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1. SURVEY OF OPHTHALMOLOGY VOLUME 53 SUPPLEMENT 1 NOVEMBER 2008
Update on the Mechanism of Action of Topical
Prostaglandins for Intraocular Pressure Reduction
Carol B. Toris, PhD,1 B’Ann T. Gabelt, MS,2 and Paul L. Kaufman, MD2
1
Department 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
Abstract. A decade has passed since the first topical prostaglandin analog was prescribed to reduce
intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are
available for clinical use around the world and more are in development. The three most efficacious of
these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor
dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less
consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly
stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the
trabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandins
have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs
release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by
prostaglandins 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 the
shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading
to 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 dynamics
and recent cellular and molecular studies designed to clarify the outflow effects. (Surv Ophthalmol
53:S107--S120, 2008. Ó 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 treatment through the uveoscleral outflow pathway but signif-
of elevated intraocular pressure (IOP) have direct icant effects on trabecular outflow facility also have
effects on one or more parameters of aqueous been reported.67,85 Three PGF2a analogs (bimato-
humor dynamics. IOP usually is reduced by slowing prost, latanoprost, and travoprost) are approved for
the production rate of aqueous humor, by de- glaucoma therapy in the United States, one addi-
creasing the resistance to flow through the trabec- tional analog (unoprostone) is prescribed in Japan
ular meshwork, by increasing drainage through the and a new analog (tafluprost) is in clinical trials in
uveoscleral outflow pathway, or by a combination of Japan. Travoprost and latanoprost are ester pro-
these mechanisms. Currently, the most effective drugs of PGF2a. Bimatoprost is the amide prodrug
outflow drugs approved for clinical use are prosta- of 17-phenyl-PGF2a86 and has been classified
glandin (PG) F2a analogs. These drugs reduce IOP by some as a prostamide,86 although this classifica-
by stimulation of aqueous humor drainage primarily tion has been somewhat controversial.7,37,56--58,86,87
S107
Ó 2008 by Elsevier Inc. 0039-6257/08/$--see front matter
All rights reserved. doi:10.1016/j.survophthal.2008.08.010
2. S108 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL
Unoprostone is an analog of a pulmonary metabo- agonists butaprost44 and 8-iso PGE223 (Table 1).
lite of PGF2a and sometimes labeled a docosanoid.26 Exceptions do exist. One drop of 17-phenyl trinor 8-
Tafluprost is a difluoroprostaglandin derivative of iso PGE2 and the selective EP4 receptor agonist 3,7-
PGF2a.62 Agonists of DP, EP, and TP receptors have dithia PGE1 increased outflow facility sufficiently in
been or are being investigated in animal models for normotensive monkey eyes to account for most, if
their IOP efficacy and potential as new glaucoma not all of the IOP reduction (Kharlamb, ARVO 2004
therapeutic drugs. None of these agonists has yet to abstract 1035, Table 1). An older study found an
be approved for clinical use. increase in outflow facility at 4 hours after one
This review summarizes recent (since 2000) topical drop of PGF2a.35
animal and clinical English-language studies of the One potential reason for the apparent differences
effects of topical PG agonists on aqueous humor in trabecular outflow facility effect among the
dynamics and recent cellular and molecular studies various PG agonists is the method of measurement.
designed to clarify the outflow effects. Two noninvasive methods, tonography and fluoro-
photometry, and two invasive methods, two-level
constant pressure perfusion and isotope accumula-
Aqueous Humor Dynamics tion, are used to make the assessment. All methods
measure trabecular outflow facility, but confound-
Latanoprost, travoprost, and bimatoprost pro-
ing factors are known to exist, including ocular
duce similar increases in uveoscleral outflow of
rigidity (a measure of eye stiffness), pseudofacility
several-fold. Increases in trabecular outflow facility
(the facility of flow of aqueous humor from the
also have been reported but this finding has not
posterior to anterior chamber resulting from the
been found consistently (Table 1). Unoprostone,
probe-induced increase in IOP), and uveoscleral
the least efficacious of the four compounds, appears
outflow facility. The name of the measured variable
to have little effect on uveoscleral outflow in
trabecular outflow facility is not entirely accurate
humans. Rather it works mainly by increasing
because of the inclusion of these other factors in
trabecular outflow facility.69 The new fluoroprosta-
the various measurements. All of the measurement
glandin F2a, tafluprost, increases uveoscleral outflow
techniques assume that uveoscleral outflow facility is
and aqueous flow in monkeys62 but has yet to be
very small and affected little by the measurement
studied in humans. Earlier studies13,89 have re-
itself. This assumption is based on monkey stud-
ported that the topical PG analogs release endoge-
ies8,68 reporting that uveoscleral outflow is relatively
nous prostaglandins that may contribute to the
pressure-independent. However, if an experimental
observed ocular hypotensive effects. Tafluprost in
manipulation were to increase uveoscleral outflow
mice reportedly works in part through FP receptor-
facility, this could be interpreted erroneously, as an
mediated prostaglandin production acting through
increase in trabecular outflow facility. It is thought
the prostanoid EP3 receptor.49 Studies published
by some that PGs increase uveoscleral outflow
between 2000 and 2008 of FP, DP, and EP receptor
facility but this has yet to be proven experimentally.
agonists and their effects on aqueous humor
These methods may not detect changes in trabecu-
dynamics in humans and nonhuman primates are
lar outflow facility if the changes are overshadowed
summarized in Table 1. Studies predating 2000 are
by strong effects on uveoscleral outflow and/or
found in an earlier review.67
uveoscleral outflow facility.
