Growth Factors in Combination, but Not Individually, Rescue rd Mouse Photoreceptors in Organ Culture

Ogilvie, Judith Mosinger; Speck, Judith D.; Lett, Jaclynn M.

doi:10.1006/exnr.1999.7291

Cited by 89 publications

(52 citation statements)

References 46 publications

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“…It has been shown in other systems that treatment with a combination of growth factors or cytokines improves the retinal morphology in vivo and in vitro as compared with administration of the individual factors alone (Ogilvie et al, 2000;Caffe et al, 2001;Cao et al, 2001). Thus, the possibility exists that additional hypoxia- inducible factors might act together with Epo to achieve full neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

Grimm¹,

Wenzel²,

Stanescu³

et al. 2004

J. Neurosci.

112

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Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments.

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Section: Discussionmentioning

confidence: 99%

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

Grimm¹,

Wenzel²,

Stanescu³

et al. 2004

J. Neurosci.

112

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“…by slow-release capsules [40] , coating onto beads [37] , transfecting retinal cells in situ to secrete neuroprotectants [44] , transscleral delivery of drugs [45] and cell-based delivery [34] . Other work has focused on combining neuroprotectants [46][47][48] to improve efficacy. Other relevant investigations include efforts to improve drug penetration into retinal tissue [49] or the penetration of viral vectors or cells that could act as drug delivery devices [50] .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Enhancement of ex vivo Gene Therapy Neuroprotection in a Rodent Model of Retinal Degeneration

Gregory-Evans

Po²,

Chang³

et al. 2011

Ophthalmic Res

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Aims: We have previously shown the benefits of cell-based delivery of neuroprotection in a rodent model of retinitis pigmentosa (RP). In order to maximise the effectiveness of this approach, we hypothesised that this could be augmented by combination with an aminoglycoside known to limit the abnormal RNA translation seen in this model. Methods: A rhodopsin TgN S334ter-4 rat model of RP underwent daily subcutaneous injection of 12.5 µg/g gentamicin from postnatal day 5 (P5). At P21, selected rats also underwent intravitreal injection of cells genetically engineered to oversecrete glial cell-derived neurotrophic factor. Histological imaging was undertaken to evaluate photoreceptor survival at P70 and compared with images from untreated TgN S334ter-4 rats and control Sprague-Dawley rats. Results: Statistically significant (p < 0.05) improvements in outer retinal indices were seen with this combination strategy when compared with results in rats treated with individual therapies alone. This improvement was most apparent in the peripheral retina, where the greatest degeneration was observed. Conclusions: We have shown that the combination of neuroprotection plus aminoglycoside read-through in an animal model of retinal degeneration improved the histological appearance of the retina such that it was statistically indistinguishable from unaffected controls. Further functional and longitudinal studies of this approach are warranted.

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“…In addition, GFLs show promise for the treatment of several neurodegenerative diseases as well as neuropathic pain (McBride and Kordower, 2002;Kirik et al, 2004;Eslamboli, 2005;Sah et al, 2005). Finally, GDNF administration slows photoreceptor cell death in animal models of retinal degeneration (Carwile et al, 1998;Frasson et al, 1999;Ogilvie et al, 2000;McGee Saftner et al, 2001;Politi et al, 2001;AndrieuSoler et al, 2005;Delyfer et al, 2005), implying that GFLmediated RET signaling can influence retinal function.…”

Section: Introductionmentioning

confidence: 99%

Neurturin-Mediated Ret Activation Is Required for Retinal Function

Brantley¹,

Jain²,

Barr³

et al. 2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) [GDNF, NRTN (neurturin), ARTN (artemin), and PSPN (persephin)] interact with GDNF family receptors (GFR␣s) and activate intracellular signaling through the Ret receptor tyrosine kinase. To characterize the role of Ret signaling in retinal activity, we examined Ret hypomorphic and Ret conditional mice using electroretinography. We found that aberrant Ret function resulted in markedly diminished scotopic and photopic responses. Using mice deficient in individual GFLs, we found that only NRTN deficiency led to reduced retinal activity. To determine the potential target cell type for NRTN, we examined the retinal expression of its coreceptors (GFR␣1 and GFR␣2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFR␣1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFR␣2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFR␣1, GFR␣2, or Ret was detected in photoreceptors or Müller cells, suggesting that these cells are not directly affected by Ret. Finally, detailed morphologic analyses of retinas from NRTN-and Ret-deficient mice demonstrated a reduction in normal horizontal cell dendrites and axons, abnormal extensions of horizontal cell and bipolar cell processes into the outer nuclear layer, and mislocalized synaptic complexes. These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice.

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Growth Factors in Combination, but Not Individually, Rescue rd Mouse Photoreceptors in Organ Culture

Cited by 89 publications

References 46 publications

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

Pharmacological Enhancement of ex vivo Gene Therapy Neuroprotection in a Rodent Model of Retinal Degeneration

Neurturin-Mediated Ret Activation Is Required for Retinal Function

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