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Displaying publications 61 - 69 of 69 in total

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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.
Tackling retinal ganglion cell apoptosis in glaucoma: role of adenosine receptors

Agarwal P, Agarwal R

Expert Opin Ther Targets, 2021 Jul;25(7):585-596.
PMID: 34402357 DOI: 10.1080/14728222.2021.1969362

INTRODUCTION: The role of adenosine receptors as therapeutic targets for neuroprotection is now widely recognized. Their role, however, in protection against retinal ganglion cell (RGC) apoptosis in glaucoma needs further investigation. Hence, in this review, we look into the possibility of adenosine receptors as potential therapeutic targets by exploring their role in modulating various pathophysiological mechanisms underlying glaucomatous RGC loss.
AREAS COVERED: This review presents a summary of the adenosine receptor distribution in retina and the cellular functions mediated by them. The major pathophysiological mechanisms such as excitotoxicity, vascular dysregulation, loss of neurotrophic signaling, and inflammatory responses involved in glaucomatous RGC loss are discussed. The literature showing the role of adenosine receptors in modulating these pathophysiological mechanisms is discussed. The literature search was conducted using Pubmed search engine using key words such as 'RGC apoptosis,' 'adenosine,' adenosine receptors' 'retina' 'excitotoxicity,' 'neurotrophins,' 'ischemia', and 'cytokines' individually and in various combinations.
EXPERT OPINION: Use of adenosine receptor agonists and antagonists, for preservation of the RGCs in glaucomatous eyes independent of the level of intraocular pressure seems a very useful strategy. Future application of this strategy would require appropriate designing of drug formulation for tissue and disease-specific receptor targeting. Furthermore, the modulation of physiological functions and potential adverse effects need further investigations.
Fulltext New solutions for old challenges in glaucoma treatment: is taurine an option to consider?

Iezhitsa I, Agarwal R

Neural Regen Res, 2021 May;16(5):967-971.
PMID: 33229737 DOI: 10.4103/1673-5374.297059

Glaucoma is a range of progressive optic neuropathies characterized by progressive retinal ganglion cell loss and visual field defects. It is recognized as a leading cause of irreversible blindness affecting more than 70 million people worldwide. Currently, reduction of intraocular pressure, a widely recognized risk factor for glaucoma development, is the only pharmacological strategy for slowing down retinal ganglion cell loss and disease progression. However, retinal ganglion cell death and visual field loss have been observed in normotensive glaucoma, suggesting that the disease process is partially independent of intraocular pressure. Taurine is one of the agents that have attracted attention of researchers recently. Taurine has been shown to be involved in multiple cellular functions, including a central role as a neurotransmitter, as a trophic factor in the central nervous system development, as an osmolyte, as a neuromodulator, and as a neuroprotectant. It also plays a role in the maintenance of the structural integrity of the membranes and in the regulation of calcium transport and homeostasis. Taurine is known to prevent N-methyl-D-aspartic acid-induced excitotoxic injury to retinal ganglion cells. A recently published study clearly demonstrated that taurine prevents retinal neuronal apoptosis both in vivo and in vitro. Protective effect of taurine may be attributed to direct inhibition of apoptosis, an activation of brain derived neurotrophic factor-related neuroprotective mechanisms and reduction of retinal oxidative and nitrosative stresses. Further studies are needed to fully explore the potential of taurine as a neuroprotective agent, so that it can be applied in clinical practice, particularly for the treatment of glaucoma. The objective of current review was to summarize recent evidence on neuroprotective properties of taurine in glaucoma.
Rodent models of glaucoma and their applicability for drug discovery

Agarwal R, Agarwal P

Expert Opin Drug Discov, 2017 Mar;12(3):261-270.
PMID: 28075618 DOI: 10.1080/17460441.2017.1281244

