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The efficacy of timolol in gel-forming solution after morning or evening dosing in Asian glaucomatous patients

Ong LB, Liza-Sharmini AT, Chieng LL, Cheong MT, Vengadasalam SR, Shin HC, et al.

J Ocul Pharmacol Ther, 2005 Oct;21(5):388-94.
PMID: 16245965

The aim of this study was to determine the effectiveness of timolol gel-forming solution as a monotherapy and to compare the efficacy of timolol gel-forming solution morning instillation versus at night application in Asians with newly diagnosed open-angle glaucoma.

Matched MeSH terms: Intraocular Pressure/drug effects
Fulltext Unilateral superior ophthalmic vein thrombosis in a user of oral contraceptives

Jaais F, Habib ZA

Med J Malaysia, 1994 Dec;49(4):416-8.
PMID: 7674980

A patient on oral contraceptives over several years developed unilateral proptosis, haemorrhagic retinopathy and increase in intraocular pressure. An orbital vein venogram confirmed the diagnosis of right superior ophthalmic vein thrombosis. There was complete resolution of thrombosis and eye signs and symptoms with discontinuation of the oral contraceptive.

Matched MeSH terms: Intraocular Pressure/drug effects
Intraocular pressure lowering effect and structure-activity relationship of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds in ocular normotensive rats: Insight on possible link with hypotensive activity

Marcus AJ, Iezhitsa I, Agarwal R, Vassiliev P, Spasov A, Zhukovskaya O, et al.

Eur J Pharm Sci, 2018 Mar 01;114:245-254.
PMID: 29274441 DOI: 10.1016/j.ejps.2017.12.015

In an effort to find new ocular hypotensive drug candidates, a total of 27 condensed benzimidazoles based compounds were screened. This study was done in normotensive rats and rebound tonometry was used to estimate IOP. All compounds were topically applied as a single drop, unilaterally, at 3 different concentrations (0.1%, 0.2% and 0.4%). The contralateral eye was instilled with vehicle and served as control. The IOP reduction was measured up to 6h. It was observed that with a single topical instillation, compounds RU 551, RU 555, RU839 (pyrimido[1,2-a]benzimidazole derivatives), and RU 615 (imidazo[1,2-a]benzimidazole derivative) showed significant IOP lowering activities in ocular normotensive rats. All other compounds showed none, weak and inconsistent IOP lowering effect. The relationship between ability of IOP lowering and hypotensive activities was studied. According to the pharmacophore analysis, the class of pyrimido[1,2-a]benzimidazole is more promising than the class of imidazo[1,2-a]benzimidazole as a source of compounds with high IOP lowering activity. Pharmacophore analysis also showed that the critical features of high IOP lowering activity are methoxyphenyl and [phenyl]alkyl fragments, and non-conjugated six-membered heterocyclic ring.

Matched MeSH terms: Intraocular Pressure/drug effects*
Mechanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats

Agarwal R, Krasilnikova AV, Raja IS, Agarwal P, Mohd Ismail N

Eur J Pharmacol, 2014 May 5;730:8-13.
PMID: 24583339 DOI: 10.1016/j.ejphar.2014.02.021

Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.

Matched MeSH terms: Intraocular Pressure/drug effects*
Effect of rocuronium compared with succinylcholine on intraocular pressure during rapid sequence induction of anaesthesia