The length of time of treatment could be another
TRABECULAR OUTFLOW FACILITY factor contributing to the differing effects of PGs on
Trabecular outflow facility is not always increased trabecular outflow facility. The immediate IOP
following topical treatment with PG analogs but effects that occur from a single dose of a PG analog
evidence is building that the effect is real and not may be mediated by cellular mechanisms different
unique to any one drug of this class. Latanoprost, from those that occur after repeated applications or
travoprost, bimatoprost, and unoprostone all have continuous exposure.9,83,90 Therefore, findings
been found to significantly increase trabecular from multiple doses of each PG should be com-
outflow facility in at least one clinical study pared before concluding that one PG analog acts
(Table 1). through mechanisms different from all others.
Compared to humans, the trabecular meshwork Mice are being used with increasing frequency to
of monkeys seems to be less affected by PG analogs. evaluate aqueous humor dynamics because of their
Trabecular outflow facility was unchanged following potential for genetic manipulation in addition to
multiple topical treatments of monkeys with PGF2a- their ocular similarities to humans. These animals
isopropyl ester,22 tafluprost,62 and travoprost,71 the exhibit increases in outflow facility 2 hours after one
DP receptor agonist AL-6598,72 and EP receptor 4-ml drop of latanoprost.18 Several limitations to
3. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS
TABLE 1
Studies of Aqueous Humor Dynamics in Humans and Nonhuman Primates Treated with Prostaglandin Analogs Published from 2000 to 2008
Type and Number Duration of
Analog of Subjects Treatment IOP Fa C Pev Fu Reference
FP receptor analogs, prostamides
Bimatoprost ONT volunteers QD Â 2 days Y(day) [(day) [day [day Brubaker et al, 200111
(n 5 25) QD Â 3 days Y(night) [(night)
OHT or POAG patients QD Â 7 days Y 4 [ [ Christiansen et al,
(n 5 29) 200416
ONT volunteers QD Â 7 days Y 4 [ [ Lim et al, 200838
(n 5 30)
Latanoprost OHT patients (n 5 30) QD Â 7 days Y 4 4 4 [ Toris et al, 200173
OHT or POAG patients QD Â 14 days Y 4 [ Dinslage et al, 200420
(n 5 30)
ONT volunteers QD Â 7 days Y 4 [ [ Lim et al , 200838
(n 5 30)
15-keto latanoprost Cynomolgus, ONT One drop Y 4 4 Wang et al, 200777
monkeys (n 5 30)
Travoprost OHT POAG patients QD Â 17 days Y(day and night) 4 [(day) 4 [(marginally Toris et al, 200770
(n 5 26) insignificant)
ONT volunteers QD Â 7 days Y 4 [ [ Lim et al, 200838
(n 5 30)
cynomolgus BID Â 3 days Y 4 4 [a Toris et al, 200571
monkeys unilateral
OHT (n 5 12)
Unoprostone OHT patients (n 5 30) BID 5 days Y 4 [ 4 4 Toris et al, 200469
and 28 days
Tafluprost cynomolgus monkeys QD Â 4 to 5 days Y [ 4 Takagi et al, 200462
(n 5 8--12)
DP receptor agonist
AL-6598 cynomolgus monkeys, BID Â 3 days YONT eye only [ONT eye only 4 [ONT eye only Toris et al, 200672
unilateral OHT
(n 5 11)
EP2 receptor agonists
Butaprost Cynomolgus monkeys, One drop YOHT and ONT 4One drop, 4One drop, ONT [QD Â 5 Nilsson et al, 200644
ONT and OHT or QD Â 5 days ONT days, ONT
(n 5 6--8)
8-iso PGE2 Cynomolgus monkeys, BID, 9--29 doses Y 4 4Two methods [ Gabelt et al, 200423
ONT (n 5 7--10)
S109
(continued on next page)
4. S110 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL
BID 5 twice daily; Cfl 5 outflow facility determined by fluorophotometry; Fa 5 aqueous flow; Fu 5 uveoscleral outflow IOP 5 Intraocular pressure; OHT 5 ocular
hypertension 5 ONT 5 ocular normotension; Pev 5 episcleral venous pressure; POAG 5 primary open angle glaucoma; QD 5 once daily; Y 5 decreased effect; 4 5 no
using this animal model should be mentioned. The
Kharlamb (ARVO 2004
size of the eye makes accurate measurement
Wang (ARVO 2007 difficult. Inflow and outflow are very slow (many-
Reference
abstract 4803)
abstract 1035)
fold slower than in humans),1 and changes in flow
can be near the limit of detection. Additionally, the
anesthesia needed for most measurements quickly
and profoundly affects IOP.31 IOPs vary among
strains of mice,30 and aqueous humor outflow rates
may vary among strains as well. Further research is
days, ONT
needed to characterize differences in aqueous
4QD Â 5
humor dynamics among the murine strains.
