Pge s

SURVEY OF OPHTHALMOLOGY VOLUME 53 � SUPPLEMENT 1 � NOVEMBER 2008

Update on the Mechanism of Action of TopicalProstaglandins for Intraocular Pressure ReductionCarol B. Toris, PhD,1 B’Ann T. Gabelt, MS,2 and Paul L. Kaufman, MD2

1Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA;and 2Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA

� 2008 byAll rights

Abstract. A decade has passed since the first topical prostaglandin analog was prescribed to reduceintraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs areavailable for clinical use around the world and more are in development. The three most efficacious ofthese drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humordynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a lessconsistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightlystimulated as well. Prostaglandin receptors and their associated mRNAs have been located in thetrabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandinshave a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogsrelease endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow byprostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix.Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in theshape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leadingto changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000)animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamicsand recent cellular and molecular studies designed to clarify the outflow effects. (Surv Ophthalmol53:S107--S120, 2008. � 2008 Elsevier Inc. All rights reserved.)

Key words. aqueous humor � intraocular pressure � matrix metalloproteinases �prostaglandin � trabecular outflow � uveoscleral outflow

All of the clinically available drugs for the treatmentof elevated intraocular pressure (IOP) have directeffects on one or more parameters of aqueoushumor dynamics. IOP usually is reduced by slowingthe production rate of aqueous humor, by de-creasing the resistance to flow through the trabec-ular meshwork, by increasing drainage through theuveoscleral outflow pathway, or by a combination ofthese mechanisms. Currently, the most effectiveoutflow drugs approved for clinical use are prosta-glandin (PG) F2a analogs. These drugs reduce IOPby stimulation of aqueous humor drainage primarily

S107

Elsevier Inc.reserved.

through the uveoscleral outflow pathway but signif-icant effects on trabecular outflow facility also havebeen reported.67,85 Three PGF2a analogs (bimato-prost, latanoprost, and travoprost) are approved forglaucoma therapy in the United States, one addi-tional analog (unoprostone) is prescribed in Japanand a new analog (tafluprost) is in clinical trials inJapan. Travoprost and latanoprost are ester pro-drugs of PGF2a. Bimatoprost is the amide prodrugof 17-phenyl-PGF2a

86 and has been classifiedby some as a prostamide,86 although this classifica-tion has been somewhat controversial.7,37,56--58,86,87

0039-6257/08/$--see front matterdoi:10.1016/j.survophthal.2008.08.010

S108 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL

Unoprostone is an analog of a pulmonary metabo-lite of PGF2a and sometimes labeled a docosanoid.26

Tafluprost is a difluoroprostaglandin derivative ofPGF2a.

62 Agonists of DP, EP, and TP receptors havebeen or are being investigated in animal models fortheir IOP efficacy and potential as new glaucomatherapeutic drugs. None of these agonists has yet tobe approved for clinical use.

This review summarizes recent (since 2000)animal and clinical English-language studies of theeffects of topical PG agonists on aqueous humordynamics and recent cellular and molecular studiesdesigned to clarify the outflow effects.

Aqueous Humor Dynamics

Latanoprost, travoprost, and bimatoprost pro-duce similar increases in uveoscleral outflow ofseveral-fold. Increases in trabecular outflow facilityalso have been reported but this finding has notbeen found consistently (Table 1). Unoprostone,the least efficacious of the four compounds, appearsto have little effect on uveoscleral outflow inhumans. Rather it works mainly by increasingtrabecular outflow facility.69 The new fluoroprosta-glandin F2a, tafluprost, increases uveoscleral outflowand aqueous flow in monkeys62 but has yet to bestudied in humans. Earlier studies13,89 have re-ported that the topical PG analogs release endoge-nous prostaglandins that may contribute to theobserved ocular hypotensive effects. Tafluprost inmice reportedly works in part through FP receptor-mediated prostaglandin production acting throughthe prostanoid EP3 receptor.49 Studies publishedbetween 2000 and 2008 of FP, DP, and EP receptoragonists and their effects on aqueous humordynamics in humans and nonhuman primates aresummarized in Table 1. Studies predating 2000 arefound in an earlier review.67

TRABECULAR OUTFLOW FACILITY

Trabecular outflow facility is not always increasedfollowing topical treatment with PG analogs butevidence is building that the effect is real and notunique to any one drug of this class. Latanoprost,travoprost, bimatoprost, and unoprostone all havebeen found to significantly increase trabecularoutflow facility in at least one clinical study(Table 1).

Compared to humans, the trabecular meshworkof monkeys seems to be less affected by PG analogs.Trabecular outflow facility was unchanged followingmultiple topical treatments of monkeys with PGF2a-isopropyl ester,22 tafluprost,62 and travoprost,71 theDP receptor agonist AL-6598,72 and EP receptor

agonists butaprost44 and 8-iso PGE223 (Table 1).

