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  1. Advances in targeting the extracellular matrix for glaucoma therapy: current updates
    Agarwal R, Iezhitsa I
    Expert Opin Ther Targets, 2023;27(12):1217-1229.
    PMID: 38069479 DOI: 10.1080/14728222.2023.2293748
    INTRODUCTION: Elevated intraocular pressure (IOP) is a well-recognized risk factor for development of primary open angle glaucoma (POAG), a leading cause of irreversible blindness. Ocular hypertension is associated with excessive extracellular matrix (ECM) deposition in trabecular meshwork (TM) resulting in increased aqueous outflow resistance and elevated IOP. Hence, therapeutic options targeting ECM remodeling in TM to lower IOP in glaucomatous eyes are of considerable importance.

    AREAS COVERED: This paper discusses the complex process of ECM regulation in TM and explores promising therapeutic targets. The role of Transforming Growth Factor-β as a central player in ECM deposition in TM is discussed. We elaborate the key regulatory processes involved in its activation, release, signaling, and cross talk with other signaling pathways including Rho GTPase, Wnt, integrin, cytokines, and renin-angiotensin-aldosterone. Further, we summarize the therapeutic agents that have been explored to target ECM dysregulation in TM.

    EXPERT OPINION: Targeting molecular pathways to reduce ECM deposition and/or enhance its degradation are of considerable significance for IOP lowering. Challenges lie in pinpointing specific targets and designing drug delivery systems to precisely interact with pathologically active/inactive signaling. Recent advances in monoclonal antibodies, fusion molecules, and vectored nanotechnology offer potential solutions.