Chiu CL, Jaais F, Wang CY

Br J Anaesth, 1999 May;82(5):757-60.
PMID: 10536557

We have compared the effect of rocuronium and succinylcholine on intraocular pressure (IOP) during rapid sequence induction of anaesthesia using propofol and fentanyl, in a randomized double-blind study. We studied 30 adult patients, allocated to one of two groups. Anaesthesia was induced with fentanyl 2 micrograms kg-1 and propofol until loss of verbal response. This was followed by succinylcholine 1.5 mg kg-1 (group S; n = 15) or rocuronium 0.9 mg kg-1 (group R; n = 15). Laryngoscopy was performed 60 s later. IOP, mean arterial pressure (MAP) and heart rate (HR) were measured before induction, immediately before intubation and every minute after intubation for 5 min. A Keeler Pulsair air impulse tonometer was used to measure IOP and the mean of two readings obtained in the right eye at each measurement time was recorded. Intubating conditions were evaluated according to a simple scoring system. IOP in the succinylcholine group was significantly greater than that in the rocuronium group (mean 21.6 (SEM 1.4) mm Hg vs 13.3 (1.4) mm Hg; P < 0.001). Intubating conditions were equally good in both groups. We conclude that with rapid sequence induction of anaesthesia using propofol and fentanyl, rocuronium did not cause as great an increase in IOP as succinylcholine and may be an alternative in open eye injury cases.

Matched MeSH terms: Intraocular Pressure/drug effects*
Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target?

Agarwal P, Agarwal R

Expert Opin Ther Targets, 2018 07;22(7):629-638.
PMID: 29883239 DOI: 10.1080/14728222.2018.1486822

INTRODUCTION: Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis. Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized. The role of RAS in ECM remodeling is discussed both in terms of its effects on ECM synthesis and its breakdown. The mechanisms of ECM remodeling involving interactions of RAS with transforming growth factor-β, Wnt/β-catenin signaling, bone morphogenic proteins, connective tissue growth factor, and matrix metalloproteinases in ocular tissue are discussed. Expert opinion: Current literature strongly indicates a significant role of RAS in ECM remodeling in TM of hypertensive eyes. Hence, IOP-lowering effect of RAS inhibitors may primarily be attributed to restoration of ECM homeostasis in aqueous outflow pathways rather than its vascular effects. However, the mechanistic targets for RAS inhibitors have much wider distribution and consequences, which remain relatively unexplored in TM.

Matched MeSH terms: Intraocular Pressure/drug effects
Fulltext Intraocular pressure variation following retrobulbar anaesthesia among the different sex, age and ethnic groups in Malaysia

Lee FN, Kong VY, Lee GP, Ho KH, Choon SC, Hoh HB

Med J Malaysia, 1999 Dec;54(4):438-41.
PMID: 11072460

A total of 114 patients (48 Chinese, 34 Malay and 32 Indian) undergoing extracapsular cataract extraction (ECCE) with intraocular lens implantation, were enrolled. All were given 3 ml of local anaesthetic (combination of equal amounts of lignocaine 2% and bupivacaine 0.5%) using retrobulbar technique. Intraocular pressure (IOP) was measured at different time intervals; before, immediately after and 5 minutes after injection with Honan balloon compression. Mean IOP increased by 5.0 mmHg immediately after injection (p < 0.001) and reduced to baseline level after 5 minutes of external compression. Although there were no statistical difference in terms of IOP variation between sex and age groups, Chinese patients demonstrated the highest IOP rise following retrobulbar anaesthesia. This is the first study to demonstrate the influence of race in the IOP response with Chinese subjects having the highest IOP rise.

Matched MeSH terms: Intraocular Pressure/drug effects*
The effect of mivacurium pretreatment on intra-ocular pressure changes induced by suxamethonium

Chiu CL, Lang CC, Wong PK, Delilkan AE, Wang CY

Anaesthesia, 1998 May;53(5):501-5.
PMID: 9659028

Forty patients without eye disease, undergoing elective nonophthalmic surgery, were studied in a double-blind, randomised, placebo-controlled study evaluating the efficacy of mivacurium pretreatment in attenuating the rise in intra-ocular pressure in response to suxamethonium administration, laryngoscopy and intubation. The patients were randomly allocated to receive either mivacurium 0.02 mg.kg-1 or normal saline as pretreatment 3 min before a rapid sequence induction technique using alfentanil, propofol and suxamethonium. Suxamethonium induced a significant increase in intra-ocular pressure in the control group but not in the mivacurium pretreatment group (mean (SEM) increase = 3.5 (1.2) mmHg vs. 0.4 (0.8) mmHg, p < 0.05). There was a decrease in intra-ocular pressure in both groups after laryngoscopy and intubation with no significant difference between the two groups. These results show that mivacurium pretreatment is effective in preventing the increase in intra-ocular pressure after suxamethonium administration.

