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  1. 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.
  2. Sadikan MZ, Abdul Nasir NA, Lambuk L, Mohamud R, Reshidan NH, Low E, et al.
    BMC Ophthalmol, 2023 Oct 19;23(1):421.
    PMID: 37858128 DOI: 10.1186/s12886-023-03155-1
    Diabetic retinopathy (DR), one of the leading causes of visual impairment and blindness worldwide, is one of the major microvascular complications in diabetes mellitus (DM). Globally, DR prevalence among DM patients is 25%, and 6% have vision-threatening problems among them. With the higher incidence of DM globally, more DR cases are expected to be seen in the future. In order to comprehend the pathophysiological mechanism of DR in humans and discover potential novel substances for the treatment of DR, investigations are typically conducted using various experimental models. Among the experimental models, in vivo models have contributed significantly to understanding DR pathogenesis. There are several types of in vivo models for DR research, which include chemical-induced, surgical-induced, diet-induced, and genetic models. Similarly, for the in vitro models, there are several cell types that are utilised in DR research, such as retinal endothelial cells, Müller cells, and glial cells. With the advancement of DR research, it is essential to have a comprehensive update on the various experimental models utilised to mimic DR environment. This review provides the update on the in vitro, in vivo, and ex vivo models used in DR research, focusing on their features, advantages, and limitations.
  3. Sadikan MZ, Abdul Nasir NA, Bakar NS, Iezhitsa I, Agarwal R
    BMC Complement Med Ther, 2023 Jun 02;23(1):179.
    PMID: 37268913 DOI: 10.1186/s12906-023-04005-9
    BACKGROUND: Diabetic retinopathy (DR) is the second commonest microvascular complication of diabetes mellitus. It is characterized by chronic inflammation and angiogenesis. Palm oil-derived tocotrienol-rich fraction (TRF), a substance with anti-inflammatory and anti-angiogenic properties, may provide protection against DR development. Therefore, in this study, we investigated the effect of TRF on retinal vascular and morphological changes in diabetic rats. The effects of TRF on the retinal expression of inflammatory and angiogenic markers were also studied in the streptozotocin (STZ)-induced diabetic rats.

    METHODS: Male Sprague Dawley rats weighing 200-250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR.

    RESULTS: TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p 

  4. Vassiliev P, Iezhitsa I, Agarwal R, Marcus AJ, Spasov A, Zhukovskaya O, et al.
    Data Brief, 2018 Jun;18:340-347.
    PMID: 29896521 DOI: 10.1016/j.dib.2018.02.067
    This article contains data that relate to the study carried out in the work of Marcus et al. (2018) [1]. Data represent an information about pharmacophore analysis of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives and results of construction of the relationship between intraocular pressure (IOP) lowering activity and hypotensive activity of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives using a multilayer perceptron artificial neural network. In particular, they include the ones listed in this article: 1) table of all pharmacophores of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives that showed IOP lowering activity; 2) table of all pharmacophores of the compounds that showed absence of IOP lowering activity; 3) table of initial data for artificial neural network analysis of relationship between IOP activity and hypotensive activity of this chemical series; 4) graphical representation of the best neural network model of this dependence; 5) original txt-file of results of pharmacophore analysis; 6) xls-file of initial data for neural network modeling; 7) original stw-file of results of neural network modeling; 8) original xml-file of the best neural network model of dependence between IOP lowering activity and hypotensive activity of these azole derivatives. The data may be useful for researchers interested in designing new drug substances and will contribute to understanding of the mechanisms of IOP lowering activity.
  5. Fazel MF, Abu IF, Mohamad MHN, Agarwal R, Iezhitsa I, Bakar NS, et al.
    PLoS One, 2020;15(7):e0236450.
    PMID: 32706792 DOI: 10.1371/journal.pone.0236450
    Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 μm length and 100 μm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.
  6. 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 
  7. 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.
  8. Agarwal R, Agarwal P, Iezhitsa I
    Expert Opin Drug Discov, 2023;18(11):1287-1300.
    PMID: 37608634 DOI: 10.1080/17460441.2023.2246892
    INTRODUCTION: Animal models are widely used in glaucoma-related research. Since the elevated intraocular pressure (IOP) is a major risk factor underlying the disease pathogenesis, animal models with high IOP are commonly used. However, models are also used to represent the clinical context of glaucomatous changes developing despite a normal IOP.