    Matched MeSH terms: Trabecular Meshwork/metabolism
  2. 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: Trabecular Meshwork/drug effects*; Trabecular Meshwork/metabolism
  3. 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: Trabecular Meshwork/drug effects; Trabecular Meshwork/metabolism; Trabecular Meshwork/physiopathology
  4. Argon laser trabeculoplasty in Asian eyes
    Singh M, Kaur B
    Int Ophthalmol, 1987 Jun;10(3):161-5.
    PMID: 3596909
    Twenty two Asian eyes suffering from open angle glaucoma were treated by argon laser trabeculoplasty and were followed for an average of eleven months. 77.27% of eyes were controlled with ALT alone. The pressure lowering effect of argon laser trabeculoplasty in this series was found to be consistent. Argon laser trabeculoplasty may become the preferred method of treating open angle glaucoma in the Asian population.
    Matched MeSH terms: Trabecular Meshwork/surgery*
  5. Effect of dexamethasone on the expression of MMPs, adenosine A1 receptors and NFKB by human trabecular meshwork cells
    Mohd Nasir NA, Agarwal R, Krasilnikova A, Sheikh Abdul Kadir SH, Iezhitsa I
    J Basic Clin Physiol Pharmacol, 2020 Jul 22;31(6).
    PMID: 32697755 DOI: 10.1515/jbcpp-2019-0373
    Objectives Steroid-induced ocular hypertension and glaucoma are associated with extracellular matrix remodeling at the trabecular meshwork (TM) of the eye due to reduced secretion of matrix metalloproteinases (MMPs), a family of enzymes regulating extracellular matrix proteolysis. Several biological functions of steroids are known to involve regulation of adenosine A1 receptors (A1AR) and nuclear factor kappa B (NFKB). Since MMPs expression in TM has been shown to be regulated by A1AR as well as transcription factors, it is likely that dexamethasone-induced changes in aqueous humor dynamics involve reduced MMP and A1AR expression and reduced NFKB activation. Hence, the current study investigated the association of dexamethasone-induced reduction in MMP secretion with reduced NFKB activation and A1AR expression. Methods Human trabecular meshwork cells (HTMCs) were characterized by estimating myocilin and alpha smooth muscle actin expression and then were treated with dexamethasone 100 nM for 2, 5 and 7 days. The MMP secretion was estimated in culture media using Western blot. Immunocytochemistry (ICC) and ELISA were done to investigate the effect of dexamethasone on NFKB phosphorylation. A1AR expression in HTMCs was determined using Western blot and ELISA. Results Dexamethasone caused a significant reduction in both MMP-2 and -9 expression compared to untreated group after five and seven days but not after two days of culture. Significantly reduced phosphorylated NFKB and A1AR protein levels were detected in dexamethasone treated compared to vehicle treated HTMCs after five days of culture. Conclusions Dexamethasone reduces MMP-2 and -9 secretion by HTMCs and this effect of dexamethasone is associated with reduced NFKB phosphorylation and A1AR expression.
    Matched MeSH terms: Trabecular Meshwork/drug effects*; Trabecular Meshwork/metabolism
  6. Effect of trans-resveratrol on dexamethasone-induced changes in the expression of MMPs by human trabecular meshwork cells: Involvement of adenosine A1 receptors and NFkB
    Mohd Nasir NA, Agarwal R, Krasilnikova A, Sheikh Abdul Kadir SH, Iezhitsa I
    Eur J Pharmacol, 2020 Nov 15;887:173431.
    PMID: 32758568 DOI: 10.1016/j.ejphar.2020.173431
    Intraocular pressure (IOP) lowering in glaucomatous eyes is currently achieved mainly by improved aqueous outflow via alternate drainage pathways. However, the focus is now shifting to trabecular meshwork (TM), the site or major pathological changes including increased extracellular matrix (ECM) deposition and reduced matrix metalloproteinases (MMPs) secretion by TM cells. Trans-resveratrol was previously shown to lower IOP and reduce ECM deposition; however, the mechanisms of action remain unclear. Therefore, we determined the effect of trans-resveratrol on MMP-2 and -9 expression by human TM cells (HTMCs) in the presence of dexamethasone and whether it also affects adenosine A1 receptors (A1AR) expression and nuclear factor kappa B (NFkB) activation. We observed that trans-resveratrol, 12.5 μM, increased MMP-2 and -9 protein expression by HTMCs despite exposure to dexamethasone (1.89- and 1.53-fold, respectively; P 
    Matched MeSH terms: Trabecular Meshwork
  7. 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: Trabecular Meshwork/cytology; Trabecular Meshwork/drug effects
  8. Fulltext Effect of postoperative corticosteroids on surgical outcome and aqueous autotaxin following combined cataract and microhook ab interno trabeculotomy
    Honjo M, Yamagishi R, Igarashi N, Ku CY, Kurano M, Yatomi Y, et al.
    Sci Rep, 2021 01 12;11(1):747.
    PMID: 33436915 DOI: 10.1038/s41598-020-80736-w
    To evaluate the effect of postoperative corticosteroids on surgical outcome and autotaxin (ATX) levels after microhook ab interno trabeculotomy combined with cataract surgery (μLOT-CS), prospective, consecutive non-randomized case series comparing outcomes of 30 eyes with primary open angle glaucoma was performed. The aqueous ATX, intraocular pressure (IOP) and glaucoma medications were monitored for 3 months postoperatively. An in-vivo mouse μLOT model was generated. In vitro, ATX and fibrotic changes induced by dexamethasone (Dex) treatment following scratch (S) in cultured human trabecular meshwork (hTM) cells were assessed by immunofluorescence, immunoenzymatic assay, and RT-qPCR. Postoperative ATX at 1 week and the number of antiglaucoma medications at 3 months were significantly lower in non-steroid group, and steroid use was the only variable significantly associated with postoperative medications at 3 months in multiregression analyses. In vitro, ATX activity was significantly upregulated in the Dex + S group, and αSMA was significantly upregulated in the Dex and Dex + S groups. Fibronectin and COL1A1 were significantly upregulated in the S group. μLOT-CS decreased IOP and medications in the overall cohort, and non-use of postoperative steroids resulted in a smaller number of postoperative medications. Limiting postoperative steroids in μLOT may minimize IOP elevation and postoperative fibrosis.
    Matched MeSH terms: Trabecular Meshwork/drug effects*
  9. Intraocular pressure-lowering effects of imidazo[1,2-a]- and pyrimido[1,2-a]benzimidazole compounds in rats with dexamethasone-induced ocular hypertension
    Marcus AJ, Iezhitsa I, Agarwal R, Vassiliev P, Spasov A, Zhukovskaya O, et al.
    Eur J Pharmacol, 2019 May 05;850:75-87.
    PMID: 30716317 DOI: 10.1016/j.ejphar.2019.01.059
    Ocular hypertension is believed to be involved in the etiology of primary open-angle glaucoma. Although many pharmaceutical agents have been shown to be effective for the reduction of intraocular pressure (IOP), a significant opportunity to improve glaucoma treatments remains. Thus, the aims of the present study were: (1) to evaluate the IOP-lowering effect of four compounds RU-551, RU-555, RU-839 (pyrimido[1,2-a]benzimidazole), and RU-615 (imidazo[1,2-a]benzimidazole) on steroid-induced ocular hypertension in rats after single drop and chronic applications; and (2) to test in silico and in vitro conventional rho-associated kinase (ROCK) inhibitory activity of the selected compound. This study demonstrated that RU-551, RU-555, RU-839, and RU-615 significantly reduced IOP in Sprague Dawley rats with dexamethasone (DEXA) induced ocular hypertension after single drop administration (0.1%), however RU-615 showed the best IOP lowering effect as indicated by maximum IOP reduction of 22.32% from baseline. Repeated dose topical application of RU-615 caused sustained reduction of IOP from baseline throughout the 3 weeks of treatment with maximum IOP reduction of 30.31% on day 15. This study also showed that the steroid-induced increase in IOP is associated with increased retinal oxidative stress and significant retinal ganglion cells (RGCs) loss. Prolonged treatment with RU-615 over 3 weeks results in normalization of IOP in DEXA-treated rats with partial restoration of retinal antioxidant status (catalase, glutathione and superoxide dismutase) and subsequent protective effect against RGC loss. Thus, IOP lowering activity of RU-615 together with antioxidant properties might be the factors that contribute to prevention of further RGC loss. In vitro part of this study explored the ROCK inhibitory activity of RU-615 using dexamethasone-treated human trabecular meshwork cells as a possible mechanism of action of its IOP lowering activity. However, this study didn't show conventional ROCK inhibition by RU-615 which was later confirmed by in silico consensus prediction. Therefore, in the future studies it is important to identify the upstream target receptors for RU-615 and then delineate the involved intracellular signalling pathways which are likely to be other than ROCK inhibition.
    Matched MeSH terms: Trabecular Meshwork
  10. 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: Trabecular Meshwork/pathology*
  11. 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: Trabecular Meshwork/drug effects; Trabecular Meshwork/physiopathology
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