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The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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2006 (English)In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 71, no 1-3, 208-218 p.Article in journal (Refereed) Published
Abstract [en]

The α-2-adrenergic receptor agonist brimonidine has been shown to increase survival of retinal ganglion cells following ischemic injury to the rat retina. Increased expression of growth factors has been suggested to be involved in this action. We investigated expressional changes of growth factors and their receptors following transient retinal ischemia induced by selective ligature of ophthalmic vessels in rats pre-treated with vehicle or 0.5% brimonidine. In addition, analysis of expression in retinal samples following unilateral administration of brimonidine to normal tissue was performed. Tissue samples of retina and superior colliculus were collected at time points between 6 h and 14 days of retinal reperfusion. Analysis of mRNA levels of the ligands BDNF, NT3, CNTF, FGF1, FGF2, FGF9 and HGF; as well as the receptors TrkB, TrkC, p75NTR, CNTFRα, FGFR1, FGFR3, FGFR4 and HGFR were performed using qRT-PCR. The cell specific markers Thy1 and GFAP were analysed. We report transiently increased retinal levels of BDNF, NT3, p75NTR, FGFR1 and HGFR and decreased levels of FGF9, HGF, TrkB, TrkC, FGFR4 and Thy1 following ischemia. The decreases were counteracted by brimonidine. Brimonidine treatment gave an increase in BDNF, NT3 and CNTF levels compared to the vehicle treated group. In superior colliculus increased levels of growth factor mRNA were found. In conclusion, transient ischemia has a profound effect on gene expression in rat retina. Alterations can also be seen in the superior colliculus but are smaller. Brimonidine pre-treatment attenuates an acute injury-induced response by decreasing the expression of several genes, among them p75NTR. Brimonidine also causes a prolonged increase of several growth factors as well as receptors in retina and superior colliculus compared to the ischemic situation. The increased expression of several growth factors represents a coordinated growth factor system response that differs from the ischemia-induced changes and is likely part of the neuroprotective activity that is elicited by BMD pre-treatment.

Place, publisher, year, edition, pages
2006. Vol. 71, no 1-3, 208-218 p.
Keyword [en]
α-2-Adrenergic receptor agonist, Injury, Neurotrophic factor, Real time PCR, Tyrosine kinase receptors, Visual system
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97695DOI: 10.1016/j.brainresbull.2006.09.005ISI: 000242735500029PubMedID: 17113948OAI: oai:DiVA.org:uu-97695DiVA: diva2:172734
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2011-02-23Bibliographically approved
In thesis
1. Experimental Injury to the Visual System: Molecular Studies of the Retina
Open this publication in new window or tab >>Experimental Injury to the Visual System: Molecular Studies of the Retina
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Retinal ganglion cells play a crucial role in the relay of visual signals from the eye to the brain. This cell type is affected and eventually lost in the eye disease glaucoma, resulting in progressive and irreversible loss of vision. Studies of the molecular mechanisms leading to retinal ganglion cell death are important for the understanding of the disease and for designing future treatments. This thesis addresses and studies these molecular mechanisms, including alterations in gene expression after experimental retinal injuries. The effects of a neuroprotective drug, brimonidine, after transient retinal ischemia were also studied in order to help explain the mechanisms behind the protective properties of this drug.

Several methods, including quantitative reverse transcriptase PCR, micro-arrays, western blot and immunohistochemistry, were used. The results showed that transient retinal ischemia triggers cell division in Müller cells and alters the gene expression of growth factors, their receptors, and intermediate filaments in the retina. Several genes related to the apoptosis process were less affected. Pre-treatment with brimonidine increased the levels of certain growth factors (BDNF, NT3, CNTF, FGF9) compared with vehicle. Brimonidine also had marked effects on genes related to progenitor cells, among them the recognized neural stem cell marker nestin. The increase in levels of nestin after ischemia was countered by brimonidine treatment. Moreover, retinal ganglion cell death following either optic nerve transection or optic nerve crush appears to involve the extrinsic apoptotic pathway although the gene expression response appears to differ between these injuries.

The results obtained in this work contribute to an increased understanding of retinal injuries and highlight the importance of Müller cells in the endogenous defense against retinal injuries.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 392
retina, injury, ischemia, gene expression, brimonidine, alpha-2-adrenergic agonist, neuroprotection, growth factors, apoptosis, Müller cells
National Category
urn:nbn:se:uu:diva-9344 (URN)978-91-554-7321-1 (ISBN)
Public defence
2008-11-28, B21, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-11-06 Created: 2008-11-06Bibliographically approved

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