    AREAS COVERED: Herein, the authors discuss the various factors that contribute to the quality of studies using animal models based on the evaluation of studies published in 2022. The factors affecting the quality of studies using animal models, such as the animal species, age, and sex, are discussed, along with various methods and outcomes of studies involving different animal models of glaucoma.

    EXPERT OPINION: Translating animal research data to clinical applications remains challenging. Our observations in this review clearly indicate that many studies lack scientific robustness not only in their experiment conduct but also in data analysis, interpretation, and presentation. In this context, ensuring the internal validity of animal studies is the first step in quality assurance. External validity, however, is more challenging, and steps should be taken to satisfy external validity at least to some extent.

  9. 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.

  10. 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.
  11. Agarwal R, Iezhitsa I, Agarwal P, Abdul Nasir NA, Razali N, Alyautdin R, et al.
    Drug Deliv, 2016 May;23(4):1075-91.
    PMID: 25116511 DOI: 10.3109/10717544.2014.943336
    Topical route of administration is the most commonly used method for the treatment of ophthalmic diseases. However, presence of several layers of permeation barriers starting from the tear film till the inner layers of cornea make it difficult to achieve the therapeutic concentrations in the target tissue within the eye. In order to circumvent these barriers and to provide sustained and targeted drug delivery, tremendous advances have been made in developing efficient and safe drug delivery systems. Liposomes due to their unique structure prove to be extremely beneficial drug carriers as they can entrap both the hydrophilic and hydrophobic drugs. The conventional liposomes had several drawbacks particularly their tendency to aggregate, the instability and leakage of entrapped drug and susceptibility to phagocytosis. Due to this reason, for a long time, liposomes as drug delivery systems did not attract much attention of researchers and clinicians. However, over recent years development of new generation liposomes has opened up new approaches for targeted and sustained drug delivery using liposomes and has rejuvenated the interest of researchers in this field. In this review we present a summary of current literature to understand the anatomical and physiological limitation in achieving adequate ocular bioavailability of topically applied drugs and utility of liposomes in overcoming these limitations. The recent developments related to new generation liposomes are discussed.
  12. Jafri AJA, Agarwal R, Iezhitsa I, Agarwal P, Ismail NM
    Amino Acids, 2019 Apr;51(4):641-646.
    PMID: 30656415 DOI: 10.1007/s00726-019-02696-4
    This study aimed to evaluate effect of TAU on NMDA-induced changes in retinal redox status, retinal cell apoptosis and retinal morphology in Sprague-Dawley rats. Taurine was injected intravitreally as pre-, co- or post-treatment with NMDA and 7 days post-treatment retinae were processed for estimation of oxidative stress, retinal morphology using H&E staining and retinal cell apoptosis using TUNEL staining. Treatment with TAU, particularly pre-treatment, significantly increased retinal glutathione, superoxide dismutase and catalase levels compared to NMDA-treated rats; whereas, the levels of malondialdehyde reduced significantly. Reduction in retinal oxidative stress in TAU pre-treated group was associated with significantly greater fractional thickness of ganglion cell layer within inner retina and retinal cell density in inner retina. TUNEL staining showed significantly reduced apoptotic cell count in TAU pre-treated group compared to NMDA group. It could be concluded that TAU protects against NMDA-induced retinal injury in rats by reducing retinal oxidative stress.