Matched MeSH terms: Intraocular Pressure/drug effects*
Raised Intraocular Pressure in Nonjuvenile Idiopathic Arthritis-Uveitis Children: Risk Factors and Effect on Retinal Nerve Fiber Layer

Md Din N, Tomkins-Netzer O, Talat L, Taylor SR, Isa H, Bar A, et al.

J Glaucoma, 2016 07;25(7):598-604.
PMID: 26900824 DOI: 10.1097/IJG.0000000000000379

PURPOSE: To determine risk factors for intraocular pressure (IOP) elevation and glaucoma in children with nonjuvenile idiopathic arthritis-related uveitis and any IOP-related changes in the retinal nerve fiber layer (RNFL) thickness.

PATIENTS AND METHODS: Clinical data were collected from children attending a tertiary referral uveitis clinic between May 2010 and October 2012. We assigned 206 eyes of 103 children into 32 normal eyes, 108 normotensive uveitics (NU), 41 hypertensive uveitics (HU: raised IOP without glaucomatous disc), and 25 glaucomatous uveitics (GU: raised IOP with glaucomatous disc). Risk factors for raised IOP, glaucoma and steroid response (SR) were evaluated and RNFL thickness across groups was compared with determine changes related to raised IOP.

RESULTS: IOP elevation occurred in 40 patients (38.8%) or 66/174 eyes with uveitis (37.9%); and SR occurred in 35.1% of all corticosteroid-treated eyes. Chronic uveitis was a significant risk factor for raised IOP [odds ratio (OR)=9.28, P=0.001], glaucoma, and SR (OR=8.4, P<0.001). Higher peak IOP was also a risk factor for glaucoma (OR=1.4, P=0.003). About 70% of SR eyes were high responders (IOP increase >15 mm Hg from baseline), associated with younger age and corticosteroid injections. Although no significant RNFL thinning was detected between HU and NU eyes, significant thinning was detected in the inferior quadrant of GU (121.3±28.9 μm) compared with NU eyes (142.1±32.0 μm, P=0.043).

CONCLUSIONS: Children with chronic uveitis are at higher risk of raised IOP and glaucoma. Thinning of the inferior RNFL quadrant may suggest glaucomatous changes in uveitic children with raised IOP.

Study site: Moorfields Eye Hospital, London

Matched MeSH terms: Intraocular Pressure/drug effects
Future target molecules in antiglaucoma therapy: tgf-Beta may have a role to play

Agarwal R, Agarwal P

Ophthalmic Res, 2010;43(1):1-10.
PMID: 19829006 DOI: 10.1159/000246571

Glaucoma, a leading cause of irreversible blindness, is often associated with increased resistance to aqueous outflow in trabecular tissue. Increased outflow resistance has been attributed to increased extracellular matrix (ECM) deposition in trabecular tissue. A critical balance between the synthesis and breakdown of the components of extracellular tissue is important in keeping the intraocular pressure within the normal range. Multiple mechanisms have been shown to affect ECM turnover in trabecular tissue. In this review, we examine the related literature to understand the role of TGF-beta in ECM turnover, in the development and progression of glaucoma, and in possible therapeutic strategies that can be devised by targeting the TGF-beta signaling pathways.