Exceptions do exist. One drop of 17-phenyl trinor 8-iso PGE2 and the selective EP4 receptor agonist 3,7-dithia PGE1 increased outflow facility sufficiently innormotensive monkey eyes to account for most, ifnot all of the IOP reduction (Kharlamb, ARVO 2004abstract 1035, Table 1). An older study found anincrease in outflow facility at 4 hours after onetopical drop of PGF2a.35

One potential reason for the apparent differencesin trabecular outflow facility effect among thevarious PG agonists is the method of measurement.Two noninvasive methods, tonography and fluoro-photometry, and two invasive methods, two-levelconstant pressure perfusion and isotope accumula-tion, are used to make the assessment. All methodsmeasure trabecular outflow facility, but confound-ing factors are known to exist, including ocularrigidity (a measure of eye stiffness), pseudofacility(the facility of flow of aqueous humor from theposterior to anterior chamber resulting from theprobe-induced increase in IOP), and uveoscleraloutflow facility. The name of the measured variabletrabecular outflow facility is not entirely accuratebecause of the inclusion of these other factors inthe various measurements. All of the measurementtechniques assume that uveoscleral outflow facility isvery small and affected little by the measurementitself. This assumption is based on monkey stud-ies8,68 reporting that uveoscleral outflow is relativelypressure-independent. However, if an experimentalmanipulation were to increase uveoscleral outflowfacility, this could be interpreted erroneously, as anincrease in trabecular outflow facility. It is thoughtby some that PGs increase uveoscleral outflowfacility but this has yet to be proven experimentally.These methods may not detect changes in trabecu-lar outflow facility if the changes are overshadowedby strong effects on uveoscleral outflow and/oruveoscleral outflow facility.

The length of time of treatment could be anotherfactor contributing to the differing effects of PGs ontrabecular outflow facility. The immediate IOPeffects that occur from a single dose of a PG analogmay be mediated by cellular mechanisms differentfrom those that occur after repeated applications orcontinuous exposure.9,83,90 Therefore, findingsfrom multiple doses of each PG should be com-pared before concluding that one PG analog actsthrough mechanisms different from all others.

Mice are being used with increasing frequency toevaluate aqueous humor dynamics because of theirpotential for genetic manipulation in addition totheir ocular similarities to humans. These animalsexhibit increases in outflow facility 2 hours after one4-ml drop of latanoprost.18 Several limitations to

TABLE 1

Studies of Aqueous Humor Dynamics in Humans and Nonhuman Primates Treated with Prostaglandin Analogs Published from 2000 to 2008

A logType and Number

of SubjectsDuration ofTreatment IOP Fa C Pev Fu Reference

F receptor analogs, prostamidesB atoprost ONT volunteers

(n 5 25)QD � 2 days

QD � 3 daysY(day)Y(night)

[(day)[(night)

[day [day Brubaker et al, 200111

OHT or POAG patients(n 5 29)

QD � 7 days Y 4 [ [ Christiansen et al,200416

ONT volunteers(n 5 30)

QD � 7 days Y 4 [ [ Lim et al, 200838

L noprost OHT patients (n 5 30) QD � 7 days Y 4 4 4 [ Toris et al, 200173

OHT or POAG patients(n 5 30)

QD � 14 days Y 4 [ Dinslage et al, 200420


QD � 7 days Y 4 [ [ Lim et al , 200838

1 eto latanoprost Cynomolgus, ONTmonkeys (n 5 30)

One drop Y 4 4 Wang et al, 200777

T oprost OHT & POAG patients(n 5 26)

QD � 17 days Y(day and night) 4 [(day) 4 [(marginallyinsignificant)

Toris et al, 200770


QD � 7 days Y 4 [ [ Lim et al, 200838

cynomolgusmonkeys unilateralOHT (n 5 12)

BID � 3 days Y 4 4 [a Toris et al, 200571

U prostone OHT patients (n 5 30) BID 5 daysand 28 days

Y 4 [ 4 4 Toris et al, 200469

T uprost cynomolgus monkeys(n 5 8--12)

QD � 4 to 5 days Y [ 4 Takagi et al, 200462

D receptor agonistA 6598 cynomolgus monkeys,

unilateral OHT(n 5 11)

BID � 3 days YONT eye only [ONT eye only 4 [ONT eye only Toris et al, 200672

E receptor agonistsB aprost Cynomolgus monkeys,

ONT and OHT(n 5 6--8)

One dropor QD � 5 days

YOHT and ONT 4One drop,ONT

4One drop, ONT [QD � 5days, ONT

Nilsson et al, 200644

8 PGE2 Cynomolgus monkeys,ONT (n 5 7--10)

BID, 9--29 doses Y 4 4Two methods [ Gabelt et al, 200423

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using this animal model should be mentioned. Thesize of the eye makes accurate measurementdifficult. Inflow and outflow are very slow (many-fold slower than in humans),1 and changes in flowcan be near the limit of detection. Additionally, theanesthesia needed for most measurements quicklyand profoundly affects IOP.31 IOPs vary amongstrains of mice,30 and aqueous humor outflow ratesmay vary among strains as well. Further research isneeded to characterize differences in aqueoushumor dynamics among the murine strains.