  13. Kamarudin SN, Iezhitsa I, Tripathy M, Alyautdin R, Ismail NM
    Acta Neurobiol Exp (Wars), 2020;80(1):1-18.
    PMID: 32214270
    Poly (lactide‑co‑glycolide) (PLGA) nanoparticles (NPs) are biodegradable carriers that participate in the transport of neuroprotective drugs across the blood brain barrier (BBB). Targeted brain‑derived neurotrophic factor (BDNF) delivery across the BBB could provide neuroprotection in brain injury. We tested the neuroprotective effect of PLGA nanoparticle‑bound BDNF in a permanent middle cerebral artery occlusion (pMCAO) model of ischemia in rats. Sprague‑Dawley rats were subjected to pMCAO. Four hours after pMCAO, two groups were intravenously treated with BDNF and NP‑BDNF, respectively. Functional outcome was assessed at 2 and 24 h after pMCAO, using the modified neurologic severity score (mNSS) and rotarod performance tests. Following functional assessments, rats were euthanized blood was taken to assess levels of the neurobiomarkers neuron‑specific enolase and S100 calcium‑binding protein β (S100β), and the brain was evaluated to measure the infarct volume. The NP‑BDNF‑treated group showed significant improvement in mNSS compared with pMCAO and BDNF‑treated groups and showed improved rotarod performance. The infarct volume in rats treated with NP‑BDNFs was also significantly smaller. These results were further corroborated by correlating differences in estimated NSE and S100β. NP‑BDNFs exhibit a significant neuroprotective effect in the pMCAO model of ischemia in rats.
  14. Nor Arfuzir NN, Agarwal R, Iezhitsa I, Agarwal P, Sidek S, Ismail NM
    Neural Regen Res, 2018 Nov;13(11):2014-2021.
    PMID: 30233077 DOI: 10.4103/1673-5374.239450
    Endothelin-1 (ET-1), a potent vasoconstrictor, is involved in retinal vascular dysregulation and oxidative stress in glaucomatous eyes. Taurine (TAU), a naturally occurring free amino acid, is known for its neuroprotective and antioxidant properties. Hence, we evaluated its neuroprotective properties against ET-1 induced retinal and optic nerve damage. ET-1 was administered intravitreally to Sprague-Dawley rats and TAU was injected as pre-, co- or post-treatment. Animals were euthanized seven days post TAU injection. Retinae and optic nerve were examined for morphology, and were also processed for caspase-3 immunostaining. Retinal redox status was estimated by measuring retinal superoxide dismutase, catalase, glutathione, and malondialdehyde levels using enzyme-linked immuosorbent assay. Histopathological examination showed significantly improved retinal and optic nerve morphology in TAU-treated groups. Morphometric examination showed that TAU pre-treatment provided marked protection against ET-1 induced damage to retina and optic nerve. In accordance with the morphological observations, immunostaining for caspase showed a significantly lesser number of apoptotic retinal cells in the TAU pre-treatment group. The retinal oxidative stress was reduced in all TAU-treated groups, and particularly in the pre-treatment group. The findings suggest that treatment with TAU, particularly pre-treatment, prevents apoptosis of retinal cells induced by ET-1 and hence prevents the changes in the morphology of retina and optic nerve. The protective effect of TAU against ET-1 induced retinal and optic nerve damage is associated with reduced retinal oxidative stress.
  15. Lambuk L, Iezhitsa I, Agarwal R, Bakar NS, Agarwal P, Ismail NM
    Neurotoxicology, 2019 01;70:62-71.
    PMID: 30385388 DOI: 10.1016/j.neuro.2018.10.009
    OBJECTIVE: N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure.

    METHODOLOGY: Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with PBS and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure respectively. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique.

