Morphometric Changes in the Rat Optic Nerve Following Short-term Intermittent Elevations in Intraocular Pressure

Joos, Karen M.; Li, Chun; Sappington, Rebecca M.

doi:10.1167/iovs.10-5212

Cited by 48 publications

(56 citation statements)

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“…There was, however, a marked disparity between the potent RGC neuroprotective effect of siRTP801 and the relatively limited axon regeneration, confirming that axon regeneration is not inevitable in surviving RGCs. 19,71 A typical rodent ON contains approximately 100,000 RGC axons, 72 and thus the number of regenerating axons we observed represents a regenerative response in fewer than 0.1% RGCs. Nonetheless, our results complement the increasing literature implicating the PI3K/ Akt/mTOR pathway as a mediator of axon regeneration in several models of CNS injury.…”

Section: Discussionmentioning

confidence: 96%

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Morgan-Warren

O'Neill

Cogan

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801.METHODS. Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a þ RGC survival, GFAP þ reactive gliosis, and GAP43 þ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. RESULTS. Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43þ axon regeneration at 400 to 1200 lm beyond the ONC site, and potentiated the reactive GFAP þ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP þ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity.CONCLUSIONS. The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

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Section: Discussionmentioning

confidence: 96%

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Morgan-Warren

O'Neill

Cogan

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Different studies have used different parameters to assess GC-related retinal morphometric changes such as number of RGC in the unit area (Koeberle and Ball, 1998;Lam et al, 1999), number of RGC in the field of view (Joos et al, 2010), volume of RGC (Zhang et al, 2000), linear density of RGCs (Chávez et al, 2003;Sun et al, 2011;Takahata et al, 2003) thickness of the GCL and IR (Chávez et al, 2003;Sun et al, 2011;Takahata et al, 2003;Lam et al, 1999). Our investigation revealed that linear density is the most sensitive parameter to evaluate cell loss in the GCL.…”

Section: Discussionmentioning

confidence: 99%

Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs

Razali

Agarwal

et al. 2015

European Journal of Pharmacology

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“…8,9 This minimally invasive technique employed the concept of oculopression to produce elevated IOP. [10][11][12] An advantage of the suture compression model is that it is not associated with ocular tissue penetration or traumatization, and therefore relatively preserves the immune privilege of the eye. It was reported that a mild, chronic IOP elevation was induced for at least 15 weeks following an initial IOP spike that appeared immediately after suture placement.…”

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confidence: 99%

A Mouse Model of Chronic Ocular Hypertension Induced by Circumlimbal Suture

Liu

Flanagan

2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To develop a chronic ocular hypertension mouse model by inducing intraocular pressure (IOP) elevation using a suture technique previously developed for rats.METHODS. C57BL/6 mice were given monocular circumlimbal suture (10/0) placement under anesthesia (ketamine/xylazine). The suture was left in place for 12 weeks (n ¼ 10). A control group had the same treatment while it was removed after day 1 (n ¼ 10). Intraocular pressure, electroretinogram (ERG), and optical coherence tomography (OCT) were measured in both groups for 12 weeks. At week 12, animals were euthanized and retina was harvested for histologic assessment.RESULTS. In the group with extended suture placement, IOP spiked from 14.3 6 0.9 to 48.4 6 4.8 mm Hg immediately after suture implantation. At day 1, it declined to 33.2 6 3.7 mm Hg and remained elevated for 12 weeks. In the suture removal group, IOP normalized to baseline within a day following suture removal. In the group with prolonged IOP elevation, the retinal ganglion cell (RGC) mediated ERG responses continued to exacerbate and were significantly reduced by week 12 (P < 0.001). Progressive loss of retinal nerve fiber layer was found and it became significant from week 4 (P < 0.001). At week 12, significant loss of RGCs (P < 0.001) was noted. In the IOP normalization group, no alteration in ERG, OCT, and RGC counting was observed.CONCLUSIONS. The circumlimbal suture approach produces a mild chronic IOP elevation in mice. Functional and structural changes under model induction are largely independent of the initial IOP spike.Keywords: glaucoma, intraocular pressure, electroretinogram, optical coherence tomography, ganglion cell G laucoma is a chronic ocular disease, which is characterized by selective retinal ganglion cell (RGC) degeneration and progressive visual field loss. Elevated intraocular pressure (IOP) is a critical risk factor for disease development, and IOP lowering is the mainstay of disease management. [1][2][3] Over the past few decades, a variety of rodent models have been developed to simulate human glaucoma. [4][5][6][7] These models aim to induce either acute or chronic ocular hypertension leading to glaucomatous-like changes. By using such models, investigators have made significant insights into understanding the pathogenesis of the disease.Previously, a rat model of chronic IOP elevation using conjunctival circumlimbal suture was developed. 8,9 This minimally invasive technique employed the concept of oculopression to produce elevated IOP. [10][11][12] An advantage of the suture compression model is that it is not associated with ocular tissue penetration or traumatization, and therefore relatively preserves the immune privilege of the eye. It was reported that a mild, chronic IOP elevation was induced for at least 15 weeks following an initial IOP spike that appeared immediately after suture placement. Progressive loss of RGC function, retinal nerve fiber layer (RNFL) defect, and eventual cell death in the ganglion cell layer were observed under model induction, ...

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Morphometric Changes in the Rat Optic Nerve Following Short-term Intermittent Elevations in Intraocular Pressure

Abstract: Controlled daily 1-hour IOP elevations can be performed with an adjustable vascular loop in rats. After only 6 weeks, intermittent elevations in IOP produce changes in optic nerve consistent with early degeneration reported in chronic models of glaucoma.

Cited by 48 publications

References 53 publications

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs

A Mouse Model of Chronic Ocular Hypertension Induced by Circumlimbal Suture

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