Fu
UVEOSCLERAL OUTFLOW
Pev
Increases in uveoscleral outflow have been re-
[One drop, ONT
ported with topical treatment of bimatoprost and
latanoprost in ocular normotensive and hyperten-
sive subjects (Table 1).11,16,20,73 Travoprost increased
[
C
uveoscleral outflow in monkeys71 and marginally
increased it in ocular hypertensive patients as well.70
Unoprostone, the weakest of the four prescribed PG
analogs, is the only one that did not affect
uveoscleral outflow in humans despite 5 days of
drop, ONT
twice-daily dosing.69
Fa
Multiple topical drops of agonists for FP receptors
YOHT and ONT, 4One
(tafluprost62), DP receptors (AL-659872), and EP2
4
receptors (butaprost44 and 8-iso PGE278) increased
uveoscleral outflow in monkeys (Table 1). In
contrast, one drop of the EP4 agonist 3,7-dithia
PGE1 had no effect on uveoscleral outflow in
IOP
monkeys (Kharlamb et al, unpublished data, ab-
stract 1035 presented at the 2004 ARVO annual
meeting). A multiple dose study is needed to clarify
Y
effect; [ 5 increased effect. Blank cell indicates no data reported.
whether the effect persists with repeat dosing.
or QD Â 5 days
Duration of
Treatment
One drop
One drop
AQUEOUS FLOW
Most studies investigating aqueous flow have
found that PG analogs produce a small (10--15%)
increase that may or may not be statistically
and OHT (n 5 6--8)
Cynomolgus monkeys,
Cynomolgus monkeys,
Type and Number
significant and is not clinically important. A
of Subjects
significant increase in aqueous flow was found at
ONT (n 5 6)
night in young healthy Japanese volunteers treated
with latanoprost,41 and during the day and at night
in healthy predominantly white volunteers treated
ONT
with bimatoprost.11 Additionally, aqueous flow in-
creased during the day in monkeys treated with a DP
agonist.72 This effect does not contribute to any
Table 1 (continued )
receptor agonist
3,7-dithia PGE1
reduction in IOP but an increase in aqueous flow
17-phenyl trinor
could be considered a healthy side effect of topical
selective EP4
8-iso PGE2
PG analogs because aqueous humor carries essential
nutrients and removes waste products, crucial for
Analog
keeping the avascular tissues of the anterior
segment healthy.
5. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S111
EPISCLERAL VENOUS PRESSURE pig organ--cultured anterior segments perfused at
Three studies have reported no change in a constant pressure of 15 mm Hg, showed increased
episcleral venous pressure in patients with ocular outflow by up to 62% at 8 hours after topical
hypertension treated for one week with latanoprost, administration of bimatoprost and by 30% at 5
travoprost, or unoprostone (Table 1). The measure- hours after intracameral administration of PGF2a.74
ments (made with a commercially available epis- Human trabecular meshwork monolayer cultures6
cleral venomanometer, EyeTech, Morton Grove, IL), treated with bimatoprost had a 78% increase in
are difficult to make with accuracy and consistency. hydraulic conductivity which also was blocked by
Nevertheless, because no study found any trend to AGN211334.76
suggest a change, it seems reasonable to conclude PGE1 increases outflow facility by 26% in human
that the PG effect on episcleral venous pressure is organ-cultured anterior segments.19 This effect
minimal. probably occurs by an adenylyl cyclase-dependent
pathway activated primarily by the predominant EP2
receptors in the trabecular meshwork.32 Stimulation
Cellular and Molecular Studies of EP2 receptors in trabecular meshwork is coupled
to the activation of high-conductance Caþ2-activated
TRABECULAR MESHWORK Kþ channels (BK) which may contribute to the
Organ-cultured anterior segments and trabecular relaxant activity of EP2 agonists in isolated trabec-
meshwork cell cultures provide strong evidence that ular meshwork strips.61 However, outflow facility was
PG analogs can alter the resistance in trabecular not stimulated and cAMP production was not
outflow (Table 2). PGs have direct effects on matrix altered after short exposure periods with PGF2a or
metalloproteinases (MMPs), neutral proteases that placebo in human organ-cultured anterior
initiate degradation of the extracellular matrix and segments.19
play a major role in regulating resistance to flow Prostaglandin receptors have been identified in
through tissues. MMPs are expressed by human human trabecular meshwork tissue but a prostamide
trabecular meshwork2 and directly control outflow receptor has not yet been cloned. The genes for all
resistance in human organ-cultured anterior seg- prostanoid receptors are expressed in human
ments.9 The activity of MMPs is regulated by tissue trabecular meshwork. Gene expression for the EP2
inhibitors of metalloproteinases (TIMPs).10 Cur- receptor is most abundant, followed by FP, TP, IP,
rently four TIMPS (TIMP-1, -2, -3, -4) have been and EP4, with DP and EP3 at the lowest levels.32
identified in mammals and each TIMP targets Immunofluorescent labeling of FP and EP prosta-
specific MMPs.42 In one study,47 cultures of human noid receptor subtypes in normal human trabecular
trabecular meshwork cells treated with latanoprost meshwork tissue showed positive staining for EP1 on
acid for 24 hours had increased expression of MMPs trabecular cells of the outer portion of the
-1, -3, -17, and -24 and TIMPs -2, -3, and -4. A study6 meshwork and cells lining Schlemm’s canal. EP2
of human organ-cultured anterior segments infused was localized to the outer wall and periphery of
with latanoprost acid found increased outflow Schlemm’s canal. EP3 and EP4 labeling was present
facility at 24 hours after administration when on trabecular cells along the entire meshwork.