Matched MeSH terms: Intraocular Pressure/drug effects
Fulltext Persistence and treatment patterns of fixed combination drugs for glaucoma: a retrospective claims database study in Japan

Kashiwagi K, Chono E, Koesters S, Yap PS

BMC Ophthalmol, 2020 Jun 10;20(1):223.
PMID: 32522181 DOI: 10.1186/s12886-020-01508-8

BACKGROUND: Poor persistence with glaucoma therapy can lead to disease progression and subsequent blindness. Persistence with second-line glaucoma combination treatment in a Japanese real-world setting and whether it differed from fixed and unfixed combination drugs was investigated.
METHODS: This was a retrospective, non-interventional, cohort study using data from a Japanese medical claims database. Patients with glaucoma aged ≥20 years with a first drug claim for glaucoma treatment between 01 July 2005 and 30 October 2014 and with data for > 6 months before and after this first prescription were included. The primary endpoint was duration of drug persistence among glaucoma patients with and without the use of fixed combination drugs in the year following initiation of second-line combination treatment.
RESULTS: Of 1403 patients included in the analysis, 364 (25.94%) received fixed combination drugs and 1039 (74.06%) received unfixed combination drugs as second-line treatment. Baseline characteristics were generally comparable between the groups. A total of 39.01% of patients on fixed combination drugs, compared with 41.67% of patients on unfixed combination drugs, persisted on their glaucoma drugs 12 months post second-index date. Median persistence durations for the fixed combination drugs and unfixed combination drugs groups were 6 (95% confidence interval [CI]: 5-8) and 7 months (95% CI 6-9), respectively. Patients who received prostaglandin analogs (PGAs) were the most persistent with their treatment (n = 99, 12.84%). Patients diagnosed with primary open-angle glaucoma were less likely to experience treatment modification (hazard ratio [HR]: 0.800, 95% CI 0.649-0.986, P = 0.036), while those diagnosed with secondary glaucoma were more likely to experience treatment modification (HR: 1.678, 95% CI 1.231-2.288, P = 0.001) compared with glaucoma suspects.
CONCLUSIONS: In this retrospective claims database study, the persistence rate of second-line glaucoma combination treatment was low, with no difference in persistence between glaucoma patients receiving unfixed combination drugs compared with fixed combination drugs. Patients on PGA showed greater persistence rates compared with other treatments.

Matched MeSH terms: Intraocular Pressure/drug effects*
Role of adenosine receptors in resveratrol-induced intraocular pressure lowering in rats with steroid-induced ocular hypertension

Razali N, Agarwal R, Agarwal P, Kumar S, Tripathy M, Vasudevan S, et al.

Clin Exp Ophthalmol, 2015 Jan-Feb;43(1):54-66.
PMID: 24995479 DOI: 10.1111/ceo.12375

BACKGROUND: Steroid-induced ocular hypertension is currently treated in the same way as primary open-angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans-resveratrol in rats with steroid-induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans-resveratrol.
METHODS: The oculohypotensive effect of unilateral single-drop application of various concentrations of trans-resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid-induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans-resveratrol after pretreating animals with AR subtype-specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein-ligand interaction, to determine the AR-trans-resveratrol interaction.
RESULTS: All concentrations of trans-resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans-resveratrol 0.2%. In oculohypertensive rats, trans-resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A₁ antagonist abolished the oculohypotensive effect of trans-resveratrol. Pretreatment with A₃ and A₂A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by trans-resveratrol application in treated eyes. Computational studies showed that trans-resveratrol has highest affinity for A₂B and A₁, followed by A2A and A₃ AR.
CONCLUSION: Topically applied trans-resveratrol reduces IOP in rats with steroid-induced ocular hypertension. Trans-resveratrol-induced oculohypotension involves its agonistic activity at the A₁ AR.
KEYWORDS: adenosine receptors; docking simulation; intraocular pressure; resveratrol; topical

Matched MeSH terms: Intraocular Pressure/drug effects*
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and Preservatives

Ramli N, Supramaniam G, Samsudin A, Juana A, Zahari M, Choo MM

Optom Vis Sci, 2015 Sep;92(9):e222-6.
PMID: 25730335 DOI: 10.1097/OPX.0000000000000542

