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.

Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

“…Morphological studies done with Lat-B and other cytoskeletal agents show that there are key common effects: relaxation of the TM and expansion of the JCT, and relaxation and flattening and spreading out of the SC inner wall endothelial cells, and consequent dilation of the canal. 10,15 The clean slit-lamp exams in our patients, the reversibility of the TM effect, the absence of anterior segment adverse events and the healthy retina studies in monkeys, all bode well for Lat-B's safety clinical use. Our findings demonstrate that INS115644 may be a safe topical agent that is effective in reducing reduces IOP in OHT and POAG patients.…”

“…8,9 Drugs that target the trabecular meshwork (TM) and Schlemm's canal (SC) include cholinomimetics, which increase TM/SC outflow facility by contracting the ciliary muscle (CM), in turn distorting the TM so as to increase facility; and epinephrine, which acts directly on beta-2 adrenergic receptors in the TM/SC cells to increase TM facility (perhaps by disturbing the TM/SC cytoskeleton). 10 Neither class is widely used clinically because of local (cholinomimetics) or both local and systemic (epinephrine) side effects, though they remain an alternative for patients refractory to conventional therapeutics, notably those with exfoliation syndrome/glaucoma and pigmentary glaucoma. Although cholinomimetics and epinephrine are approved and available, they are used infrequently, and there are currently no drugs commonly used clinically that directly target the TM.…”

“…[11][12][13] Interference with TM/IWSC cellular contractility, and cell-cell or cell-extracellular matrix adhesion, whether by inhibiting the Rho kinase or myosin light-chain kinase cascades or by disrupting actin microfilaments (whether by direct disruption or inhibition of their assembly) can result in increased outflow facility in live nonhuman primates 10,14,15 and in both human and primate organ-cultured anterior segments. [16][17][18][19][20] Several Rho kinase inhibitor compounds are in development [21][22][23][24][25][26] aiming to lower IOP by targeting trabecular outflow.…”

Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction

“…While the source of resistance to the flow of aqueous humor through its primary outflow pathway from the eye is still a topic of active research (Keller and Acott, 2013; Overby et al, 2009; Swaminathan et al, 2013), a number of laboratories have now converged on the hypothesis that the contractile state of cells in the aqueous outflow pathway can regulate outflow resistance (Junglas et al, 2012; Peterson et al, 1999; Rao et al, 2005, 2001; Sabanay et al, 2000; Tian et al, 2009; Tian and Kaufman, 2012; Zhou et al, 2012). Changes in the contractile state of the cell are associated with changes in cell stiffness (Zhou et al, 2012).…”

Exciting directions in glaucoma

“…A novel strategy is targeting the trabecular meshwork cytoskeleton aiming to increase fluid outflow through the trabecular meshwork (TM) /conventional outflow pathway. (1, 2) There are several targets for this approach: 1) TM – cytoskeleton-actin microfilament disruption using marine macrolides such as latrunculins (Lat-A/B) (WARF) (3–9) (FIG 1), swinholide A, jasplakinolide (10) (WARF); 2) Protein kinase inhibition using serine–threonine kinase inhibitors such as H-7 (WARF) (11), myosin light chain kinase inhibitor ML-7 (12) and rho kinase inhibitors including Y-39983/SNJ-1656/RKI-983 (Senju / Novartis) (13–15), AR-12286 (Aerie) (16,17), AR-13324 (Aerie) (18), PG324 (which is AR-13324 combined with latanoprost) (Aerie), K-115 (Kowa) (19,20), AMA0076 (Amakem) (21); 3) targeting actomyosin contractility using nonmuscle caldesmon (WARF) (22,23) or focal adhesions and cell-cell adhesions with exoenzyme C3 transferase (C3) (WARF) (24). A number of these compounds are moving through clinical trials with a mechanism of action that features relaxation of the TM, expansion of juxtacanlicular spaces (JCT), dilation of Schlemm’s canal SC and inhibition of actomyosin contractility.…”