compared to control anterior segments (67% vs Moderate expression of FP receptor protein was
6%) but no changes in the amount of MMPs or present in the outer portion of the trabecular
scleral hydraulic conductivity.6 Histological exami- meshwork and endothelial cells of Schlemm’s canal,
nation found regions of focal detachment and loss collector channels and aqueous veins.55
of Schlemm’s canal endothelial cells and extracel- Human trabecular meshwork cells in culture
lular matrix in some areas of the trabecular express many of the same PG receptors as are found
meshwork.6 The focal cell loss was reasoned to be in intact tissue. Cultured trabecular meshwork cells
due to cytoskeletal and focal adhesion changes6 can produce PGE2 and low levels of PGF2a.83,84
because PGs in aortic smooth muscle cells cause Additionally, FP receptors have been identified in
disassembly of actin stress fibers and inhibition of human trabecular meshwork cells as determined by
phosphorylation of paxillin and other focal adhe- the presence of mRNA, protein, and a functional
sion proteins.12 response (increased inositol phosphate accumula-
Bimatoprost increases outflow facility by 40% in tion and intracellular calcium release) to PGF2a5
human organ-cultured anterior segments within 48 and numerous synthetic FP-selective PG agonists.58
hours of treatment. This effect was blocked by PGE2 elicits its biological effects via four G-protein-
preincubation with AGN211334, thought to be coupled receptor subtypes which stimulate
a prostamide-selective antagonist,76 or , alternatively, phosphoinositide turnover with elevation in intra-
an inhibitor of bimatoprost hydrolysis.7 Similarly, cellular-free calcium (EP1 and some EP3), activation
6. TABLE 2
S112
Molecular and Cellular Studies of the Effects of Prostaglandin-Related Compounds on the Aqueous Humor Outflow Pathways
Cellular/Molecular
Surv Ophthalmol 53 (Suppl 1) November 2008
Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events Reference
Trabecular meshwork
PGF2a, fluprostenol trabecular meshwork Up to 2 hours FP receptor mediated Thieme 200664
strips (bovine) inhibition of
endothelin-1
contractility; no effect
on baseline tension or
carbachol-induced
contraction
PGF2a human trabecular 1 hour FP mediated inositol Anthony 19985
meshwork cells phosphate
accumulation;
intracellular calcium
release
PGF2a human anterior segments 60 minutes per dose outflow facility no change in cAMP Dijkstra 199919
unchanged production
PGF2a, butaprost human trabecular 6 hours upregulate mRNA for Liang 2003,200436,37
meshwork cells Nur77 and connective
tissue growth factor
Bimatoprost human anterior segments 48--72 hour continuous outflow facility increase Wan 200776
infusion
Bimatoprost human trabecular 48--72 hour continuous hydraulic conductivity Wan 200776
meshwork monolayer infusion increase
Bimatoprost human trabecular 6 hours no change in Nur77 Liang 2003, 200436,37
meshwork cells mRNA and connective
tissue growth factor
expression
bimatoprost acid (B), human trabecular 1 hr (PI turnover); 3 min FP receptor activation: Sharif 200358
latanoprost acid (L), meshwork cells (Ca 2þ mobilization) stimulate
travoprost acid (T), phosphoinositide
unoprostone (U), turnover
PGF2a (P) (B,L,T,U,P)stimulate
intracellular Ca 2þ
mobilization (T,U,P)
latanoprost acid, PGE1 human trabecular 24 hours increase mRNA for MMP- Oh 200646
meshwork cells 1,-3,-17,-24; TIMP-2,-3,-4
latanoprost acid; PGE1 human anterior segments 24 hours outflow facility increase; focal detachment and loss Bahler 20086
TORIS ET AL
scleral hydraulic of Schlemm’s canal
conductivity cells; extracellular
unchanged matrix loss; no change
in MMPs
latanoprost acid human trabecular 9 days in vivo increase insulin growth Zhao 200390
meshwork cells factor-1 gene and
fibroleukin gene
expression
7. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS
Unoprostone human trabecular Up to 2 hours decrease activity of L-type Thieme 200565
