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(Investigative Ophthalmology and Visual Science. 2001;42:3187-3192.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Effects of the Marine Macrolides Swinholide A and Jasplakinolide on Outflow Facility in Monkeys

Baohe Tian, Julie A. Kiland and Paul L. Kaufman

From the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison Medical School.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To determine effects of the marine macrolides swinholide A (Swin A) and jasplakinolide (Jas), alone or in conjunction with latrunculin B (Lat B) on outflow facility in monkeys.

METHODS. Total outflow facility was measured by two-level constant-pressure perfusion of the anterior chamber before and after exchange with Swin A, Jas, or vehicles followed by continuous anterior chamber infusion of drug or vehicle, in opposite eyes of cynomolgus monkeys. The effect of a facility-ineffective dose of Jas plus a threshold or submaximal facility-effective dose of the actin depolymerizer Lat B on outflow facility was also determined.

RESULTS. Ten or 100 nM Swin A or 20, 100, or 500 nM Jas had no significant effect on outflow facility. However, 500 nM Swin A and 2.5 µM Jas significantly increased facility by 80% ± 21% and 157% ± 57% (mean ± SEM) respectively, adjusted for corresponding baselines and resistance washout in contralateral control eyes. The facility increase in the eye treated with 500 nM Jas with 60 or 200 nM Lat B was similar to that in the eye treated with 60 or 200 nM Lat B only.

CONCLUSIONS. Swin A (which severs actin filaments and sequesters actin dimers) and Lat B (which sequesters actin monomers) similarly increase outflow facility. The potent inducer of actin polymerization Jas (500 nM) neither inhibits nor potentiates the facility increase induced by Lat B (60 or 200 nM). A higher dose of Jas increases rather than decreases outflow facility.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Swinholide A (Swin A), isolated from the marine sponge Theonella swinhoei, is a 44-carbon-ring dimeric dilactone macrolide with a twofold axis of symmetry1 2 that has antifungal and cytotoxic and antitumor activities.3 4 Swin A disrupts the actin cytoskeleton in cultured cells, rapidly severing actin filaments but stabilizing actin in a dimeric form.5 6 7 8 Previous studies indicate that the marine macrolides latrunculin (Lat) A and B sequester monomeric actin (G-actin) from polymerization, leading to an increase in the level of G-actin and a decrease of polymeric actin (F-actin) in cultured cells.8 9 10 In living monkeys, Lat A and B increase outflow facility, probably by separating cell–cell junctions in the trabecular meshwork (TM) or Schlemm canal (SC) and relaxing, expanding, and extending the TM and SC.11 12 13 However, the exact mechanism for the Lat-induced outflow facility increase is still not clear. Because Swin A decreases the level of F-actin without significantly increasing the concentration of G-actin,8 measurements of outflow facility after application of Swin A in the live monkey eye could help to determine whether Lat’s effect on outflow facility is related to an F-actin decrease or a G-actin increase.

Jasplakinolide (Jas), derived from the Indo-Pacific marine sponge Jaspis johnstoni, is a cyclic peptide with a 15-carbon macrocyclic ring containing three amino acid residues,14 15 which has both fungicidal and antiproliferative activities similar to Swin A.16 17 Jas is a potent inducer of actin polymerization in rabbit skeletal muscle actin18 and is believed to stabilize actin filaments by binding F-actin. It competes for actin binding with phalloidin, a well-known F-actin–stabilizing peptide isolated from the mushroom Amanita phalloides. Chemically, the 15-carbon macrocyclic ring of Jas bears little resemblance to that of phalloidin. However, phalloidin and Jas have similar affinities for F-actin, and Jas seems to stabilize filaments more effectively.18

It is generally believed that the actin depolymerization induced by Lat A and B leads to deterioration of the actin filaments and alterations of intercellular adherens junctions and cell shape.9 19 In living monkeys and enucleated porcine eyes, those cellular changes have been considered to be related to Lat-induced outflow facility elevation.11 12 13 20 21 Therefore, actin depolymerization has been hypothesized to be one of the main mechanisms by which cytoskeletal drugs increase outflow facility. However, phalloidin, an actin filament stabilizer with no effect on outflow facility itself, only partially inhibits the facility-increasing action of cytochalasin B, a fungal metabolite that is widely used as an actin depolymerizer.22 One possibility for the incomplete inhibition of cytochalasin B’s facility-increasing action by phalloidin is that cytochalasins may not produce net depolymerization of actin filaments,23 24 although they may decrease the average filament length in vivo. However, phalloidin’s poor cellular penetration may also be a factor.22 Lats are more specific inhibitors of actin polymerization than are cytochalasins, and Jas is reportedly more potent at stabilizing actin filaments and has better cell membrane penetration than phalloidin.18 Therefore, we thought that Jas alone or in conjunction with Lat A or B could be a useful tool to further clarify the relationship between actin depolymerization and the outflow facility–increasing actions of cytoskeletal drugs.