UVEOSCLERAL OUTFLOW

Increases in uveoscleral outflow have been re-ported with topical treatment of bimatoprost andlatanoprost in ocular normotensive and hyperten-sive subjects (Table 1).11,16,20,73 Travoprost increaseduveoscleral outflow in monkeys71 and marginallyincreased it in ocular hypertensive patients as well.70

Unoprostone, the weakest of the four prescribed PGanalogs, is the only one that did not affectuveoscleral outflow in humans despite 5 days oftwice-daily dosing.69

Multiple topical drops of agonists for FP receptors(tafluprost62), DP receptors (AL-659872), and EP2

receptors (butaprost44 and 8-iso PGE278) increased

uveoscleral outflow in monkeys (Table 1). Incontrast, one drop of the EP4 agonist 3,7-dithiaPGE1 had no effect on uveoscleral outflow inmonkeys (Kharlamb et al, unpublished data, ab-stract 1035 presented at the 2004 ARVO annualmeeting). A multiple dose study is needed to clarifywhether the effect persists with repeat dosing.

AQUEOUS FLOW

Most studies investigating aqueous flow havefound that PG analogs produce a small (10--15%)increase that may or may not be statisticallysignificant and is not clinically important. Asignificant increase in aqueous flow was found atnight in young healthy Japanese volunteers treatedwith latanoprost,41 and during the day and at nightin healthy predominantly white volunteers treatedwith bimatoprost.11 Additionally, aqueous flow in-creased during the day in monkeys treated with a DPagonist.72 This effect does not contribute to anyreduction in IOP but an increase in aqueous flowcould be considered a healthy side effect of topicalPG analogs because aqueous humor carries essentialnutrients and removes waste products, crucial forkeeping the avascular tissues of the anteriorsegment healthy.

TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S111

EPISCLERAL VENOUS PRESSURE

Three studies have reported no change inepiscleral venous pressure in patients with ocularhypertension treated for one week with latanoprost,travoprost, or unoprostone (Table 1). The measure-ments (made with a commercially available epis-cleral venomanometer, EyeTech, Morton Grove, IL),are difficult to make with accuracy and consistency.Nevertheless, because no study found any trend tosuggest a change, it seems reasonable to concludethat the PG effect on episcleral venous pressure isminimal.

Cellular and Molecular Studies

TRABECULAR MESHWORK

Organ-cultured anterior segments and trabecularmeshwork cell cultures provide strong evidence thatPG analogs can alter the resistance in trabecularoutflow (Table 2). PGs have direct effects on matrixmetalloproteinases (MMPs), neutral proteases thatinitiate degradation of the extracellular matrix andplay a major role in regulating resistance to flowthrough tissues. MMPs are expressed by humantrabecular meshwork2 and directly control outflowresistance in human organ-cultured anterior seg-ments.9 The activity of MMPs is regulated by tissueinhibitors of metalloproteinases (TIMPs).10 Cur-rently four TIMPS (TIMP-1, -2, -3, -4) have beenidentified in mammals and each TIMP targetsspecific MMPs.42 In one study,47 cultures of humantrabecular meshwork cells treated with latanoprostacid for 24 hours had increased expression of MMPs-1, -3, -17, and -24 and TIMPs -2, -3, and -4. A study6

of human organ-cultured anterior segments infusedwith latanoprost acid found increased outflowfacility at 24 hours after administration whencompared to control anterior segments (67% vs6%) but no changes in the amount of MMPs orscleral hydraulic conductivity.6 Histological exami-nation found regions of focal detachment and lossof Schlemm’s canal endothelial cells and extracel-lular matrix in some areas of the trabecularmeshwork.6 The focal cell loss was reasoned to bedue to cytoskeletal and focal adhesion changes6

because PGs in aortic smooth muscle cells causedisassembly of actin stress fibers and inhibition ofphosphorylation of paxillin and other focal adhe-sion proteins.12

Bimatoprost increases outflow facility by 40% inhuman organ-cultured anterior segments within 48hours of treatment. This effect was blocked bypreincubation with AGN211334, thought to bea prostamide-selective antagonist,76 or , alternatively,an inhibitor of bimatoprost hydrolysis.7 Similarly,

pig organ--cultured anterior segments perfused ata constant pressure of 15 mm Hg, showed increasedoutflow by up to 62% at 8 hours after topicaladministration of bimatoprost and by 30% at 5hours after intracameral administration of PGF2a.74

