Delayed administration of glial cell line-derived neurotrophic factor (GDNF) protects retinal ganglion cells in a pig model of acute retinal ischemia

Kyhn, Maria Voss; Klassen, Henry; Johansson, Ulrica Englund; Warfvinge, Karin; Lavik, Erin B.; Kiilgaard, Jens Folke; Prause, Jan Ulrik; Scherfig, Erik; Young, Michael J.; Cour, Morten la

doi:10.1016/j.exer.2009.08.014

Cited by 36 publications

(33 citation statements)

References 35 publications

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“…The NeuN expression pattern was in accordance with that of the original literature describing NeuN (Mullen et al 1992;Sarnat et al 1998). As a nuclear marker, NeuN was useful for quantifying numbers of neurons remaining in the GCL in a pig model of acute retinal ischemia (Kyhn et al 2009a). NeuN may also label displaced amacrine cells in the GCL.…”

Section: Neun a Marker For Neurons In The Gclsupporting

confidence: 84%

A Battery of Cell- and Structure-specific Markers for the Adult Porcine Retina

Johansson

Eftekhari

Warfvinge

2010

J Histochem Cytochem.

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S U M M A R Y The pig is becoming an increasingly used non-primate model in experimental studies of human retinal diseases and disorders. The anatomy, size, and vasculature of the porcine eye and retina closely resemble their human counterparts, which allows for application of standard instrumentation and diagnostics used in the clinic. Despite many reports that demonstrate immunohistochemistry as a useful method for exploring neuropathological changes in the mammalian central nervous system, including the pig, the porcine retina has been sparsely described. Hence, to facilitate further immunohistochemical analysis of the porcine retina, we report on the successful use of a battery of antibodies for staining of paraformaldehyde-fixed cryosectioned retina. The following antibodies were evaluated for neuronal cells and structures: recoverin (cones and rods), Rho4D2 (rods), transducin-g (cones), ROM-1 (photoreceptor outer segments), calbindin (horizontal cells), PKC-a (bipolar cells), parvalbumin (amacrine and displaced amacrine cells), and NeuN (ganglion cells and displaced amacrines). For detecting synaptic connections in fiber layers, we used an antibody against synaptobrevin. For detecting retinal pigment epithelium, we studied antibodies against cytokeratin and RPE65, respectively. The glial cell markers used were bFGF (Müller cells and displaced amacrine cells), GFAP (Müller cells and astrocytes), and vimentin (Müller cells). Each staining effect was evaluated with regard to its specificity, sensitivity, and reproducibility in the identification of individual cells, specific cell structures, and fiber layers, respectively. The markers parvalbumin and ROM-1 were tested here for the first time for the porcine retina. All antibodies tested resulted in specific staining of high quality. In conclusion, all immunohistochemical protocols presented here will be applicable in fixed, cryosectioned pig retina. (J Histochem Cytochem 58:377-389, 2010)

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Section: Neun a Marker For Neurons In The Gclsupporting

confidence: 84%

A Battery of Cell- and Structure-specific Markers for the Adult Porcine Retina

Johansson

Eftekhari

Warfvinge

2010

J Histochem Cytochem.

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“…Several recent studies have also used this model at similar levels of elevated IOP in the pig to study the effect of ischemia on neural/glial cells and on gene/protein expression in neural retina and retinal vessels. The results from those studies demonstrated that short-term ischemia (60 minutes to 2 hours) followed by reperfusion was sufficient to promote Müller cell gliosis 31 and loss of ganglion cells, 32,33 and to increase expression of inflammatory proteins (mitogen-activated protein kinases and tumor necrosis factor alpha) in neural and vascular retina. 34,35 Our findings further support use of the porcine model and provide direct evidence for the effect of acute retinal ischemia alone on retinal arteriolar function.…”

Section: Figurementioning

confidence: 93%

Acute Retinal Ischemia Inhibits Endothelium-Dependent Nitric Oxide–Mediated Dilation of Retinal Arterioles via Enhanced Superoxide Production

