Niki Mastrodimou

University of Crete

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Kyriaki Thermos

University of Crete

Ioannis Charalampopoulos

University of Crete

Despina Kokona

University Hospital of Bern

Achille Gravanis

University of Crete

Silvia Lisa

Instituto de Estudios de Ciencias de la Salud de Castilla y León

George Notas

University of Crete

Dimitris Spyridakos

University of Crete

Anna Vasilaki

University of Thessaly

Stavroula Dionysopoulou

University of Crete

Ruth Ibán Arias

University of Crete

Cooperative Institutions

University of Crete

University Hospital of Heraklion

National and Kapodistrian University of Athens

Foundation for Research and Technology Hellas

Crete University Press

Aristotle University of Thessaloniki

Northeastern University

National Hellenic Research Foundation

Harvard University

FORTH Institute of Molecular Biology and Biotechnology

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Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina

Graefe s Archive for Clinical and Experimental Ophthalmology (2019)

Ruth Ibán‐Arias Silvia Lisa Smaragda Poulaki Niki Mastrodimou Ioannis Charalampopoulos

10.1007/s00417-019-04460-6

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The MICRONEUROTROPHIN BNN27 PROVIDES NEUROPROTECTION TO RETINAL NEURONS THROUGH NGF TrkA RECEPTOR, WHEN IT IS ADMINISTERED EITHER INTRAPERITONEALLY OR AS EYE-DROPS

Ruth Ibán Arias Silvia Lisa Smaragda Poulaki Niki Mastrodimou Despina Kokona

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The neurosteroid DHEA protects the retina against chemical ischemia

Panagiotis Giannogonas Niki Mastrodimou Ioannis Charalampopoulos Achille Gravanis Kyriaki Thermos

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Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats

International Journal of Molecular Sciences (2022)

Dimitris Spyridakos Niki Mastrodimou Kiran Vemuri Thanh C. Ho Spyros P. Nikas

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease.

10.3390/ijms24010240

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Effect of Somatostatin on Nitric Oxide Production in Human Retinal Pigment Epithelium Cell Cultures

Investigative Ophthalmology & Visual Science (2004)

Anna Vasilaki Thekla Papadaki George Notas George Kolios Niki Mastrodimou

purpose. To investigate the presence of somatostatin and its receptors (sst1–5 receptors) and their possible involvement in the regulation of nitric oxide (NO) production in human RPE cell cultures. methods. Human RPE cells (D407) were used for all studies performed. Somatostatin levels were detected by radioimmunoassay, and RT-PCR and immunocytochemistry studies were performed to identify the somatostatin receptors (sst1-sst5). Radioligand binding assays were also performed examining the ability of certain somatostatin ligands (sst1, sst2, sst5) to compete for [125I]Tyr11 somatostatin binding. The presence of NO synthase in the cultures was assayed with NADPH-diaphorase cytochemistry, and RT-PCR, and NO levels were assessed by examining the production of its stable metabolites NO2 − and NO3 − (NOx −). results. SRIF was detected in a concentration of 0.56 ± 0.13 picomoles/mg protein. sst1, sst2, and sst5 mRNAs were detected, yet only sst2B and sst5 immunoreactivity was observed in human RPE cell cultures. sst1- and sst5- but not sst2-selective ligands displaced the specific [125I]Tyr11 somatostatin binding to RPE cell membranes. NADPH-diaphorase stain and iNOS mRNA were detected. SRIF and the sst2-selective analogue MK678 increased the levels of NOx − in a concentration-dependent manner. This increase was blocked by the sst2 antagonist CYN-154806 (Ac-4NO2-Phe-c(dCys-Tyr-dTrp-Lys-Thr-Cys)-dTyr-NH2). conclusions. These results demonstrate the presence of somatostatin, and its receptors sst1, sst2B, and sst5 in human RPE cells and suggest an autocrine or paracrine role for somatostatin. Somatostatin's ability to regulate NO production, by activating sst2 receptors, provides a functional role of somatostatin in the RPE.

10.1167/iovs.03-0835

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Topically administered NOX4 inhibitor, GLX7013114, is efficacious in treating the early pathological events of diabetic retinopathy

Stavroula Dionysopoulou Per Wikström Claudio Bucolo Giovanni Luca Romano Vincenzo Micale

<p>NADPH oxidases (NOX) are major players in generating reactive oxygen species (ROS), implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of NOX4 inhibitor (GLX7013114), in two <em>in vivo </em>experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Diabetic-treated animals received GLX7013114 topically (20μl/eye, 10mg/ml, once daily), for 14d (Paradigm A/preventive) and 7d (Paradigm B/treated), 48hr and four wks post STZ-injection, respectively. A number of methodologies were employed (immunohistochemistry, western blot, real time PCR, ELISA, PERG) to assess the diabetes induced early events of DR, namely oxidative stress, neurodegeneration and neuroinflammation, and the effect of GLX7013114 on the diabetic insults. GLX7013114, administered as eye-drops (paradigms A,B) was beneficial in treating the oxidative nitrative stress, activation of caspase-3 and micro/macroglia and attenuation of neuronal markers. It also attenuated the diabetes induced increase in VEGF, Evans-Blue leakage and proinflammatory cytokine levels (TNF-α protein, IL-1β/IL-6 mRNA). PERG amplitude values suggested that GLX7013114 protected retinal ganglion cell (RGC) function (Paradigm B). In conclusion, this study provides new findings regarding the pharmacological profile of the novel NOX4 inhibitor GLX7013114, as a promising therapeutic candidate, for the treatment of the early stage of DR.</p>

