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1

Increased intraocular pressure alters the cellular distribution of HuR protein in retinal ganglion cells

100%

Smedowski A.

Acta Neurobiologiae Experimentalis

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2019

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tom 79

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nr Suppl.1

Glaucoma is a group of progressive optic neuropathies that lead to irreversible loss of retinal ganglion cells (RGC); the disease can be characterized by several symptoms with a common feature of the visual field loss. Until now, various risk factors of glaucoma development have been identified, but the detailed biological basis of this disease has remained unclear. It has been postulated that the efficiency of cellular endogenous neuroprotective systems can be one of crucial factors affecting the RGC’s apoptotic susceptibility. More recently, in vivo evidences revealed that changes in HuR subcellular localization within RGCs occurred at early times after IOP induction in an animal model of glaucoma; these effects were followed at longer times by a progressive decrease of cytoplasmic HuR levels, including the expression of proteins essential for cell homeostasis (p53, Hsp70) and likely contributes to chronic IOP‑induced RGC degeneration. Similar alterations in HuR content and subcellular localization were found in human POAG samples, in support of the involvement of HuR in glaucoma. The potential of HuR as a new pharmacological target is shown by an increasing interest in medicinal chemistry by the field. The role of post‑transcriptional mechanisms controlling gene expression in glaucoma, needs to be further explored.

2

Spontaneous and inducible reinervation of human cornea

63%

Smedowski A., Wylegala A.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

Correct innervation of the ocular surface is, in addition to the endothelial barrier, a leading mechanism conditioning the transparency of the cornea. Corneal nerves are involved in perception of pain, as well as touch, thermal and chemical stimuli. Moreover, they are involved in modulating the blink reflex and tears production. Corneal nerve plexus insufficiency might occur as a primary or secondary sign of ocular or systemic disorders. Neuropathic keratopathy is a corneal disorder due to the partial or complete denervation of the eye surface tissues associated with damage or dysfunction of ophthalmic nerve branches originating from the trigeminal ganglion (V cranial nerve). This damage leads to a complete or partial corneal analgesia, destabilization of corneal epithelium and production of tear film, resulting in the development of corneal epithelial erosion, ulceration or melting. Total denervation of corneal tissue is observed following corneal grafting, while within weeks after transplant procedure, spontaneous innervation of graft might be observed using in vivo confocal microscopy technology. Neuropathy associated with viral keratitis (HSV and HZV), chemical burn, contact lenses wearing, corneal dystrophies or diabetes are rather unusual to be associated with spontaneous nerves growth. In these cases novel therapeutic approaches, which are still at the stage of development, represent a promising alternative for patients with neurotrophic keratopathy. Topical application of recombinant human Nerve Growth Factor (NGF) is a recent achievement of regenerative medicine for ocular surface disorders. Currently it is undergoing Phase II Clinical Study for treatment of neurotrophic keratopathy. The latest possible therapeutic option to induce corneal innervation is a topical supplementation of extracellular matrix components supporting the healing process of the cornea. The combination of clinical and basic science knowledge results currently developing novel therapeutic options, which in the future may contribute to a better prognosis for neuropathic keratopathy treatment.

3

Schwann cells induced neuroprotection and regeneration of retinal ganglion cells

51%

Lewin-Kowalik J., Smedowski A., Pietrucha-Dutczak M.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

To investigate neuroprotective effect of intravitreally applied Schwann cells therapy towards Retinal Ganglion Cells (RGCs) in rat experimental glaucoma. Twenty male Wistar rats were included to this study. Experimental glaucoma was induced in the left eye of each rat by intraocular pressure (IOP) elevation using intracameral injection of polystyrene microbeads. The right eye served as a healthy control. Ten animals received intravitreal injection of 5 μl Schwann cells suspension (about 106 cells), another 10 received injection of equivallent volume of PBS. Animals were breaded for 6 weeks and IOP was monitored using laboratory tonometer once a week. After 6 weeks animals were sacrificed, eyes with optic nerves were enucleated and processed for histology and immunohistochemistry. RGCs survival was compared by counting RGCs bodies and optic nerve axons from control eyes (healthy and PBS) and Schwann cells treated. Mean 6 weeks IOP in ocular hypertension eyes was significantly higher in comparison to healthy contralateral eyes (31.02±5.5 mmHg and 10.32±0.54 mmHg, mean±SD, Wilcoxon paired test, P<0.05). There were significant differences between RGCs bodies and optic nerve axons numbers in Schwann cell-treated vs. PBS-treated vs. healthy control eyes (P<0.05, Kruskall-Wallis test). Mean 6-weeks loss of RGCs bodies was 21.7% in glaucoma eyes treated with Schwann cells and 45% in glaucoma eyes treated with PBS. Immunofluorescent staining with GAP43 showed neurites outgrowth within optic nerves from eyes treated with Schwann cells. Applied cellular therapy using predegenerated Schwann cells showed neuroprotective and regenerative effect towards RGCs in rat glaucoma model.