Hein¹,

Ren²,

Potts

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Because retinal vascular disease is associated with ischemia and increased oxidative stress, the vasodilator function of retinal arterioles was examined after retinal ischemia induced by elevated intraocular pressure (IOP). The role of superoxide anions in the development of vascular dysfunction was assessed. METHODS. IOP was increased and maintained at 80 to 90 mm Hg for 30, 60, or 90 minutes by infusing saline into the anterior chamber of a porcine eye. The fellow eye with normal IOP (10 -20 mm Hg) served as control. In some pigs, superoxide dismutase mimetic TEMPOL (1 mM) or vehicle (saline) was injected intravitreally before IOP elevation. After enucleation, retinal arterioles were isolated and pressurized without flow for functional analysis by recording diameter changes using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production in isolated retinal arterioles. RESULTS. Isolated retinal arterioles developed stable basal tone and the vasodilations to endothelium-dependent nitric oxide (NO)-mediated agonists bradykinin and L-lactate were significantly reduced only by 90 minutes of ischemia. However, vasodilation to endothelium-independent NO donor sodium nitroprusside was unaffected after all time periods of ischemia. DHE staining showed that 90 minutes of ischemia significantly increased superoxide levels in retinal arterioles. Intravitreal injection of membrane-permeable radical scavenger but not vehicle before ischemia prevented elevation of vascular superoxide and preserved bradykinin-induced dilation. CONCLUSIONS. Endothelium-dependent NO-mediated dilation of retinal arterioles is impaired by 90 minutes of ischemia induced by elevated IOP. The inhibitory effect appears to be mediated by the alteration of NO signaling via vascular superoxide. T he neural retina tissue in patients exposed to acute periods of retinal ischemia suffers from blood flow deficit, which can lead to visual impairment and blindness.1,2 Ocular diseases and complications such as acute angle-closure glaucoma, retinal vascular occlusion, and elevated intraocular pressure during vitreous surgery or after vitreoretinal surgery, are associated with retinal ischemia.1-3 Currently, treatment modalities for restoring neural retina function are relatively limited. Experimental evidence demonstrating a reduction in retinal blood flow after the initial retinal ischemia suggests that dysfunction of arterioles, the major site for flow regulation, contributes to the persistent retinal damage. 4,5 However, studies are lacking to directly address whether vasomotor function of retinal arterioles is altered after acute retinal ischemia.In the retinal circulation, the vascular endothelium is important in regulating local blood flow by the release of vasoactive factors such as the potent vasodilator nitric oxide (NO) 6 and vasoconstrictor endothelin-1. 7 It has been shown in pigs that endothelium-dependent arterial dilation and release of NO surrounding the retinal arterioles are reduced in vivo after acute ...

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“…The data presented here support the findings of a neuroprotective effect of GDNF on the electrophysiological function of ischemiareperfusion-damaged rat 33 and porcine retinas. 26 The effect was most pronounced on the induced mfERG, as iN1 amplitude ratios (BRVO/healthy) were greatest in the GDNF group and as GDNF-treated BRVO eyes produced amplitudes not significantly different from those of healthy eyes. Previously, after inner retinal damage, a strong correlation was found between histopathology and iN1 amplitudes in pigs, 15 and iN1 was nearly abolished by blocking retinal ganglion cell activity with tetrodotoxin.…”

Section: Consequences Of Gdnf Treatment In Brvo Eyesmentioning

confidence: 96%

“…GDNF has been proposed as a neuroprotectant for retinal ganglion cells (RGCs) in axotomized animal eyes, [19][20][21][22][23] while other studies have shown that GDNF increases the survival of RGCs in glaucomatous retinas of rats 24 and mice, 25 as well as in postischemic retinas of pigs. 26 Moreover, GDNF maintained photoreceptors following retinal degeneration in mice, 27 in rats, 28 and in rat eyes with detached retinas. 29 Recently, GDNF was proven to support transplanted sheets of fetal retina and improve visual function by reinforcing proper synaptic connections and reducing apoptosis.…”

mentioning

confidence: 99%

Effect of Glial Cell Line-Derived Neurotrophic Factor on Retinal Function after Experimental Branch Retinal Vein Occlusion

Ejstrup

Cour

Kyhn

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The objective of the study was to investigate the effect of glial cell line-derived neurotrophic factor (GDNF) on the multifocal electroretinogram (mfERG) following an induced branch retinal vein occlusion (BRVO) in pigs.METHODS. Electrophysiological examination of the retina was performed in 20 pigs with standard and four-frame mfERG 4 weeks after induced BRVO and intravitreal injection of GDNF or vehicle. BRVO was induced by intraocular diathermia of the superior retinal vein. Inner retinal function was measured by analysis of the four-frame mfERG (iN1) and outer retinal function with standard mfERG (P1).RESULTS. In GDNF-treated BRVO eyes, P1 and iN1 amplitudes (P ¼ 0.51 and 0.78) or implicit times (P ¼ 0.08 and 0.99) did not differ from those in healthy fellow eyes. After vehicle injection, P1 and iN1 amplitudes of BRVO eyes were significantly lower than in the healthy fellow eye (P ¼ 0.022 and 0.013). The log ratios of mfERG amplitudes between experimental and healthy fellow eyes were calculated (BRVO/healthy). GDNF improved the ratios of the four-frame mfERG CONCLUSIONS. GDNF appears neuroprotective on retinal electrophysiological function after BRVO. The efficacy and safety of GDNF remain to be investigated in primate eyes. (Invest Ophthalmol Vis Sci. 2012;53:6207-6213)

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Delayed administration of glial cell line-derived neurotrophic factor (GDNF) protects retinal ganglion cells in a pig model of acute retinal ischemia

Cited by 36 publications

References 35 publications

A Battery of Cell- and Structure-specific Markers for the Adult Porcine Retina

A Battery of Cell- and Structure-specific Markers for the Adult Porcine Retina

Acute Retinal Ischemia Inhibits Endothelium-Dependent Nitric Oxide–Mediated Dilation of Retinal Arterioles via Enhanced Superoxide Production

Effect of Glial Cell Line-Derived Neurotrophic Factor on Retinal Function after Experimental Branch Retinal Vein Occlusion

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