    RESULTS: Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 μm length (by 1.5-fold, p 

  16. 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.
  17. Nor Arfuzir NN, Agarwal R, Iezhitsa I, Agarwal P, Ismail NM
    Exp Eye Res, 2020 05;194:107996.
    PMID: 32156652 DOI: 10.1016/j.exer.2020.107996
    Endothelin-1 (ET-1), a potent vasoconstrictor, plays a significant role in the pathophysiology of ocular conditions like glaucoma. Glaucoma is characterized by apoptotic loss of retinal ganglion cells (RGCs) and loss of visual fields and is a leading cause of irreversible blindness. In glaucomatous eyes, retinal ischemia causes release of pro-inflammatory mediators such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and promotes activation of transcription factors such as nuclear factor kappa B (NFKB) and c-Jun. Magnesium acetyltaurate (MgAT) has previously been shown to protect against ET-1 induced retinal and optic nerve damage. Current study investigated the mechanisms underlying these effects of MgAT, which so far remain unknown. Sprague dawley rats were intravitreally injected with ET-1 with or without pretreatment with MgAT. Seven days post-injection, retinal expression of IL-1β, IL-6, TNF-α, NFKB and c-Jun protein and genes was determined using multiplex assay, Western blot and PCR. Animals were subjected to retrograde labeling of RGCs to determine the extent of RGC survival. RGC survival was also examined using Brn3A staining. Furthermore, visual functions of rats were determined using Morris water maze. It was observed that pre-treatment with MgAT protects against ET-1 induced increase in the retinal expression of IL-1β, IL-6 and TNF-α proteins and genes. It also protected against ET-1 induced activation of NFKB and c-Jun. These effects of MgAT were associated with greater RGC survival and preservation of visual functions in rats. In conclusion, MgAT prevents ET-1 induced RGC loss and loss of visual functions by suppressing neuroinflammatory reaction in rat retinas.
  18. Abd Aziz NAW, Iezhitsa I, Agarwal R, Abdul Kadir RF, Abd Latiff A, Ismail NM
    Neurol Res, 2020 Mar;42(3):189-208.
    PMID: 32013788 DOI: 10.1080/01616412.2020.1716470
    Objective:Trans-resveratrol has been shown to have neuroprotective effects and could be a promising therapeutic agent in the treatment of intracerebral haemorrhage (ICH). This study aimed to investigate the involvement of the adenosine A1 receptor (A1R) in trans-resveratrol-induced neuroprotection in rats with collagenase-induced ICH.Methods: Sixty male Sprague-Dawley rats weighing 330-380 g were randomly divided into five groups (n = 12): (i) control, (ii) sham-operated rats, (iii) ICH rats pretreated with vehicle (0.1% DMSO saline, i.c.v.), (iv) ICH rats pretreated with trans-resveratrol (0.9 µg, i.c.v.) and (v) ICH rats pretreated with trans-resveratrol (0.9 µg) and the A1R antagonist, DPCPX (2.5 µg, i.c.v.). Thirty minutes after pretreatment, ICH was induced by intrastriatal injection of collagenase (0.04 U). Forty-eight hours after ICH, the rats were assessed using a variety of neurobehavioural tests. Subsequently, rats were sacrificed and brains were subjected to gross morphological examination of the haematoma area and histological examination of the damaged area.Results: Severe neurobehavioural deficits and haematoma with diffuse oedema were observed after intrastriatal collagenase injection. Pretreatment with trans-resveratrol partially restored general locomotor activity, muscle strength and coordination, which was accompanied with reduction of haematoma volume by 73.22% (P < 0.05) and damaged area by 60.77% (P < 0.05) in comparison to the vehicle-pretreated ICH group. The trans-resveratrol-induced improvement in neurobehavioural outcomes and morphological features of brain tissues was inhibited by DPCPX pretreatment.Conclusion: This study demonstrates that the A1R activation is possibly the mechanism underlying the trans-resveratrol-induced neurological and neurobehavioural protection in rats with ICH.
  19. Jafri AJA, Arfuzir NNN, Lambuk L, Iezhitsa I, Agarwal R, Agarwal P, et al.
    J Trace Elem Med Biol, 2017 Jan;39:147-154.
    PMID: 27908408 DOI: 10.1016/j.jtemb.2016.09.005
    Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL(-1)). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL(-1)) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.
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