Human trabecular meshwork monolayer cultures6

treated with bimatoprost had a 78% increase inhydraulic conductivity which also was blocked byAGN211334.76

PGE1 increases outflow facility by 26% in humanorgan-cultured anterior segments.19 This effectprobably occurs by an adenylyl cyclase-dependentpathway activated primarily by the predominant EP2

receptors in the trabecular meshwork.32 Stimulationof EP2 receptors in trabecular meshwork is coupledto the activation of high-conductance Caþ2-activatedKþ channels (BK) which may contribute to therelaxant activity of EP2 agonists in isolated trabec-ular meshwork strips.61 However, outflow facility wasnot stimulated and cAMP production was notaltered after short exposure periods with PGF2a orplacebo in human organ-cultured anteriorsegments.19

Prostaglandin receptors have been identified inhuman trabecular meshwork tissue but a prostamidereceptor has not yet been cloned. The genes for allprostanoid receptors are expressed in humantrabecular meshwork. Gene expression for the EP2

receptor is most abundant, followed by FP, TP, IP,and EP4, with DP and EP3 at the lowest levels.32

Immunofluorescent labeling of FP and EP prosta-noid receptor subtypes in normal human trabecularmeshwork tissue showed positive staining for EP1 ontrabecular cells of the outer portion of themeshwork and cells lining Schlemm’s canal. EP2

was localized to the outer wall and periphery ofSchlemm’s canal. EP3 and EP4 labeling was presenton trabecular cells along the entire meshwork.Moderate expression of FP receptor protein waspresent in the outer portion of the trabecularmeshwork and endothelial cells of Schlemm’s canal,collector channels and aqueous veins.55

Human trabecular meshwork cells in cultureexpress many of the same PG receptors as are foundin intact tissue. Cultured trabecular meshwork cellscan produce PGE2 and low levels of PGF2a.83,84

Additionally, FP receptors have been identified inhuman trabecular meshwork cells as determined bythe presence of mRNA, protein, and a functionalresponse (increased inositol phosphate accumula-tion and intracellular calcium release) to PGF2a

5

and numerous synthetic FP-selective PG agonists.58

PGE2 elicits its biological effects via four G-protein-coupled receptor subtypes which stimulatephosphoinositide turnover with elevation in intra-cellular-free calcium (EP1 and some EP3), activation

TABLE 2

Molecular and Cellular Studies of the Effects of Prostaglandin-Related Compounds on the Aqueous Humor Outflow Pathways

Analog Animal/ Tissue Duration of Treatment Pathway/EffectCellular/Molecular

Events Reference

Trabecular meshworkPGF2a, fluprostenol trabecular meshwork

strips (bovine)Up to 2 hours FP receptor mediated

inhibition ofendothelin-1contractility; no effecton baseline tension orcarbachol-inducedcontraction

Thieme 200664

PGF2a human trabecularmeshwork cells

1 hour FP mediated inositolphosphateaccumulation;intracellular calciumrelease

Anthony 19985

PGF2a human anterior segments 60 minutes per dose outflow facilityunchanged

no change in cAMPproduction

Dijkstra 199919

PGF2a, butaprost human trabecularmeshwork cells

6 hours upregulate mRNA forNur77 and connectivetissue growth factor

Liang 2003,200436,37

Bimatoprost human anterior segments 48--72 hour continuousinfusion

outflow facility increase Wan 200776

Bimatoprost human trabecularmeshwork monolayer

48--72 hour continuousinfusion

hydraulic conductivityincrease

Wan 200776

Bimatoprost human trabecularmeshwork cells

6 hours no change in Nur77mRNA and connectivetissue growth factorexpression

Liang 2003, 200436,37

bimatoprost acid (B),latanoprost acid (L),travoprost acid (T),unoprostone (U),PGF2a (P)

human trabecularmeshwork cells

1 hr (PI turnover); 3 min(Ca 2þ mobilization)

FP receptor activation:stimulatephosphoinositideturnover(B,L,T,U,P)stimulateintracellular Ca 2þ

mobilization (T,U,P)

Sharif 200358

latanoprost acid, PGE1 human trabecularmeshwork cells

24 hours increase mRNA for MMP-1,-3,-17,-24; TIMP-2,-3,-4

Oh 200646

latanoprost acid; PGE1 human anterior segments 24 hours outflow facility increase;scleral hydraulicconductivityunchanged

focal detachment and lossof Schlemm’s canalcells; extracellularmatrix loss; no changein MMPs

Bahler 20086

latanoprost acid human trabecularmeshwork cells

9 days in vivo increase insulin growthfactor-1 gene andfibroleukin geneexpression

Zhao 200390

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Unoprostone human trabecularmeshwork cells

Up to 2 hours decrease activity of L-typeCa 2þ channels viatyrosine kinasepathways

