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Neuroprotection by α2-Adrenergic Receptor Stimulation after Excitotoxic Injury of Chicken Retinal Ganglion Cells: A Population Study
Uppsala University. (Finn Hallböök group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience. Uppsala University. (Finn Hallböök group)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Retinal ganglion cells (RGCs) loss is one of the most common causes of blindness in worldwide. In this work we studied the RGC population in normal and excitotoxically injured chicken retina after pretreatment with the α2-adrenergic receptor (α2-ADR) agonist brimonidine. The main objective of this work was to study the effects of brimonidine on injured chicken RGCs. A lesion was inflicted by intraocular injection of N-methyl-D-aspartate (NMDA) at embryonic day 18 and the total population of retinal ganglion cells was studied using an automated cell counting of cells positive for the retinal ganglion cell marker Brn3a in flat-mounted retinas. Surviving Brn3a positive RGCs and their distribution in the retina were analyzed 7 and 14 days post lesion. In addition, the total population of retinal ganglion cells was analyzed in a series of normal embryonic day 8 to post-hatch day 11 retinas. The result showed the distribution of total population of RGCs both in embryonic and post-nantal chicken retina. The pretreatment with brimonidine in excitotoxic retina significantly reduced RGC death as seen both 7 and 14 days post lesion. The excitotoxic lesion was more severe in the dorsal quadrants of the retina than in the ventral ones. The regional difference was also seen in the effect of brimonidine. Thus, we conclude that α2-ADR signaling protects RGCs against the excitotoxic injury in the chicken retina.

Keyword [en]
Alpha2-adrenergic receptor agonist, brimonidine, Brn3a, excitotoxin, flat-mount retina, NMDA, retinal ganglion cells, topographical distribution, development
National Category
Neurosciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-281583OAI: oai:DiVA.org:uu-281583DiVA: diva2:914641
Available from: 2016-03-24 Created: 2016-03-24 Last updated: 2016-05-12
In thesis
1. Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina: Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems
Open this publication in new window or tab >>Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina: Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Müller cells are major glial cells in the retina and have a broad range of functions that are vital for the retinal neurons. During retinal injury gliotic response either leads to Müller cell dedifferentiation and formation of a retinal progenitor or to maintenance of mature Müller cell functions. The overall aim of this thesis was to investigate the intra- and extracellular signaling of Müller cells, to understand how Müller cells communicate during an injury and how their properties can be regulated after injury. Focus has been on the α2-adrenergic receptor (α2-ADR) and endothelin receptor (EDNR)-induced modulation of Müller cell-properties after injury.

The results show that α2-ADR stimulation by brimonidine (BMD) triggers Src-kinase mediated ligand-dependent and ligand-independent transactivation of epidermal growth factor receptor (EGFR) in both chicken and human Müller cells. The effects of this transactivation in injured retina attenuate injury-induced activation and dedifferentiation of Müller cells by attenuating injury-induced ERK signaling. The attenuation was concomitant with a synergistic up-regulation of negative ERK- and RTK-feedback regulators during injury. The data suggest that adrenergic stress-signals modulate glial responses during retinal injury and that α2-ADR pharmacology can be used to modulate glial injury-response. We studied the effects of this attenuation of Müller cell dedifferentiation on injured retina from the perspective of neuroprotection. We analyzed retinal ganglion cell (RGC) survival after α2-ADR stimulation of excitotoxically injured chicken retina and our results show that α2-ADR stimulation protects RGCs against the excitotoxic injury. We propose that α2-ADR-induced protection of RGCs in injured retina is due to enhancing the attenuation of the glial injury response and to sustaining mature glial functions. Moreover, we studied endothelin-induced intracellular signaling in Müller cells and our results show that stimulation of EDNRB transactivates EGFR in Müller cells in a similar way as seen after α2-ADR stimulation. These results outline a mechanism of how injury-induced endothelins may modulate the gliotic responses of Müller cells.

The results obtained in this thesis are pivotal and provide new insights into glial functions, thereby uncovering possibilities to target Müller cells by designing neuroprotective treatments of retinal degenerative diseases or acute retinal injury.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1201
Keyword
Alpha2-adrenergic receptor, Brimonidine, Brn3a, Dedifferentiation, Endothelin, EGFR, ERK1/2, Neuroprotection, NMDA, MIO-M1 human Müller cell, Müller cells, Retina, Retinal ganglion cells, Src-kinase, Transactivation.
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-281569 (URN)978-91-554-9527-5 (ISBN)
Public defence
2016-05-19, B21, BMC, Husagatan 03, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-04-28 Created: 2016-03-24 Last updated: 2016-05-12

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