Ocular hypertension impairs optic nerve axonal transport leading to progressive retinal ganglion cell degeneration

Salinas‐Navarro, Manuel; Alarcón-Martínez, Luis; Valiente‐Soriano, Francisco J.; Jiménez-López, Manuel; Mayor–Torroglosa, S.; Avilés‐Trigueros, Marcelino; Villegas‐Pérez, María Paz; Vidal‐Sanz, Manuel

doi:10.1016/j.exer.2009.10.003

Cited by 135 publications

(142 citation statements)

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“…Intra‐ocular pressure (IOP) was measured using a Tono‐Pen (Tono‐Pen; Medtronic Co., Dublin, Ireland), following previously described methods (Salinas‐Navarro et al. 2010; Ortín‐Martínez et al. 2015; Valiente‐Soriano et al.…”

Section: Methodsmentioning

confidence: 99%

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MicroRNA regulation in an animal model of acute ocular hypertension

Wang

Valiente‐Soriano

Nadal-Nicolás

et al. 2016

Acta Ophthalmologica

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PurposeTo analyse miRNA regulation in a rat model of acute ocular hypertension (AOH).MethodsAcute ocular hypertension (AOH) was induced in the left eye of adult albino rats by inserting a cannula connected with a saline container into the anterior chamber. The contralateral eye served as a control. Seven days later, animals were killed. Retinas were used either for quantitative analysis of retinal ganglion cells (RGCs) and microglial cells or for miRNA array hybridization, qRT‐PCR and Western blotting.ResultsAnatomically, AOH caused axonal degeneration, a significant loss of RGCs and a significant increase in microglial cells in the ganglion cell layer. The miRNAs microarray analysis revealed 31 differentially expressed miRNAs in the AOH versus control group, and the regulation of 12 selected microRNAs was further confirmed by qRT‐PCR. Bioinformatic analysis indicates that several signalling pathways are putatively regulated by the validated miRNAs. Of particular interest was the inflammatory pathway signalled by mitogen‐activated protein kinases (MAPKs). In agreement with the in silico analysis, p38 MAP kinase, tumour necrosis factor‐alpha (TNF‐α) and iNOS proteins were significantly upregulated in the AOH retinas.ConclusionsAcute IOP elevation led to changes in the expression of miRNAs, whose target genes were associated with the regulation of microglia‐mediated neuroinflammation or neural apoptosis. Addressing miRNAs in the process of retinal ischaemia and optic nerve damage in association with high IOP elevation may open new avenues in preventing retinal ganglion cell apoptosis and may serve as target for future therapeutic regimen in acute ocular hypertension and retinal ischaemic conditions.

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Section: Methodsmentioning

confidence: 99%

“…2015) and immunodetected following previously described methods (Salinas‐Navarro et al. 2010; Nadal‐Nicolás et al. 2012).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA regulation in an animal model of acute ocular hypertension

Wang

Valiente‐Soriano

Nadal-Nicolás

et al. 2016

Acta Ophthalmologica

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“…During the past years we have documented the number and spatial distribution of different retinal populations in the retina of the adult rodent, both in intact animals [32][33][34][35][36][37][38][39][40] or in animals with inherited retinal degeneration [41][42][43][44][45][46] and also after different insults such as ocular hypertension, [47][48][49][50] axotomy, 37,[51][52][53][54] or light-induced retinal degeneration. 40,55,56 In some of these studies, we have shown that manipulations or injuries to one eye or optic nerve, followed or not by IVI of trophic agents, may have molecular and cellular effects on the contralateral retina.…”

Section: Discussionmentioning

confidence: 99%

Different Ipsi- and Contralateral Glial Responses to Anti-VEGF and Triamcinolone Intravitreal Injections in Rats

Pierdomenico

García‐Ayuso

Jiménez-López

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Di Pierdomenico J, García-Ayuso D, Jiménez-López M, AgudoBarriuso M, Vidal-Sanz M, VillegasPérez MP. Different ipsi-and contralateral glial responses to anti-VEGF and triamcinolone intravitreal injections in rats. Invest Ophthalmol Vis Sci. 2016;57:3533-3544. DOI:10.1167/iovs.16-19618 PURPOSE. To investigate the glial response of the rat retina to single or repeated intravitreal injections (IVI).METHODS. Albino Sprague-Dawley rats received one or three (one every 7 days) IVI of anti-rat VEGF (5 lL; 0.015 lg/lL), triamcinolone (2.5 or 5 lL; 40 lg/lL; Trigón Depot), bevacizumab (5 lL; 25 lg/lL; Avastin), or their vehicles (PBS and balanced salt solution) and were processed 7 days after the last injection. Retinas were dissected as whole mounts and incubated with antibodies against: Iba1 (Ionized Calcium-Binding Adapter Molecule 1) to label retinal microglia, GFAP (Glial Fibrillary Acidic Protein) to label macroglial cells, and vimentin to label Müller cells. The retinas were examined with fluorescence and confocal microscopy, and the numbers of microglial cells in the inner retinal layers were quantified using a semiautomatic method.RESULTS. All the injected substances caused an important micro-and macroglial response locally at the injection site and all throughout the injected retina that was exacerbated by repeated injections. The microglial response was also observed but was milder in the contralateral noninjected eyes. The IVI of the humanized antibody bevacizumab caused a very strong microglial reaction in the ipsilateral retina. Two types of macroglial response were observed: astrocyte hypertrophy and Müller end-foot hypertrophy. While astrocyte hypertrophy was widespread throughout the injected retina, Müller end-foot hypertrophy was localized and more extensive with triamcinolone use or after repeated injections. CONCLUSIONS.Intravitreal injections cause micro-and macroglial responses that vary depending on the injected agent but increase with repeated injections. This inflammatory glial response may influence the effects of the injected substances on the retina.

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“…In addition, there are several spontaneous models of experimental glaucoma in mice with a targeted type I collagen mutation (Aihara et al, 2003) or the DBA/2J mice which develops a pigmentary glaucoma Danias et al, 2003;Filippopoulos et al, 2006;Panagis et al, 2010;Pérez de Lara et al, 2014;Reichstein et al, 2007). In our laboratory, laser photocoagulation (LP) of the limbar tissues has been the method of choice to induce OHT in adult albino rats Ramírez et al, 2010;Salinas-Navarro et al, 2010;Schnebelen et al, 2009;Valiente-Soriano et al, 2015b) and in albino de Hoz et al, 2013;Dekeyster et al, 2015;Gallego et al, 2012;Rojas et al, 2014;Salinas-Navarro et al, 2009c) or pigmented (Nguyen et al, 2011;Valiente-Soriano et al, 2015a) mice. In the LP-OHT models, typical observations are a sectorial loss of RGCs, an initial damage to RGC axons somewhere near the ON head, and an alteration of the retrograde axoplasmic transport that precedes RGC death (Chidlow et al, 2011;Martin et al, 2006;Soto et al, 2011;Vidal-Sanz et al, 2012) all of which are also found in a classic model of glaucoma, the DBA/2J mouse Crish et al, 2010;Filippopoulos et al, 2006;Jakobs et al, 2005), thus making this model relevant to advance our knowledge on the retinal pathology induced by OHT.…”

Section: Introductionmentioning

confidence: 93%