Rodents have widely been used to represent glaucomatous changes both in the presence and absence of elevated intraocular pressure (IOP) as they offer clear advantages over other animal species. IOP elevation is commonly achieved by creating an obstruction in the aqueous outflow pathways, consequently leading to retinal ganglion cell and optic nerve (ON) damage, the hallmark of glaucoma. These changes may also be achieved in the absence of elevated IOP by directly inflicting injury to retina or ON. Areas covered: This paper presents a summary of currently used rodent models of glaucoma. The characteristics of these models from several studies are summarized. The benefits and shortcomings of these models are also discussed. Expert opinion: The choice of animal model that closely represents human disease is key for successful translational of preclinical research to clinical practice. Rodent models of rapid IOP elevation are likely to be least representative, whereas models such as steroid-induced glaucoma models more closely resemble the trabecular meshwork changes seen in glaucomatous human eyes. However, this model needs further characterization. Rodent models based on direct retinal and ON injury are also useful tools to investigate molecular mechanisms involved at the site of final common pathology and neuroprotective strategies.
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.
Genetic rodent models of glaucoma in representing disease phenotype and insights into the pathogenesis

Agarwal R, Iezhitsa I

Mol Aspects Med, 2023 Dec;94:101228.
PMID: 38016252 DOI: 10.1016/j.mam.2023.101228

Genetic rodent models are widely used in glaucoma related research. With vast amount of information revealed by human studies about genetic correlations with glaucoma, use of these models is relevant and required. In this review, we discuss the glaucoma endophenotypes and importance of their representation in an experimental animal model. Mice and rats are the most popular animal species used as genetic models due to ease of genetic manipulations in these animal species as well as the availability of their genomic information. With technological advances, induction of glaucoma related genetic mutations commonly observed in human is possible to achieve in rodents in a desirable manner. This approach helps to study the pathobiology of the disease process with the background of genetic abnormalities, reveals potential therapeutic targets and gives an opportunity to test newer therapeutic options. Various genetic manipulation leading to appearance of human relevant endophenotypes in rodents indicate their relevance in glaucoma pathology and the utility of these rodent models for exploring various aspects of the disease related to targeted mutation. The molecular pathways involved in the pathophysiology of glaucoma leading to elevated intraocular pressure and the disease hallmark, apoptosis of retinal ganglion cells and optic nerve degeneration, have been extensively explored in genetic rodent models. In this review, we discuss the consequences of various genetic manipulations based on the primary site of pathology in the anterior or the posterior segment. We discuss how these genetic manipulations produce features in rodents that can be considered a close representation of disease phenotype in human. We also highlight several molecular mechanisms revealed by using genetic rodent models of glaucoma including those involved in increased aqueous outflow resistance, loss of retinal ganglion cells and optic neuropathy. Lastly, we discuss the limitations of the use of genetic rodent models in glaucoma related research.
Fulltext Magnesium acethyltaurate as a potential agent for retinal and optic nerve protection in glaucoma

Iezhitsa I, Agarwal R

Neural Regen Res, 2018 May;13(5):807-808.
PMID: 29863006 DOI: 10.4103/1673-5374.232470
Fulltext Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

Agarwal R, Agarwal P

Exp Biol Med (Maywood), 2017 Feb;242(4):374-383.
PMID: 27798117 DOI: 10.1177/1535370216675065

Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.
Fulltext Recent advance s in pathophysiology and pharmacotherapy of glaucoma

Agarwal R

Medical Health Reviews, 2009;2009(1):75-93.
MyJurnal

Glaucoma, recognized as optic neuropathy is the second largest cause of blindness worldwide. The disease is characterized by progressive loss of retinal ganglion cells and visual field defects. The pathophysiological factors involved in the onset and progression of glaucoma are not fully understood. However, it is now well accepted that elevated intraocular pressure is not the only causative factor. The pathophysiology of glaucoma involves multiple factors that interact in a highly complex manner to favor development of glaucomatous optic neuropathy. As the knowledge of molecular mechanisms involved is expanding, more and more therapeutic targets are being recognized for the development of safe and effective pharmacotherapy of glaucoma. Although at present the intraocular pressure lowering drugs are still the first line of treatment, the prospect of introducing neuroprotective therapies that can directly protect and perhaps stimulate regeneration of dying and dead retinal ganglion cells, shows considerable promise. This review presents recent developments in the pathophysiology and pharmacotherapy of glaucoma.