Comparisons of actin filament disruptors and Rho kinase inhibitors as potential antiglaucoma medications

Abstract

Dynamics of the actin cytoskeleton in the trabecular meshwork play a crucial role in the regulation of trabecular outflow resistance. The actin filament disruptors and Rho kinase inhibitors affect the dynamics of the actomyosin system by either disrupting the actin filaments or inhibiting the Rho kinase-activated cellular contractility. Both approaches induce similar morphological changes and resistance decreases in the trabecular outflow pathway, and thus both have potential as antiglaucoma medications. Although the drugs might induce detrimental changes in the cornea following topical administration, lower drug concentrations in larger volumes as used clinically, but not higher drug concentrations in smaller volumes as used experimentally, could minimize corneal toxicity. Additionally, developments of trabecular meshwork-specific actin filament disruptors or Rho kinase inhibitors, prodrugs and new drug-delivery methods might avoid the drugs’ toxicity to the cornea. Gene therapies with cytoskeleton-modulating proteins may mimic the effects of the cytoskeleton-modulating agents and have the potential to permanently decrease trabecular outflow resistance.

Keywords::

• actin filament disruptor
• actomyosin
• cytoskeleton
• glaucoma
• intraocular pressure
• outflow facility
• Rho kinase inhibitor
• trabecular meshwork

Acknowledgements

This article was supported by grants from the US National Eye Institute (EY002698 and EY016665), Research to Prevent Blindness, the Wisconsin Alumni Research Foundation, and the Ocular Physiology Research and Education Foundation.

Financial & competing interests disclosure

The studies related to H-7 and latrunculins from the authors’ laboratory in this article arose, in whole or in part, from direct costs funded by the NIH (EY002698 and EY016665). The University of Wisconsin–Wisconsin Alumni Research Foundation holds a patent related to latrunculin B and H-7; accordingly, P Kaufman has a proprietary interest. P Kaufman also serves as a consultant for and receives an honorarium from Alcon Laboratories, Inc., Allergan, Inc., Altheos, Inc., Amakem Therapeutics, Bausch & Lomb, Inc., Johnson & Johnson, Merck, Inc., Pfizer, Inc., QLT, and Santen. P Kaufman also received grants, royalty and/or travel financial support from Santen, WARF, Pfizer and Alcon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.