Based on the mechanisms of Swin A, Jas, and Lat B (Table 1) and the rationales described herein, we determined the effects of Swin A alone, Jas alone, and Jas+Lat B on outflow facility in living monkeys.


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  		Table 1. Effects of Agents Studied on the Actin Cytoskeleton

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Anesthesia
Forty-four normal cynomolgus monkeys (Macaca fascicularis), weighing 2 to 5 kg, were studied. Most monkeys had undergone prior anterior chamber (AC) perfusions but not within the preceding 5 to 6 weeks. All were free of AC cells and flare when examined by slit lamp biomicroscopy. No animal appeared more than once in any dose–drug grouping, but some animals appeared in two different dose groups for the same drug or drug combination. Limited animal availability precluded using only virginal eyes. Our previous Lat A and B data show specifically that there are no significant differences between the initial baseline and the baseline 4 weeks or more after Lat A or B administration.11 12 Based on our vast experience and data bank, we have learned that 5 to 6 weeks is a reasonable interval to allow between perfusions to preclude residual effects from the prior perfusion. All investigations were in accordance with University of Wisconsin and National Institutes of Health guidelines and with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Anesthesia was induced by intramuscular ketamine (10 mg/kg), followed by intravenous (15 mg/kg) or intramuscular (35 mg/kg) pentobarbital Na.

Drug Preparation and Administration
Swin A was obtained from Benjamin Geiger (Rehovot, Israel), or Alexis Corporation (San Diego, CA) and stored as a 100-µM stock solution in dimethyl sulfoxide (DMSO; Sigma, St. Louis, MO) at -20°C. Jas was obtained from Molecular Probes (Eugene, OR) and stored as a 0.1- or 1-mM stock solution in DMSO at -20°C. Lat B was obtained from Calbiochem-Novabiochem, Inc. (La Jolla, CA) and stored as a 0.2- or 2-mM stock solution in DMSO at -20°C. Swin A solution (10–500 nM), Jas solution (20 nM–2.5 µM) and corresponding vehicle (0.01%–0.25% DMSO), or Jas+Lat B solution (60 or 200 nM Lat B + 500 nM Jas) and corresponding control Lat B–only solution (60 or 200 nM) for intracameral exchange perfusion, were freshly prepared in Bárány’s solution.25

Outflow Facility
Total outflow facility was determined by two-level constant-pressure perfusion of the anterior chamber (AC) with Bárány’s mock aqueous humor, correcting for the internal resistance of the perfusion apparatus as appropriate.26 The ACs of both eyes of the monkey were cannulated with a branched needle, with one branch connected to a reservoir and the other to a pressure transducer and an unbranched needle with tubing clamped off. After 35 minutes of baseline facility measurement bilaterally, the clamped tubing from the unbranched needle was then connected to a syringe containing drug(s), or corresponding vehicle (or drug) for the control eye. The syringe was placed in a variable-speed infusion pump and the tubing previously leading to the reservoir was disconnected from the reservoir and opened to air as a temporary outflow line. This allowed infusion of 2 ml solution through the AC to exchange the contents of the AC over 10 to 15 minutes. IOP was maintained at approximately 15 mm Hg by adjusting the height (e.g., 15–16 cm higher than the eye) of the end of the "temporary outflow" tubing. The reservoir was emptied and refilled with the same solution being perfused through the eye. The "temporary outflow" tubing was reconnected to the reservoir and the syringe tubing was clamped again, allowing infusion from the reservoir into the eye. Postexchange outflow facility was then measured for 80 to 90 minutes.

To determine the effects of different doses of Swin A on outflow facility, after baseline facility measurement, the ACs of opposite eyes were exchanged with 10, 100, or 500 nM Swin A or corresponding vehicle, with the reservoirs filled with corresponding drug–vehicle solution. Postdrug facility was measured for 80 or 90 minutes, beginning 60 minutes after drug administration.

To determine the effects of different doses of Jas on outflow facility, after baseline facility measurement, the ACs of opposite eyes were exchanged with 20, 100, or 500 nM or 2.5 µM Jas or corresponding vehicle, with the reservoirs filled with corresponding drug–vehicle solution. Postdrug facility was measured for 90 minutes beginning 30 minutes after drug administration.

To determine whether the actin polymerization inducer would inhibit the effect of actin depolymerizer Lat B on outflow facility, Jas and Lat B were administered concurrently. After measurement of baseline facility, the AC of one eye was exchanged with 500 nM Jas + 60 or 200 nM Lat B solution, and the AC of the opposite eye was exchanged only with 60 or 200 nM Lat B solution alone. The reservoirs were filled with the corresponding solutions. Postdrug facility was measured for 90 minutes beginning 30 minutes after drug administration.

