Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Abstract

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function

“…Fasudil is also used in the treatment of glaucoma [191], pulmonary hypertension [190], and coronary vasospam [190]. Recently, other RhoA/ROCK inhibitors have been proposed as treatments for sepsis cardiovascular complications [192] and diabetic macular edema [193]. It has also been suggested to be beneficial in the management of Raynaud's disease [100,105,106,194] and multiple sclerosis [195].…”

Neuroprotective effects of nobiletin on cerebral ischemia/reperfusion injury rats by inhibiting Rho/ROCK signaling pathway

“…The Rho/ROCK signaling pathway inhibitor, fasudil, attenuates chemical-induced nephrotoxicity, inhibits inflammatory factors, apoptotic factors, fibrogenic factors, schistin-activated proteases, and nitrogen oxidation pathways, and improves nephrotic conditions ( 50 ). The novel, specific ROCK2 inhibitor, FSD-C10, induces axon growth, BV-2 microglial cell network formation, and promotes the production of brain-derived and glial cell lineage neurotrophic factors ( 51 ).…”

The Application of Rho Kinase Inhibitors in the Management of Glaucoma

“…ROCK inhibitors also play a significant role in the management of diabetic retinopathy (DR). The ROCK signaling pathway upregulates vascular endothelial growth factors (VEGFs), which are pivotal in the pathogenesis of microvascular complications such as increased retinal vessel permeability, macular edema, vascular occlusion, and retinal ischemia in diabetic patients [ 91 ]. Over the past decade, numerous in vitro and in vivo studies have explored the effects of ROCK pathway inhibition on DR and diabetic macular edema (DME), consistently yielding positive outcomes [ 91 , 92 ].…”