Thieme 200565

PGE1 human anterior segments 60 minutes increase outflow facility increase cAMPproduction

Dijkstra 199919

AH13205 human trabecularmeshwork cells

Less than 10 minutes EP2 agonist activation ofBK calcium channels

Stumpff 200561

Uveoscleral tissues

PGF2a monkeys multiple topicaltreatments

decrease collagen types I,III, IV in ciliary muscle

Sagara 199953


increase MMP-1,-2,-3 inciliary muscle

Gaton 200125


scleral permeability increase MMP-1,-2,-3 insclera

Weinreb 200179

PGF2a human sclera explants collagen gelatinization Molik 2006 (ARVO 2006abstract)

PGF2a, latanoprost human sclera 1--3 days increase scleralpermeability

increase MMP-1,-2,-3 Kim 200133

PGF2a, PhXA85 scleral organ cultures 24 hr increase mRNA for MMPsand TIMPx

Weinreb 200482

PGF2a, latanoprost acid human ciliary musclecells

5 min for ERK1/2, PKC;4hr for MMP-2 analysis

increase MMP-2 viaprotein kinase C- andextracellular signalregulated proteinkinase 1/2- dependentpathways

Husain 200528

PGF2a, latanoprost acid,bimatoprost acid,travoprost acid

human ciliary musclecells

1hr for PI turnover; 3 minfor Ca2þ mobilization;5 min for p42/p44 MAPkinase

increase mitogenactivated protein kinaseactivity;phosphoinositidehydrolysis; intracellularcalcium mobilization;inhibited by FPantagonist AL-8810

Sharif 200356

PGF2a, latanoprost,PhXA85

ciliary muscle tissue(several species)

5--10 min increase phospholipaseA2 and release ofarachidonic acidleading to formation ofPGE2, PGD2 and PGF2a

Yousufzai 199689

PGF2a, butaprost human ciliary musclecells

6 hours upregulate Nur77 andconnective tissuegrowth factor

Liang 2003, 200436,37

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Table 2 (continued)

Analog Animal/ Tissue Duration of Treatment Pathway/EffectCellular/Molecular

Events Reference

latanoprost acid human ciliary musclecells

24 hours increase mRNA for MMP-3,-9,-17; increase mRNAfor TIMP-3; decreasemRNA for MMP-1,-2,-12,-14,-15,-16, TIMP-4

Oh 200647


24 hours increase MMP-1,-3,-9 Weinreb 200281


Up to 24 hours increase TIMP-1 Anthony 20024

latanoprost acid nonpigmented ciliaryepithelial cells

Up to 48 hr Cyclooxygenase-2induction leading toincrease MMP-1

Hinz 200527

latanoprost acid rats Single topical dose Initial IOP elevationfollowed by prolongedIOP reduction

Husain 200629


9 days in vivo decrease aquaporin-1 andversican geneexpression; decrease inmRNA for FP receptor

Zhao 200390

latanoprost, bimatoprost,sulprostone, AH13205

monkeys topical treatments for oneyear

tissue spaces of ciliarymuscle enlarged andorganized; myelinatednerve fiber bundlespresent

Richter 200352

Bimatoprost human ciliary musclecells

6 hours no change in Nur77 andconnective tissuegrowth factorexpression;upregulation of Cyr61

Liang 2003, 200436,37

3,7-dithia PGE1 ciliary muscle tissue(human and monkey)

No details -- probably lessthan 2 hours

no EP4 mediatedrelaxation

Kharlamb, 2006 (ARVO2006 abstract)

Genetic studies

latanoprost, travoprost,bimatoprost,unoprostone

FP knockout mice single topical treatment IOP decrease FP receptor needed forIOP decrease

Ota 200548

Latanoprost FP knockout mice 7 days topical sclera intact FP receptor geneneeded forupregulation of MMP-2,-3,-9

Crowston 2007 (ARVO2007 abstract)

latanoprost, travoprost,bimatoprost,unoprostone

EP1, EP2, EP3 knockoutmice

single topical treatment IOP decrease EP1 and EP2 not involvedin IOP decrease; EP3

may have a role

Ota 200548

IOP 5 intraocular pressure; MMP 5 matrix metalloproteinase; PG 5 prostaglandin; PI 5 phospholipase C-mediated phosphoinositide; TIMP 5 tissue inhibitor ofmetalloproteinase.