meshwork cells Ca 2þ channels via
tyrosine kinase
pathways
PGE1 human anterior segments 60 minutes increase outflow facility increase cAMP Dijkstra 199919
production
AH13205 human trabecular Less than 10 minutes EP2 agonist activation of Stumpff 200561
meshwork cells BK calcium channels
Uveoscleral tissues
PGF2a monkeys multiple topical decrease collagen types I, Sagara 199953
treatments III, IV in ciliary muscle
PGF2a monkeys multiple topical increase MMP-1,-2,-3 in Gaton 200125
treatments ciliary muscle
PGF2a monkeys multiple topical scleral permeability increase MMP-1,-2,-3 in Weinreb 200179
treatments sclera
PGF2a human sclera explants collagen gelatinization Molik 2006 (ARVO 2006
abstract)
PGF2a, latanoprost human sclera 1--3 days increase scleral increase MMP-1,-2,-3 Kim 200133
permeability
PGF2a, PhXA85 scleral organ cultures 24 hr increase mRNA for MMPs Weinreb 200482
and TIMPx
PGF2a, latanoprost acid human ciliary muscle 5 min for ERK1/2, PKC; increase MMP-2 via Husain 200528
cells 4hr for MMP-2 analysis protein kinase C- and
extracellular signal
regulated protein
kinase 1/2- dependent
pathways
PGF2a, latanoprost acid, human ciliary muscle 1hr for PI turnover; 3 min increase mitogen Sharif 200356
bimatoprost acid, cells for Ca2þ mobilization; activated protein kinase
travoprost acid 5 min for p42/p44 MAP activity;
kinase phosphoinositide
hydrolysis; intracellular
calcium mobilization;
inhibited by FP
antagonist AL-8810
PGF2a, latanoprost, ciliary muscle tissue 5--10 min increase phospholipase Yousufzai 199689
PhXA85 (several species) A2 and release of
arachidonic acid
leading to formation of
PGE2, PGD2 and PGF2a
PGF2a, butaprost human ciliary muscle 6 hours upregulate Nur77 and Liang 2003, 200436,37
cells connective tissue
growth factor
(Continued on next page)
S113
8. Table 2 (continued )
S114
Cellular/Molecular
Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events Reference
Surv Ophthalmol 53 (Suppl 1) November 2008
latanoprost acid human ciliary muscle 24 hours increase mRNA for MMP- Oh 200647
cells 3,-9,-17; increase mRNA
for TIMP-3; decrease
mRNA for MMP-1,-2,-
12,-14,-15,-16, TIMP-4
latanoprost acid human ciliary muscle 24 hours increase MMP-1,-3,-9 Weinreb 200281
cells
latanoprost acid human ciliary muscle Up to 24 hours increase TIMP-1 Anthony 20024
cells
latanoprost acid nonpigmented ciliary Up to 48 hr Cyclooxygenase-2 Hinz 200527
epithelial cells induction leading to
increase MMP-1
latanoprost acid rats Single topical dose Initial IOP elevation Husain 200629
followed by prolonged
IOP reduction
latanoprost acid human ciliary muscle 9 days in vivo decrease aquaporin-1 and Zhao 200390
cells versican gene
expression; decrease in
mRNA for FP receptor
latanoprost, bimatoprost, monkeys topical treatments for one tissue spaces of ciliary Richter 200352
sulprostone, AH13205 year muscle enlarged and
organized; myelinated
nerve fiber bundles
present
Bimatoprost human ciliary muscle 6 hours no change in Nur77 and Liang 2003, 200436,37
cells connective tissue
growth factor
expression;
upregulation of Cyr61
3,7-dithia PGE1 ciliary muscle tissue No details -- probably less no EP4 mediated Kharlamb, 2006 (ARVO
(human and monkey) than 2 hours relaxation 2006 abstract)
Genetic studies
latanoprost, travoprost, FP knockout mice single topical treatment IOP decrease FP receptor needed for Ota 200548
bimatoprost, IOP decrease
unoprostone
Latanoprost FP knockout mice 7 days topical sclera intact FP receptor gene Crowston 2007 (ARVO
needed for 2007 abstract)
TORIS ET AL
upregulation of MMP-
2,-3,-9
latanoprost, travoprost, EP1, EP2, EP3 knockout single topical treatment IOP decrease EP1 and EP2 not involved Ota 200548
bimatoprost, mice in IOP decrease; EP3
unoprostone may have a role
IOP 5 intraocular pressure; MMP 5 matrix metalloproteinase; PG 5 prostaglandin; PI 5 phospholipase C-mediated phosphoinositide; TIMP 5 tissue inhibitor of
metalloproteinase.
9. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S115
of adenylyl cyclase and elevation of intracellular 2006 ARVO annual meeting), PGF2a and latano-
cAMP (EP2 and EP4) or inhibition of adenylyl prost did not.88
cyclase (EP3).17,43 Prolonged treatment of human Remodeling of the extracellular matrix within the
trabecular meshwork cells with latanoprost or PGF2a ciliary muscle and sclera is the most thoroughly
ethanolamide causes an increase in expression of understood effect of PG treatment. Dissolution of
genes for insulin-like growth factor-1 (IGF-1) and collagen types I and III within the connective tissue-
fibroleukin that could act to increase outflow filled spaces between the outer longitudinally
facility. IGF-1 is reported to increase the level of oriented muscle bundles39,63 results from PG-stim-
MMPs, stromelysin, and gelatinase in trabecular ulated induction of enzymes MMP-1, -2, and -3 in
meshwork cells. The protease activity of fibroleukin the ciliary muscle and surrounding sclera. 25 Long-
may be active against a component in the extracel- term (1 year) unilateral treatment of monkey eyes
lular matrix.90 with topical bimatoprost, latanoprost, sulprostone
Unoprostone free acid (UF-021) shows low (EP3/EP1 agonist) or AH13205 and butaprost (EP2
affinity for all prostanoid receptors and weak agonists) found that in all cases the tissue spaces of
functional responses via FP receptor activation.57 the ciliary muscle were enlarged and organized into
Several molecular events have been associated with elongated tube-like spaces, covered by endothelial-
unoprostone exposure. A reduction in the activity of like cells often in contact with the basement
L-type Ca2þ channels via a signal transduction membrane, and contained myelinated nerve fiber
pathway was mediated by tyrosine kinases.65 Activa- bundles.44,52 These fluid pathways resembled a kind
tion of BK channels by unoprostone free acid of lymphatic system described in the choroid.34
inhibited trabecular meshwork contraction leading Changes in the trabecular meshwork also were
to an increase in outflow.66 present. MMP expression in human ciliary body
Endothelin-1 is involved in regulating the con- tissue and ciliary muscle cells was determined after
tractility of the trabecular meshwork. FP receptor latanoprost acid treatment for 24 hours. The mRNA
agonists can block endothelin-1 induced contractil- of MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, and
ity of the trabecular meshwork. Evidence indicates -24 as well as TIMP-1 to -4 were found in ciliary body
this inhibition is mediated by the FP receptor.64 tissue and ciliary muscle cells. Latanoprost increased
MMP-3, -9, -17, and TIMP-3 and down-regulated
MMP-1, -2, -12, -14, -15, and -16 and TIMP-4.46
UVEOSCLERAL TISSUES Latanoprost acid induced a concentration-depen-
Immunohistochemistry studies of EP and FP dent increase in MMP-1, -3, and -9 gene transcrip-
receptor localization in the uveoscleral tissue in tion81 and a concentration- and time-dependent
normal human donor eyes indicate the presence of increase in TIMP-1 but not TIMP-2 mRNA and
EP-1, -2, -3, -4 and FP receptors in the ciliary body protein.4
and sclera. FP receptors are most abundant in the Loss of cyclooxygenase (COX)-2 expression in the
circular portion of the ciliary muscle.55 ciliary body of humans has been associated with
Several mechanisms have been proposed to glaucoma.40 This association has led to studies
explain the PG-induced increase in uveoscleral investigating the connection between PGs, COX-2
outflow: remodeling of the extracellular matrix of expression and MMPs. Indeed, the IOP-lowering
the ciliary muscle45,53,80 and sclera33,82 (Molik et al, action of latanoprost appears to be associated with
unpublished data, abstract 406 presented at the induction of COX-2 and subsequent MMP-1 expres-
2006 ARVO annual meeting) causing changes in the sion in human nonpigmented epithelial cells.27
permeability of these tissues; widening of the MMP-1 released into the aqueous humor would be
connective tissue-filled spaces among the ciliary expected to flow into the ciliary muscle and through
muscle bundles,39,63 which may be caused in part the trabecular meshwork and Schlemm’s canal to
by relaxation of the ciliary muscle51,75 and changes potentially increase outflow via multiple routes.
in the shape of ciliary muscle cells as a result of Studies to elucidate additional cellular mecha-
alterations in actin and vinculin localization within nisms associated with PG-induced MMP secretion are
the cells.60 ongoing. PGF2a- and latanoprost-induced secretion
Ciliary muscle relaxation has been suggested as and activation of MMP-2 in ciliary muscle cells were
responsible for the initial reduction in IOP from shown to occur via protein kinase C and extracellular
topical PGs. This does not appear to be the case for signal regulated protein kinase 1/2-dependent
all PGs and their agonists. PGE1 and PGE2 relaxed pathways.28 Mitogen-activated protein kinase activity
isolated monkey ciliary muscle strips precontracted was stimulated in human ciliary muscle cells with
with carbachol88 but 3,7-dithia PGE1 (Kharlamb et travoprost acid O PGF2a O latanoprost acid O
al, unpublished data, abstract 413 presented at the bimatoprost O latanoprost 5 bimatoprost acid. The
10. S116 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL
FP antagonist AL-8810 completely inhibited the subtypes in mediating the IOP-lowering response to
mitogen-activated protein kinase activity induced by clinical PG analogs. Studies in FP receptor--deficient
bimatoprost and bimatoprost acid, indicating that mice have shown that the FP receptor is essential for
both agonists were activating the FP receptor.57 the early IOP-lowering response to topical latano-
Inhibition of the latanoprost-induced reduction prost, travoprost, bimatoprost, and unoprostone.48
of IOP in rats by thalidomide suggested that the The involvement of the FP receptor in the IOP
IOP-lowering response is mediated, in part, through reduction with long-term dosing is unknown.