Statistical Analysis
Data are presented as mean ± SEM for n eyes or animals. Pre- or postdrug-treated versus contralateral control, postdrug or postvehicle versus ipsilateral baseline, and baseline-corrected postdrug-treated versus control comparisons were made using a two-tailed paired t-test for ratios versus 1.0.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Swin A
In 80- or 90-minute postdrug perfusions, 10 or 100 nM Swin A had no significant effect on outflow facility, with ([postdrug facility/baseline]Treated/[postdrug facility/baseline]Control) = 0.91 ± 0.11 (n = 8, P > 0.4) or 1.25 ± 0.16 (n = 8, P > 0.1), respectively. However, 500 nM Swin A significantly increased outflow facility by 80% ± 21% (double ratio = 1.80 ± 0.21, n = 8, P < 0.01), adjusted for baseline and resistance washout in contralateral control eyes (Fig. 1 ; Table 2 ).



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  		Figure 1. Effect of AC exchange (Ex) plus continuous intracameral infusion with 10, 100, or 500 nM swinholide (Swin) A on outflow facility. Data are mean ± SEM microliters per minute per millimeter of mercury for n monkeys, each contributing one Swin A–treated and one vehicle-treated eye. Baseline was measured for 35 minutes and postdrug facility was measured for 80 to 90 minutes beginning 60 minutes after drug administration. BL, baseline; Res, reservoir; Veh, vehicle. Arrows indicate period of AC exchange.

 

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  		Table 2. Effect of Swin A on Outflow Facility

 
Jasplakinolide
In 90-minute postdrug perfusions, 20, 100, or 500 nM Jas had no significant effect on outflow facility, with ([postdrug facility/baseline]Treated/[postdrug facility/baseline]Control) = 1.10 ± 0.05 (n = 4, P > 0.2), 0.91 ± 0.10 (n = 7, P > 0.3), or 1.21 ± 0.16 (n = 9, P > 0.2), respectively. However, 2.5 µM Jas significantly increased outflow facility by 157% ± 57% (double ratio = 2.57 ± 0.57, n = 9, P < 0.025), adjusted for baseline and resistance washout in contralateral control eyes (Fig. 2 ; Table 3 ).



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  		Figure 2. Effect of AC exchange (Ex) plus continuous intracameral infusion with 20, 100 or 500 nM, or 2.5 µM Jas on outflow facility. Data are mean ± SEM micrometers per minute per millimeter of mercury for n monkeys, each contributing one jasplakinolide-treated and one vehicle-treated eye. Baseline was measured for 35 minutes, and postdrug facility was measured for 90 minutes beginning 30 minutes after drug administration. For abbreviations, see Figure 1 .

 

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  		Table 3. Effect of Jas on Outflow Facility

 
Jasplakinolide+Latrunculin B
The 500 nM Jas dose did not affect the 200 nM Lat B–induced facility increase, with an increase from baseline of 593% ± 113% (n = 5, P < 0.01) in the Jas+Lat B-treated eyes and 618% ± 215% (n = 5, P < 0.05) in the Lat B only–treated eyes in the overall 90-minute perfusion. The 500 nM Jas dose also did not affect the 60 nM Lat B–induced facility increase, with a 45% ± 9% increase (n = 5, P < 0.01) in the Jas+Lat B–treated eye and a 44% ± 8% increase (n = 5, P < 0.05) in the Lat B only–treated eye in the overall 90-minute perfusion (Fig. 3 ; Table 4 ).



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  		Figure 3. Combined effect of AC exchange plus continuous intracameral infusion with 500 nM Jas plus 60 or 200 nM Lat B on outflow facility. Data are mean ± SEM micrometers per minute per millimeter of mercury for n monkeys, each contributing one Jas + Lat B-treated eye and one Lat B only–treated eye. Baseline was measured for 35 minutes, and postdrug facility was measured for 90 minutes beginning 30 minutes after drug administration. For abbreviations, see Figure 1 .

 

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  		Table 4. Effect of Jas on Lat B’s Outflow Facility