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of adenylyl cyclase and elevation of intracellularcAMP (EP2 and EP4) or inhibition of adenylylcyclase (EP3).17,43 Prolonged treatment of humantrabecular meshwork cells with latanoprost or PGF2a

ethanolamide causes an increase in expression ofgenes for insulin-like growth factor-1 (IGF-1) andfibroleukin that could act to increase outflowfacility. IGF-1 is reported to increase the level ofMMPs, stromelysin, and gelatinase in trabecularmeshwork cells. The protease activity of fibroleukinmay be active against a component in the extracel-lular matrix.90

Unoprostone free acid (UF-021) shows lowaffinity for all prostanoid receptors and weakfunctional responses via FP receptor activation.57

Several molecular events have been associated withunoprostone exposure. A reduction in the activity ofL-type Ca2þ channels via a signal transductionpathway was mediated by tyrosine kinases.65 Activa-tion of BK channels by unoprostone free acidinhibited trabecular meshwork contraction leadingto an increase in outflow.66

Endothelin-1 is involved in regulating the con-tractility of the trabecular meshwork. FP receptoragonists can block endothelin-1 induced contractil-ity of the trabecular meshwork. Evidence indicatesthis inhibition is mediated by the FP receptor.64

UVEOSCLERAL TISSUES

Immunohistochemistry studies of EP and FPreceptor localization in the uveoscleral tissue innormal human donor eyes indicate the presence ofEP-1, -2, -3, -4 and FP receptors in the ciliary bodyand sclera. FP receptors are most abundant in thecircular portion of the ciliary muscle.55

Several mechanisms have been proposed toexplain the PG-induced increase in uveoscleraloutflow: remodeling of the extracellular matrix ofthe ciliary muscle45,53,80 and sclera33,82 (Molik et al,unpublished data, abstract 406 presented at the2006 ARVO annual meeting) causing changes in thepermeability of these tissues; widening of theconnective tissue-filled spaces among the ciliarymuscle bundles,39,63 which may be caused in partby relaxation of the ciliary muscle51,75 and changesin the shape of ciliary muscle cells as a result ofalterations in actin and vinculin localization withinthe cells.60

Ciliary muscle relaxation has been suggested asresponsible for the initial reduction in IOP fromtopical PGs. This does not appear to be the case forall PGs and their agonists. PGE1 and PGE2 relaxedisolated monkey ciliary muscle strips precontractedwith carbachol88 but 3,7-dithia PGE1 (Kharlamb etal, unpublished data, abstract 413 presented at the

2006 ARVO annual meeting), PGF2a and latano-prost did not.88

Remodeling of the extracellular matrix within theciliary muscle and sclera is the most thoroughlyunderstood effect of PG treatment. Dissolution ofcollagen types I and III within the connective tissue-filled spaces between the outer longitudinallyoriented muscle bundles39,63 results from PG-stim-ulated induction of enzymes MMP-1, -2, and -3 inthe ciliary muscle and surrounding sclera. 25 Long-term (1 year) unilateral treatment of monkey eyeswith topical bimatoprost, latanoprost, sulprostone(EP3/EP1 agonist) or AH13205 and butaprost (EP2

agonists) found that in all cases the tissue spaces ofthe ciliary muscle were enlarged and organized intoelongated tube-like spaces, covered by endothelial-like cells often in contact with the basementmembrane, and contained myelinated nerve fiberbundles.44,52 These fluid pathways resembled a kindof lymphatic system described in the choroid.34

Changes in the trabecular meshwork also werepresent. MMP expression in human ciliary bodytissue and ciliary muscle cells was determined afterlatanoprost acid treatment for 24 hours. The mRNAof MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, and-24 as well as TIMP-1 to -4 were found in ciliary bodytissue and ciliary muscle cells. Latanoprost increasedMMP-3, -9, -17, and TIMP-3 and down-regulatedMMP-1, -2, -12, -14, -15, and -16 and TIMP-4.46

Latanoprost acid induced a concentration-depen-dent increase in MMP-1, -3, and -9 gene transcrip-tion81 and a concentration- and time-dependentincrease in TIMP-1 but not TIMP-2 mRNA andprotein.4

Loss of cyclooxygenase (COX)-2 expression in theciliary body of humans has been associated withglaucoma.40 This association has led to studiesinvestigating the connection between PGs, COX-2expression and MMPs. Indeed, the IOP-loweringaction of latanoprost appears to be associated withinduction of COX-2 and subsequent MMP-1 expres-sion in human nonpigmented epithelial cells.27

MMP-1 released into the aqueous humor would beexpected to flow into the ciliary muscle and throughthe trabecular meshwork and Schlemm’s canal topotentially increase outflow via multiple routes.

Studies to elucidate additional cellular mecha-nisms associated with PG-induced MMP secretion areongoing. PGF2a- and latanoprost-induced secretionand activation of MMP-2 in ciliary muscle cells wereshown to occur via protein kinase C and extracellularsignal regulated protein kinase 1/2-dependentpathways.28 Mitogen-activated protein kinase activitywas stimulated in human ciliary muscle cells withtravoprost acid O PGF2a O latanoprost acid Obimatoprost O latanoprost 5 bimatoprost acid. The


FP antagonist AL-8810 completely inhibited themitogen-activated protein kinase activity induced bybimatoprost and bimatoprost acid, indicating thatboth agonists were activating the FP receptor.57

Inhibition of the latanoprost-induced reductionof IOP in rats by thalidomide suggested that theIOP-lowering response is mediated, in part, throughtumor necrosis factor-a-dependent signaling path-ways. Treatment of human ciliary muscle cells withtumor necrosis factor-a increased the secretion ofMMP-1, and -2 (Husain et al, unpublished data,abstract 219 presented at the 2006 ARVO annualmeeting).