4

Decrease of RGCs number in glaucoma model vs. optic nerve transaction in rats

51%

Pietrucha-Dutczak M., Smedowski A., Wylegala E., Lewin-Kowalik J.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

|

nr Suppl.1

Introduction: Transection of the optic nerve and glaucoma causes both structural and functional damage to retinal ganglion cells with subsequent vision defect or loss. This study was undertaken to compare the lost of RGCs after optic nerve transection and glaucoma model. Materials and methods: Wistar rats were divided into two groups. The first group underwent bilateral stereotactic injection of fluorescent tracer – Fluorogold (FG) into the superior colliculus to label RGCs. After one week the right optic nerve was transected. Left eye without optic nerve axotomy was established as control. In the second group intraocular pressure (right eye) was elevated by injection of polystyrene microbeads into anterior chamber (Bead model) and measured by Icare TonoLab. RGCs were labeled by FG before euthanasia. Fourteenth days following optic nerve transection and intraocular pressure elevation the total number of FG-positive RGCs was counted in seven radial sections through the optic disk. Results and conclusions: After axotomy the number of surviving cells was reduced to 20.2 % (from 2249.5 ± 127.2 – in control group to 454.7 ± 96.5 – in group after axotomy), in glaucoma model to 79.9% (from 2249.5 ± 127.2 – in control group to 1798.3 ± 118.96 – in glaucoma model).

5

Elevated intraocular pressure impairs distribution of RNA-binding protein HuR in glaucomatous rat retina

33%

Lewin-Kowalik J., Smedowski A., Liu X., Podracka L., Trzeciecka A., Pietrucha-Dutczak M., Varjosalo M., Kaarniranta K., Amadio M.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

INTRODUCTION: Glaucoma is a serious social problem as it may result in blindness. Most often, it is related to increased intraocular pressure, but the exact biologic mechanism is not known yet. RNA-binding proteins may be one of the pathogenetic factors for this disease. AIM(S): To evaluate impact of increased intraocular pressure (IOP) on HuR protein expression in retina and optic nerve in rat glaucoma model. METHOD(S): IOP was increased unilaterally using modified rat bead model. Fellow eye was used as a healthy control. Animals were sacrificed 1 day, 1‑, 4‑, 6‑ or 8‑weeks after beads injection. Retinas and optic nerves were collected and processed for Western blot (WB) analysis, mass spectrometry (MS), PCR and immunostainings. RESULTS: The loss of retinal ganglion cells (RGCs) was at the level of 36% after 8‑weeks of IOP elevation. The presence of HuR protein and its transcipt was confirmed in retinas and optic nerves using WB, MS and PCR analysis. Additionally, Gene Ontology enrichment analysis revealed that the most significant alterations in glaucoma retinas were linked to the molecular function of binding proteins. In fractionated WB of retinal homogenates, the level of cytoplasmic fraction of HuR was decreased approximately 3-times when compared with healthy tissue (p<0.05). This decrease was accompanied by alteration of the cytoplasmic level of HuR-regulated proteins, i.e. Hsp70 decrease in retina and p53 decrease in optic nerve. Stereological analysis of retinas revealed that some RGCs have lost visible HuR expression. Immunostaining of retinal and optic nerves cross sections showed decreased staining for HuR within RGCs and increased within optic nerve glia, with nuclear polarisation of HuR expression in glaucoma samples. CONCLUSIONS: Increased intraocular pressure results in alteration of RNA-binding protein HuR within retina and, subsequently, decreased expression of HuR-dependent stress-response regulatory proteins. This alterations might contribute to the development of glaucomatous degeneration.

Ograniczanie wyników

5 Acta Neurobiologiae Experimentalis

5 Smedowski A.

3 Lewin-Kowalik J.

3 Pietrucha-Dutczak M.

1 Amadio M.

1 Kaarniranta K.

1 Liu X.

1 Podracka L.

1 Trzeciecka A.

1 Varjosalo M.

1 Wylegala A.

1 Wylegala E.

1 2019

1 2017

2 2015

1 2013

Increased intraocular pressure alters the cellular distribution of HuR protein in retinal ganglion cells

Spontaneous and inducible reinervation of human cornea

Schwann cells induced neuroprotection and regeneration of retinal ganglion cells

Decrease of RGCs number in glaucoma model vs. optic nerve transaction in rats

Elevated intraocular pressure impairs distribution of RNA-binding protein HuR in glaucomatous rat retina