PURPOSE: To evaluate the prevalence of ocular surface disease (OSD) in glaucoma and nonglaucoma subjects using different clinical tests and to determine the effect of number of antiglaucoma medications and preservatives on OSD.
METHODS: This is a cross-sectional, case-comparison study at the Eye Clinic of the University of Malaya Medical Centre, Malaysia, between June 2012 and January 2013. Glaucoma subjects (n = 105) using topical antiglaucoma medications were compared with control subjects (n = 102) who were not on any topical medications. The presence of OSD was assessed using the tear film breakup time (TBUT) test, corneal staining, Schirmer test, and Ocular Surface Disease Index (OSDI) questionnaire grading.
RESULTS: The prevalence of OSD varied from 37 to 91% in the glaucoma group, depending on the type of clinical test. More subjects in the glaucoma group had corneal staining (63% vs. 36%, p = 0.004), abnormal Schirmer tests (39% vs. 25%, p = 0.049), and moderate OSDI symptoms (17% vs. 7%, p = 0.028). The percentage with abnormal TBUT increased with higher numbers of topical medications and was high with both benzalkonium chloride-containing and preservative-free eye drops (90% and 94%, respectively, both p < 0.001). Benzalkonium chloride was associated with a nearly three times higher odds ratio of showing abnormal OSDI.
CONCLUSIONS: Ocular surface disease is common in those using topical antiglaucoma medications. Abnormal TBUT is associated with increasing number of eye drops and benzalkonium chloride-containing eye drops, although this also occurs with the use of preservative-free eye drops.
Study site: Eye Clinic, University of Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia,

Matched MeSH terms: Intraocular Pressure/drug effects
Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs

Razali N, Agarwal R, Agarwal P, Kapitonova MY, Kannan Kutty M, Smirnov A, et al.

Eur J Pharmacol, 2015 Feb 15;749:73-80.
PMID: 25481859 DOI: 10.1016/j.ejphar.2014.11.029

Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects.

Matched MeSH terms: Intraocular Pressure/drug effects
Topical trans-resveratrol ameliorates steroid-induced anterior and posterior segment changes in rats

Razali N, Agarwal R, Agarwal P, Tripathy M, Kapitonova MY, Kutty MK, et al.

Exp Eye Res, 2016 Feb;143:9-16.
PMID: 26424219 DOI: 10.1016/j.exer.2015.09.014

Steroid-induced hypertension and glaucoma is associated with increased extracellular meshwork (ECM) deposition in trabecular meshwork (TM). Previous studies have shown that single drop application of trans-resveratrol lowers IOP in steroid-induced ocular hypertensive (SIOH) rats. This IOP lowering is attributed to activation of adenosine A1 receptors, which may lead to increased matrix metalloproteinase (MMP)-2 activity. This study evaluated the effect of repeated topical application of trans-resveratrol for 21 days in SIOH animals on IOP, changes in MMP-2 level in aqueous humor, trabecular meshwork and retinal morphology and retinal redox status. We observed that treatment with trans-resveratrol results in significant and sustained IOP reduction in SIOH rats. This IOP reduction is associated with significantly higher aqueous humor total MMP-2 level; significantly reduced TM thickness and increased number of TM cells. Treatment with trans-resveratrol also significantly increased ganglion cell layer (GCL) thickness, the linear cell density in the GCL and inner retina thickness; and significantly reduced retinal oxidative stress compared to the SIOH vehicle-treated group. In conclusion, repeated dose topical application of trans-resveratrol produces sustained IOP lowering effect, which is associated with increased level of aqueous humor MMP-2, normalization of TM and retinal morphology and restoration of retinal redox status.