PGF2a can stimulate the formation of endogenousPGs by stimulation of phospholipase A2 and releaseof arachidonic acid for PG synthesis.89 Humanciliary muscle cells exposed to PGF2a ethanolamideor latanoprost for 9 days show a downregulation ofthe FP receptor. In the same study, downregulationof the aquaporin-1 and versican genes are proposedto increase flow through the ciliary muscle anddecrease IOP.90

PG-induced changes in the sclera also areimportant in the regulation of uveoscleral outflowand may be used to enhance transscleral delivery ofpeptides and other high-molecular-weight sub-stances to the posterior segment of the eye. Fivedays of topical treatment with PGF2a-isopropyl esterincreased MMP-1, -2, and -3 in the sclera ofmonkeys.79 Immunocytochemistry studies andmRNA analysis of human sclera and culturedhuman scleral fibroblasts showed the presence ofEP1, EP2 and FP receptor subtypes but not EP3 andEP4 subtypes.3 Human scleral permeability todextrans was measured in an Ussing chamberfollowing exposure to PGF2a and latanoprost acidfor 1--3 days. Scleral permeability increased in a dose-and time-dependent manner. This was accompaniedby an increase in MMP concentration in the mediawith the greatest increases in MMP-2 and -3compared to MMP-1.33 PGF2a and latanoprost acidalso induced increases in mRNA for MMPs andTIMPs in human scleral organ cultures.82 X-raydiffraction analysis of human scleral explantsshowed that incubation in PGF2a-containing mediacaused the collagen helix to undergo gelatinizationsimilar to what was found after incubation withMMP-enriched media (Molik et al, unpublisheddata, abstract 406 presented at the 2006 ARVOannual meeting).

GENETIC STUDIES

Mice deficient in various PG receptors have beenused to determine the role of prostanoid receptor

subtypes in mediating the IOP-lowering response toclinical PG analogs. Studies in FP receptor--deficientmice have shown that the FP receptor is essential forthe early IOP-lowering response to topical latano-prost, travoprost, bimatoprost, and unoprostone.48

The involvement of the FP receptor in the IOPreduction with long-term dosing is unknown.Upregulation of MMP-2, -3, -9 and FP mRNA inthe sclera following 7 days of topical treatment withlatanoprost also was dependent on an intact FPreceptor gene (Crowston et al, unpublished data,abstract 1551 presented at the 2007 ARVO annualmeeting). EP receptor-deficient mice have beenstudied in similar ways. When EP1, EP2, and EP3

receptor--deficient mice and their wild-type back-ground strain were treated topically with latano-prost, travoprost, bimatoprost, or unoprostone, itwas found that EP3 receptors were involved in theIOP-lowering response to latanoprost, travoprost,and bimatoprost at 3 hours after drug administra-tion but EP1 and EP2 receptors were not.50

PHARMACOLOGIC DIFFERENCES AMONG THE

PROSTAGLANDINS

Natural prostaglandins (PGF2a, PGE2, PGD2,PGI2) have the highest affinity for their respectivereceptors (FP, EP, DP, IP) but are relatively non-selective for these and other PG receptors (TP) andtheir subtypes (DP1, DP2, EP1--4) in receptor-bindingstudies.57 Prostamides are also naturally occurringneutral lipids which have very little activity atprostaglandin receptors but, thus far, only pharma-cologic evidences exists for a prostamide receptor.87

The therapeutic derivatives of PGF2a, either amideor ester prodrugs, are powerful ocular hypotensivedrugs and either mediate their effects primarily viaFP receptor activation or potentially via some yetunidentified receptor activation.57

It has been reported that the prostamide bimato-prost stimulates neither FP nor EP2 receptors and itseffects on aqueous humor outflow, although similarto latanoprost and travoprost, are accomplished viaa receptor distinct from these pure FP receptoragonists. However, bimatoprost acid (17-phenylPGF2a), which is found in the aqueous humor ofhumans after topical application of bimatoprost(Dahlin et al, ARVO 2004 abstract 2096),14,15

exhibits a relatively high affinity for three differentPG receptors (i.e., FP [Ki 5 83 nM], EP1 [Ki 5 95nM], EP3 [Ki 5 387 nM]). Bimatoprost acid alsoexhibits functional activity (phosphoinositide turn-over) at the EP1 (EC50 5 2.7 nM) and FP (EC50 5

2.8--3.8 nM) receptors in most cell types.57 Bimato-prost acid is a potent, non-selective PGF2a analog.