NOX4

Proinflammatory cytokine

10.2337/figshare.22134833.v1

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Nitric oxide and cGMP protect the retina from ischemia and mediate somatostatin's neuroprotective effects

Acta Ophthalmologica (2009)

Kyriaki Thermos Foteini Kiagiadaki Niki Mastrodimou

Abstract Purpose The neuropeptide somatostatin has been shown to modulate retinal circuitry by activating its receptors (sst1‐sst5) found in retinal neurons and to influence the levels of other neuroactive substances such as nitric oxide (NO) and cGMP. In addition, it displays neuroprotective properties against retinal chemical ischemia and excitotoxicity. In another paradigm, somatostatin was shown to protect cortical cultures against NMDA induced neuronal death via a cGMP mechanism. These findings led us to investigate whether NO and/or cGMP could protect the retina from ischemia, and possibly underlie somatostatin’s neuroprotective actions. Methods A model of chemical ischemia was employed in rat retina in order to examine the neuroprotective effects of arginine, the substrate of nitric oxide synthase (NOS), and a number of NO donors. Subsequently, blockade of NOS and guanylyl cyclase in the presence of somatostatin receptor (sst2) agonists was attempted to investigate the role of NO/cGMP in somatostatin’s protection of the retina in the chemical ischemia model and in a model of AMPA induced excitotoxicity. Results The NO donors SIN‐1 and NONOate and 8‐Br‐cGMP protected the retina in a concentration‐dependent manner, as shown by ChAT immunoreactivity and TUNEL staining. L‐cysteine (the peroxynitrite scavenger) partially reduced the SIN‐1 protective effect. NOS and guanyl cyclase inhibitors reversed the protective effect of sst2 agonists in the chemical ischemia and excitotoxicity model. Conclusion NO/peroxynitrite and cGMP appear to be important mediators in the protection of the retina from chemical ischemia. The NO/sGC/cGMP pathway is involved in the neuroprotective effects of the sst2 ligands in the same model and against AMPA excitotoxic insults.

Excitotoxicity

Soluble guanylyl cyclase

10.1111/j.1755-3768.2009.2325.x

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Immunohistochemistry and Western blot methodologies to evaluate neuroprotective agents in models of retinopathies

Acta Ophthalmologica (2010)

Kyriaki Thermos Panagiotis Giannogonas Emmanuil Koulakis Despina Kokona Niki Mastrodimou

Purpose Many retinopathies that lead to visual loss and blindness are characterized by neovascularization and neural retinal defects, such as a marked loss in retinal neurons and an increase in apoptosis. There are no therapeutic agents for the treatment of the neurodegenerative component of retinal disease. Immunohistochemistry and western blot methodologies were employed to determine retinal viability and to elucidate the putative neuroprotective properties of new therapeutic targets, in animal models of retinopathy (chemical ischemia, excitotoxicity, STZ). Methods To assay retinal viability, the following antibodies for retinal markers were employed in immunohistochemical assays: PKC (rod bipolar cells), ChAT, bNOS, TH (cholinergic-, nitric oxide synthetase-, and dopamine- containing amacrine cells, respectively), calbindin-containing horizontal, amacrine and cone bipolar cells, NFL and MAP1 (ganglion axons and cells, respectively). Antibodies against various pro-survival or pro-death molecules (western blots), as well as the TUNEL-assay, were employed to examine retinal apoptosis and neuroprotection. Results Loss of retinal marker immunoreactivity was differentially observed according to the animal model employed. The neuroprotection of specific retinal neurons by the new therapeutic targets examined (somatostatin and neurosteroids) reflect the existence of protein substrates involved in the mechanism of action of these molecules. Conclusion Immunohistochemical and western blot analysis techniques provide important information on the retinal damage induced by ischemic insults and the neuroprotection afforded by new targets of retinal therapeutics.

Retinal Disorder

10.1111/j.1755-3768.2010.4412.x

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Somatostatin receptor immunoreactivity in the eye of the adult newt (Pleurodeles waltlii Michan)

Neuroscience Letters (2003)

E. N. Grigoryan Anna Vasilaki Niki Mastrodimou Kyriaki Thermos

Immunostaining

10.1016/s0304-3940(02)01326-5

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Citations (8)

The somatostatin receptor (sst1) modulates the release of somatostatin in rat retina