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, 500 nM Swin A time dependently increased outflow facility in the monkey eye, similar to the Lats.11 12 In a previous study, Lat A elevated the level of G-actin, whereas Swin A elevated the level of dimeric actin in cultured cells, but both macrolides similarly reduced the level of F-actin, accompanied by similar changes in cell morphology.8 Therefore, the current physiology data suggest that depolymerization of F-actin or consequent disorganization of the actin cytoskeleton in the TM and SC could be a common mechanism for their outflow facility actions. In previous cultured cells, the increase of G-actin after Lat A inhibits actin synthesis, whereas the formation of dimeric actin after addition of Swin A reduces G-actin and in turn enhances actin synthesis.8 The effect of Swin A on actin synthesis is similar to that of phalloidin, although their effects on F-actin are different. Phalloidin stabilizes F-actin, reduces the level of G-actin, and enhances actin synthesis,24 27 28 29 whereas Swin A severs F-actin filaments, reduces G-actin, and stabilizes the actin into a dimeric form.8 Unlike Swin A, phalloidin has no effect on outflow facility itself and partially inhibits the effect of cytochalasin B on outflow facility.22 The different effects of Swin A and phalloidin on the actin cytoskeleton in cultured cells and on outflow facility in living monkeys further suggest that reduction of F-actin or disorganization of the actin structures, rather than alterations of G-actin, dimeric actin, or actin synthesis, is involved in the facility-increasing mechanism of these cytoskeletal drugs.

In contrast to the Lats and Swin A, Jas stabilizes actin filaments by binding F-actin, as does phalloidin.18 Twenty, 100 or 500 nM Jas had no effect on outflow facility in living monkeys. However, 2.5 µM Jas dramatically increased outflow facility in the live monkey eye. It is not clear yet why this potent actin filament stabilizer increases outflow facility similar to actin depolymerizers. The higher dose of Jas could act directly on F-actin, causing abnormal aggregation, including induction of polymerization of G-actin into amorphous masses of disordered F-actin. During this process, Jas may deplete G-actin, leading to a cellular environment in which there is insufficient polymerization-competent G-actin to maintain stress fibers.30 Evidence has shown that Jas induces morphologic changes in human prostate carcinoma cells by disrupting the actin cytoskeleton, similar to cytochalasin E.31 A recent study has also confirmed that higher concentrations of Jas have two distinct and apparently opposite effects—destabilization of F-actin bundles in the cytoplasm, and increase of the F-actin mass in the perinuclear region.32 When Jas is used in cultured cells for the short term, it inhibits actin filament disassembly without perturbation of cellular actin organization, whereas when it is used for a longer term, it promotes appearance of filament aggregates, and gross disruption of actin organization.33 A recent atomic force microscopy study determined the effects on cell elasticity of various drugs that disrupt or stabilize the actin networks. In spite of different biochemical mechanisms, the common denominator of the effects of cytochalasins, Lat A, and Jas is a 2.5- to 2.9-fold reduction in the cell’s average elastic modulus.34 All the data suggest that inhibition of depolymerization can perturb the actin cytoskeleton similar to inhibition of polymerization and that proper assembly of the actin cytoskeleton strongly depends on actin dynamics. It seems likely that the increase in outflow facility by the higher dose of Jas is related to actin disorganization.

Although Jas is a more potent actin stabilizer and has better cell membrane penetration than phalloidin,18 31 500 nM Jas did not inhibit the facility-increasing effect of 60 or 200 nM Lat B, which are threshold and submaximal facility-effective doses. The reasons for the absence of inhibition remain unclear, but the finding suggests that Lat B may depolymerize the actin filaments by a mechanism that cannot be affected by Jas. For instance, Jas, which mainly promotes the initial nucleation stage of the actin polymerization process and prevents depolymerization of assembled actin filaments,30 may not promote polymerization of the 1:1 molar Lat B–G-actin complex,10 whereas Lat B may still sequester G-actin from polymerization even though the F-actin is bound by Jas. On the contrary, although a higher dose of Jas increased outflow facility alone, the 500 nM Jas dose also failed to potentiate the facility effect of 60 or 200 nM Lat B. In our previous studies, a subthreshold dose of one actin-disrupting agent potentiated the effect of a subthreshold or submaximally effective dose of another actin-disrupting agent on outflow facility.35 36 The absence of potentiation of outflow facility after combined treatment with threshold or submaximal facility-effective doses of Lat B and a just-subthreshold dose of Jas in the present study suggests that the higher dose of Jas induces disorganization of the actin cytoskeleton by a totally different mechanism than Lat B. Presumably, it could be related to overpolymerization. However, information on the effects of Jas from the literature is contradictory and indicates concentration and cell-type dependencies.34 Further studies, perhaps in cultured TM and SC cells, are needed to clarify the issue.


   Acknowledgements
 
The authors thank Alexander D. Bershadsky, Weizmann Institute of Science, Rehovot, Israel, for helpful comments.


   Footnotes
 
Supported by Grant EY02698 from the National Eye Institute and by grants from the Glaucoma Research Foundation, Research to Prevent Blindness, the Wisconsin Alumni Research Foundation, and the Ocular Physiology Research and Education Foundation.

Submitted for publication March 26, 2001; revised August 9, 2001; accepted August 14, 2001.

Commercial relationships policy: P (PLK); N (all others).

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Paul L. Kaufman, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, F4/328 CSC, 600 Highland Avenue, Madison, WI 53792-3220. kaufmanp{at}mhub.ophth.wisc.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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