Unlike PGF2a or the EP2 agonist butaprost,bimatoprost did not upregulate orphan nuclearreceptor (Nur77) or connective tissue growth factor(CTNF) expression in human ciliary muscle cells ortrabecular meshwork. In addition, the FP antagonistAL-8810 blocked the PGF2a-induced Nur77 mRNAexpression in human ciliary muscle cells andtrabecular meshwork indicating PGF2a-inducedNur77 mRNA expression is via the activation of FPreceptors.36,37 Bimatoprost induced the upregula-tion of Cyr61 (cysteine-rich angiogenic protein 61)gene expression in cat iris and human ciliary musclecells. Cry61 is involved in regulating extracellularmatrix-associated signaling proteins and may bea unique mechanism by which bimatoprost exerts itspharmacological action to lower IOP independentof Nur77 or CTNF.37 The importance of theinduction or lack of induction of these variousgenes for IOP reduction remains to be determined.The production of transgenic mice lacking thesegenes and their IOP responses to PGF2a, bimato-prost, and butaprost is needed.

Bimatoprost appears to reduce the IOP ofpatients who are unresponsive to latanoprost,24

suggesting that the prostamide bimatoprost andthe FP receptor agonist latanoprost stimulatedifferent receptor populations. This is consistentwith studies on isolated iridial cells where bimato-prost stimulated an entirely different cell popula-tion to those sensitive to PGF2a and bimatoprostacid (17-phenyl PGF2a).59 An equally plausibleexplanation is that some eyes may be deficient incorneal esterase and thus are not able to adequatelyconvert the prodrug latanoprost into its free acidactive form.21 Also splice variants of the FP receptormay exist that have not yet been discovered. Singlenucleotide polymorphisms in the promoter andintron 1 regions of the FP receptor gene arecorrelated with the variability in the IOP-loweringresponse to latanoprost in normal human eyes.54

Summary

Clinical and animal studies of aqueous humordynamics have reported that PG analogs effectivelyreduce IOP by enhancing aqueous humor outflow.The relative effects of PG analogs on each of the twooutflow pathways may vary, but it appears that theyreduce IOP predominantly by increasing uveoscleraloutflow and to a lesser extent trabecular outflowfacility. Morphological studies have identified PGreceptors and described significant cellular changesin PG-treated tissues of both outflow pathways.Biochemical studies have reported many complexcellular events in PG-treated outflow tissues,

including activation of multiple signaling pathways,and increased expression of some factors anddownregulation of others. Genetic studies of knock-out mice treated with PGs have found that a re-duction in IOP requires intact FP and EP3 receptors.

Many questions remain unanswered but progresscontinues to be made. Prostamide antagonists havebeen described76,87 but this has raised new ques-tions.7 A prostamide receptor needs to be clonedand its biosynthesis enzyme identified to concludethat a unique prostamide-sensitive receptor exists.Further work is required to confirm that bimato-prost acts through this receptor. Multiple-dosingstudies of each PG should be compared beforeconcluding that one PG analog acts throughmechanisms different from all others. Live animaland clinical studies are needed to support claimsmade by in vitro experiments. Receptor subtypeselectivity of topical PGs should be identified. Theimportance of induction or lack of induction ofvarious genes for IOP reduction needs to beclarified. One day, the current research may leadto future new drugs that exceed the utility of thePGF2a analogs.

Method of Literature Search

These studies, dating between 2000 and 2008were found from a series of literature searches ofPubMed and from the reference lists of thesearticles. The searches included the following termsin various combinations: anterior segment organculture, aqueous flow, aqueous humor dynamics, bimato-prost, ciliary muscle, DP receptor, EP receptor, fluoropho-tometry, FP receptor, latanoprost, matrix metalloproteinase,monkey, ocular, outflow facility, prostaglandins, prosta-mide, prostanoid, tafluprost, tonography, travoprost,unoprostone, uveoscleral outflow. Original researcharticles, review articles, and meeting abstracts areincluded in this review.

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The supplement in which this article is published wasfunded by Pfizer. The authors reported no proprietary orcommercial interest in any product mentioned or conceptdiscussed in this article. The article was supported in part byunrestricted grants from Research to Prevent Blindness, Inc.,New York, NY (C.T., P.K.), NIH/NEI EY002698 (P.K.); NEI P30EY016665 (Core Grant for Vision Research) (P.K.); unre-stricted departmental and Physician-Scientist awards (P.K.);Ocular Physiology Research and Education Foundation (P.K.);and the Walter Helmerich Chair from the Retina ResearchFoundation (P.K.).

Reprint address: Carol B. Toris, PhD, Department ofOphthalmology, 985840 Nebraska Medical Center, Omaha, NE68198-5840. e-mail: [email protected].

mailto:[email protected]

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