Matched MeSH terms: Intraocular Pressure/drug effects*
The Relationship Between Long-term Use of Intranasal Corticosteroid and Intraocular Pressure

Mohd Zain A, Md Noh UK, Hussein S, Che Hamzah J, Mohd Khialdin S, Md Din N

J Glaucoma, 2019 04;28(4):321-324.
PMID: 30585941 DOI: 10.1097/IJG.0000000000001164

PURPOSE: The purpose of this study was to investigate the association between long-term intranasal steroid use and intraocular pressure (IOP) elevation.
PATIENTS AND METHODS: In total, 100 eyes from 50 patients on long-term intranasal steroids (>2 y) for allergic rhinitis and 90 eyes from 45 controls were included in this study. Patients on other forms of steroids and risk factors for glaucoma were excluded. IOP was measured and nonmydriatic stereoscopic optic disc photos were taken for each eye. The vertical cup-to-disc ratio and the status of the optic disc were evaluated.
RESULTS: The mean IOP for intranasal steroids group was significantly higher (15.24±2.31 mm Hg) compared to the control group (13.91±1.86 mm Hg; P=0.000). However, there were no significant differences in the vertical cup-to-disc ratio and the status of glaucomatous optic disc changes between the groups.
CONCLUSIONS: Prolonged use of intranasal steroids cause statistical significant increase in IOP in patients with allergic rhinitis although no significant glaucomatous disc changes were seen. We suggest patients on long-term use of intranasal steroid have a yearly eye examination to be monitored for IOP elevation and those with additional risk factors for glaucoma is closely monitored for glaucoma.

Matched MeSH terms: Intraocular Pressure/drug effects*
IOP lowering effect of topical trans-resveratrol involves adenosine receptors and TGF-β2 signaling pathways

Razali N, Agarwal R, Agarwal P, Froemming GRA, Tripathy M, Ismail NM

Eur J Pharmacol, 2018 Nov 05;838:1-10.
PMID: 30171854 DOI: 10.1016/j.ejphar.2018.08.035

Trans-resveratrol was earlier shown to lower intraocular pressure (IOP) in rats; however, its mechanisms of action remain unclear. It has been shown to modulate adenosine receptor (AR) and TGF-β2 signaling, both of which play a role in regulating IOP. Hence, we investigated effects of trans-resveratrol on AR and TGF-β2 signaling. Steroid-induced ocular hypertensive (SIOH) rats were pretreated with A1AR, phospholipase C (PLC) and ERK1/2 inhibitors and were subsequently treated with single drop of trans-resveratrol. Metalloproteinases (MMP)-2 and -9 were measured in aqueous humor (AH). In another set of experiments, effect of trans-resveratrol on AH level of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) was determined after single and multiple drop administration in SIOH rats. Effect of trans-resveratrol on ARs expression, PLC and pERK1/2 activation and MMPs, tPA and uPA secretion was determined using human trabecular meshwork cells (HTMC). Further, effect of trans-resveratrol on TGF-β2 receptors, SMAD signaling molecules and uPA and tPA expression by HTMC was determined in the presence and absence of TGF-β2. Pretreatment with A1AR, PLC and ERK1/2 inhibitors antagonized the IOP lowering effect of trans-resveratrol and caused significant reduction in the AH level of MMP-2 in SIOH rats. Trans-resveratrol increased A1AR and A2AAR expression, cellular PLC, pERK1/2 levels and MMP-2, tPA and uPA secretion by HTMC. Additionally, it produced TGFβRI downregulation and SMAD 7 upregulation. In conclusion, IOP lowering effect of trans-resveratrol involves upregulation of A1AR expression, PLC and ERK1/2 activation and increased MMP-2 secretion. It downregulates TGFβRI and upregulates SMAD7 hence, inhibits TGF-β2 signaling.

Matched MeSH terms: Intraocular Pressure/drug effects*
Newer targets for modulation of intraocular pressure: focus on adenosine receptor signaling pathways

Agarwal R, Agarwal P

Expert Opin Ther Targets, 2014 May;18(5):527-39.
PMID: 24579961 DOI: 10.1517/14728222.2014.888416

The homeostatic role of adenosine in regulating intraocular pressure (IOP) is now widely recognized, and hence, the drugs targeting adenosine receptors have become the focus of investigation. In this review, we summarize the adenosine receptor signaling pathways, which could be potential therapeutic targets for the management of glaucoma.

Matched MeSH terms: Intraocular Pressure/drug effects*

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