Longitudinal Evaluation of Retinal Ganglion Cell Function and IOP in the DBA/2J Mouse Model of Glaucoma

Saleh, Maher; Nagaraju, M.; Porciatti, Vittorio

doi:10.1167/iovs.07-0483

Cited by 117 publications

(146 citation statements)

References 77 publications

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“…This is consistent with findings of a considerable number of surviving axons in older optic nerves, even with diminished physiological activity (Fig. 6B) (14,17,36).…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

316

482

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An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to-proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target.axon transport | optic neuropathy | retinal ganglion cell | glaucoma | optic nerve

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“…This is consistent with findings of a considerable number of surviving axons in older optic nerves, even with diminished physiological activity (Fig. 6B) (14,17,36).…”

Section: Discussionsupporting

confidence: 92%

“…A small number of younger DBA/2 (3-5 mo) had transport deficits without IOP elevation (Fig. 2), so additional pathogenic mechanisms must be at work early (30,36). Retrograde transport from the SC to the retina in the DBA/2 is maintained at 20% to 30% capacity up to 18 mo of age (16,17).…”

Section: Discussionmentioning

confidence: 99%

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

316

482

View full text Add to dashboard Cite

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“…In agreement with previous results, reporting IOP increase from an age of 6 months [19,31], we showed that IOP is already elevated in 7 month DBA/2J mice remaining elevated at later ages. We previously demonstrated that IOP elevation plays a critical role in influencing visual response and in causing RGC dysfunction [19].…”

Section: Discussionsupporting

confidence: 93%

“…IOP was already elevated in 7 month-old-DBA/2J mice [31] (C57BL/6J control mice, n=20 eyes, mean=8.12 mmHg, SEM=0.34; 3 month DBA/2J, n eyes=20, mean=8.10 mmHg, SEM=0.33; 7 month DBA/2J, n eyes=12, mean=11.59 mmHg, SEM=0.40; 10-13 month DBA/2J, n eyes=12, mean=13.00 mmHg, SEM=0.65; 15-18 month DBA/2J, n eyes =12, mean=12.85 mmHg, SEM=0.62) shown in figure 1A. These data are in agreement to previous results [19]; here we show that IOP elevation in DBA/2J mice persists at the late ages of 13-18 months.…”

Section: Resultsmentioning

confidence: 90%

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Fabiani¹,

Cerri²

2016

J Clin Exp Ophthalmol

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Glaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder. It is characterized by the retinal ganglion cells (RGCs) loss of axons as well as optic nerve atrophy, progressive degeneration of RGCs till cell death. In this work, we used DBA/2J mice as a model of spontaneous glaucoma and we investigated the involvement of BDNF and Mitogen-Activated Protein Kinases (MAPK) pathways in correlation with IOP elevation and progression of neurodegenerative processes in the retina of DBA/2J mice. In particular, we performed western blot analysis to study retinal levels of the BDNF and its receptor, TrkB, and to better understand possible modulation of p38 MAPK and ERK1/2 activation at different stages of retinal degeneration in DBA/2J mice. We showed that BDNF starts to decrease already at an early stage in correspondence to IOP elevation (7 months of age). MAPKs, in particular p38 MAPK and ERK1/2, appeared maximally affected at more advanced stages of neurodegeneration (10-12 and 18 months of age) characterized by RGC degeneration and death, optic nerve atrophy. Thus, BDNF signaling and MAPKs are differentially activated at different stages of retinal degeneration in DBA/2J mice, a murine model of glaucoma.

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“…These mice develop glaucoma as a result of iris pigment dispersion and atrophy of the iris stroma caused by mutations in Glycoprotein non-metastatic b and Tyrosinase-related protein 1 (John et al, 1998). Pigment accumulation in the trabecular meshwork causes clogging and reduced flow of aqueous humor, causing a moderate increase in IOP between 2 and 6 months and a strong increase between 8 and 12 months (Saleh et al, 2007;Harazny et al, 2009). The increase in IOP produces changes in the retina and optic nerve (Libby et al, 2005;Pérez de Lara et al, 2014) Most of the experiments performed to date with melatonin and 5-MCA-NAT have been carried out in either normotensive animals (Pintor et al, 2001) or in hypertensive/glaucoma conditions (Serle et al, 2004;Martínez-Águila et al, 2013), but not in an animal model that develops the disease spontaneously.…”

Section: Introductionmentioning

confidence: 99%

Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice

Martínez-Águila

Fonseca

Lara

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Melatonin is a neurohormone that is produced not only by the pineal gland but also by several ocular structures. One of the main physiologic roles of melatonin is the reduction of intraocular pressure (IOP). Using both control C57BL/6J and glaucomatous DBA/2J mice as well as TonoLab tonometry, this study evaluated the effect of melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) when glaucomatous pathology was fully established and compared pharmacological behavior in treated mice versus control mice. In addition, 5-MCA-NAT was tested to determine its effects on ameliorating increased IOP in a glaucoma model. The results demonstrate that melatonin and 5-MCA-NAT can reduce IOP in a concentration-dependent manner. The EC 50 values for melatonin in control and glaucomatous animals were 34 mM and 50 mM, respectively. Interestingly, melatonin decreased IOP in 19.4% 6 3.7% and 32.6% 6 6.0% of control and glaucomatous mice, respectively, when the animals were studied at age 12 months. 5-MCA-NAT reduced IOP in the same manner and was able to stop IOP progression in glaucomatous mice. Use of melatonin receptor antagonists showed that hypotensive effects were blocked by the MT 2 receptor antagonists luzindole and 4-phenyl-2-propionamidotetralin in the case of melatonin and by only 4-phenyl-2-propionamidotetralin in the case of 5-MCA-NAT. In conclusion, melatonin and 5-MCA-NAT can effectively reduce IOP in a glaucoma model, and their hypotensive effects are more profound in the glaucoma model than in control animals.

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Longitudinal Evaluation of Retinal Ganglion Cell Function and IOP in the DBA/2J Mouse Model of Glaucoma

Cited by 117 publications

References 77 publications

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice

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