tumor necrosis factor-a-dependent signaling path- Upregulation of MMP-2, -3, -9 and FP mRNA in
ways. Treatment of human ciliary muscle cells with the sclera following 7 days of topical treatment with
tumor necrosis factor-a increased the secretion of latanoprost also was dependent on an intact FP
MMP-1, and -2 (Husain et al, unpublished data, receptor gene (Crowston et al, unpublished data,
abstract 219 presented at the 2006 ARVO annual abstract 1551 presented at the 2007 ARVO annual
meeting). meeting). EP receptor-deficient mice have been
PGF2a can stimulate the formation of endogenous studied in similar ways. When EP1, EP2, and EP3
PGs by stimulation of phospholipase A2 and release receptor--deficient mice and their wild-type back-
of arachidonic acid for PG synthesis.89 Human ground strain were treated topically with latano-
ciliary muscle cells exposed to PGF2a ethanolamide prost, travoprost, bimatoprost, or unoprostone, it
or latanoprost for 9 days show a downregulation of was found that EP3 receptors were involved in the
the FP receptor. In the same study, downregulation IOP-lowering response to latanoprost, travoprost,
of the aquaporin-1 and versican genes are proposed and bimatoprost at 3 hours after drug administra-
to increase flow through the ciliary muscle and tion but EP1 and EP2 receptors were not.50
decrease IOP.90
PG-induced changes in the sclera also are
important in the regulation of uveoscleral outflow
and may be used to enhance transscleral delivery of PHARMACOLOGIC DIFFERENCES AMONG THE
peptides and other high-molecular-weight sub- PROSTAGLANDINS
stances to the posterior segment of the eye. Five Natural prostaglandins (PGF2a, PGE2, PGD2,
days of topical treatment with PGF2a-isopropyl ester PGI2) have the highest affinity for their respective
increased MMP-1, -2, and -3 in the sclera of receptors (FP, EP, DP, IP) but are relatively non-
monkeys.79 Immunocytochemistry studies and selective for these and other PG receptors (TP) and
mRNA analysis of human sclera and cultured their subtypes (DP1, DP2, EP1--4) in receptor-binding
human scleral fibroblasts showed the presence of studies.57 Prostamides are also naturally occurring
EP1, EP2 and FP receptor subtypes but not EP3 and neutral lipids which have very little activity at
EP4 subtypes.3 Human scleral permeability to prostaglandin receptors but, thus far, only pharma-
dextrans was measured in an Ussing chamber cologic evidences exists for a prostamide receptor.87
following exposure to PGF2a and latanoprost acid The therapeutic derivatives of PGF2a, either amide
for 1--3 days. Scleral permeability increased in a dose- or ester prodrugs, are powerful ocular hypotensive
and time-dependent manner. This was accompanied drugs and either mediate their effects primarily via
by an increase in MMP concentration in the media FP receptor activation or potentially via some yet
with the greatest increases in MMP-2 and -3 unidentified receptor activation.57
compared to MMP-1.33 PGF2a and latanoprost acid It has been reported that the prostamide bimato-
also induced increases in mRNA for MMPs and prost stimulates neither FP nor EP2 receptors and its
TIMPs in human scleral organ cultures.82 X-ray effects on aqueous humor outflow, although similar
diffraction analysis of human scleral explants to latanoprost and travoprost, are accomplished via
showed that incubation in PGF2a-containing media a receptor distinct from these pure FP receptor
caused the collagen helix to undergo gelatinization agonists. However, bimatoprost acid (17-phenyl
similar to what was found after incubation with PGF2a), which is found in the aqueous humor of
MMP-enriched media (Molik et al, unpublished humans after topical application of bimatoprost
data, abstract 406 presented at the 2006 ARVO (Dahlin et al, ARVO 2004 abstract 2096),14,15
annual meeting). exhibits a relatively high affinity for three different
PG receptors (i.e., FP [Ki 5 83 nM], EP1 [Ki 5 95
nM], EP3 [Ki 5 387 nM]). Bimatoprost acid also
exhibits functional activity (phosphoinositide turn-
GENETIC STUDIES over) at the EP1 (EC50 5 2.7 nM) and FP (EC50 5
Mice deficient in various PG receptors have been 2.8--3.8 nM) receptors in most cell types.57 Bimato-
used to determine the role of prostanoid receptor prost acid is a potent, non-selective PGF2a analog.
11. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S117
Unlike PGF2a or the EP2 agonist butaprost, including activation of multiple signaling pathways,
bimatoprost did not upregulate orphan nuclear and increased expression of some factors and
receptor (Nur77) or connective tissue growth factor downregulation of others. Genetic studies of knock-
(CTNF) expression in human ciliary muscle cells or out mice treated with PGs have found that a re-
trabecular meshwork. In addition, the FP antagonist duction in IOP requires intact FP and EP3 receptors.
AL-8810 blocked the PGF2a-induced Nur77 mRNA Many questions remain unanswered but progress
expression in human ciliary muscle cells and continues to be made. Prostamide antagonists have
trabecular meshwork indicating PGF2a-induced been described76,87 but this has raised new ques-
Nur77 mRNA expression is via the activation of FP tions.7 A prostamide receptor needs to be cloned
receptors.36,37 Bimatoprost induced the upregula- and its biosynthesis enzyme identified to conclude
tion of Cyr61 (cysteine-rich angiogenic protein 61) that a unique prostamide-sensitive receptor exists.
gene expression in cat iris and human ciliary muscle Further work is required to confirm that bimato-
cells. Cry61 is involved in regulating extracellular prost acts through this receptor. Multiple-dosing
matrix-associated signaling proteins and may be studies of each PG should be compared before
a unique mechanism by which bimatoprost exerts its concluding that one PG analog acts through
pharmacological action to lower IOP independent mechanisms different from all others. Live animal
of Nur77 or CTNF.37 The importance of the and clinical studies are needed to support claims
induction or lack of induction of these various made by in vitro experiments. Receptor subtype
genes for IOP reduction remains to be determined. selectivity of topical PGs should be identified. The
The production of transgenic mice lacking these importance of induction or lack of induction of
genes and their IOP responses to PGF2a, bimato- various genes for IOP reduction needs to be
prost, and butaprost is needed. clarified. One day, the current research may lead
Bimatoprost appears to reduce the IOP of to future new drugs that exceed the utility of the
patients who are unresponsive to latanoprost,24 PGF2a analogs.
suggesting that the prostamide bimatoprost and
the FP receptor agonist latanoprost stimulate
different receptor populations. This is consistent Method of Literature Search
with studies on isolated iridial cells where bimato- These studies, dating between 2000 and 2008
prost stimulated an entirely different cell popula- were found from a series of literature searches of
tion to those sensitive to PGF2a and bimatoprost PubMed and from the reference lists of these
acid (17-phenyl PGF2a).59 An equally plausible articles. The searches included the following terms
explanation is that some eyes may be deficient in in various combinations: anterior segment organ
corneal esterase and thus are not able to adequately culture, aqueous flow, aqueous humor dynamics, bimato-
convert the prodrug latanoprost into its free acid prost, ciliary muscle, DP receptor, EP receptor, fluoropho-
active form.21 Also splice variants of the FP receptor tometry, FP receptor, latanoprost, matrix metalloproteinase,
may exist that have not yet been discovered. Single monkey, ocular, outflow facility, prostaglandins, prosta-
nucleotide polymorphisms in the promoter and mide, prostanoid, tafluprost, tonography, travoprost,
intron 1 regions of the FP receptor gene are unoprostone, uveoscleral outflow. Original research
correlated with the variability in the IOP-lowering articles, review articles, and meeting abstracts are
response to latanoprost in normal human eyes.54 included in this review.
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glandin-ethanolamides) and their pharmacology. Br J
funded by Pfizer. The authors reported no proprietary or
Pharmacol 153:410--9, 2008
commercial interest in any product mentioned or concept
88. Yamaji K, Yoshitomi T, Ishikawa H, et al: Prostaglandins E1
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unrestricted grants from Research to Prevent Blindness, Inc.,
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New York, NY (C.T., P.K.), NIH/NEI EY002698 (P.K.); NEI P30
89. Yousufzai SY, Ye Z: Abdel-Latif AA: Prostaglandin F2 alpha
EY016665 (Core Grant for Vision Research) (P.K.); unre-
and its analogs induce release of endogenous prostaglan-
stricted departmental and Physician-Scientist awards (P.K.);
dins in iris and ciliary muscles isolated from cat and other
Ocular Physiology Research and Education Foundation (P.K.);
mammalian species. Exp Eye Res 63:305--10, 1996
and the Walter Helmerich Chair from the Retina Research
90. Zhao X, Pearson KE, Stephan DA, et al: Effects of
Foundation (P.K.).
prostaglandin analogues on human ciliary muscle and
Reprint address: Carol B. Toris, PhD, Department of
trabecular meshwork cells. Invest Ophthalmol Vis Sci 44:
Ophthalmology, 985840 Nebraska Medical Center, Omaha, NE
1945--52, 2003
68198-5840. e-mail: ctoris@unmc.edu.