinopathy.

Main Results:

• PKC activation and elevated VEGF are implicated in the pathogenesis of diabetic retinopathy.
• PKC comprises 12 isomers with distinct properties, suggesting isomer-selective inhibition as a therapeutic approach.
• Ruboxistaurin targets PKC βII, showing potential for treating diabetic retinopathy, but oral administration raises toxicity concerns due to widespread PKC βII distribution.

Conclusions:

• Targeting PKC βII isomer with Ruboxistaurin is a promising therapeutic strategy for diabetic retinopathy.
• The widespread distribution of PKC βII necessitates careful consideration of drug delivery methods.
• Ocular delivery may offer a safer alternative to oral administration for Ruboxistaurin to mitigate systemic toxicity in diabetic retinopathy treatment.