Effects of anti-glaucoma medications on gangion cell survival: the DBA/2J mouse model

Schuettauf, Frank; Quinto, Kristine; Naskar, Rita; Zurakowski, David

doi:10.1016/s0042-6989(02)00188-8

Cited by 96 publications

(79 citation statements)

References 15 publications

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“…Many RGC studies have relied on retrograde labeling (Schuettauf et al, 2002;Vecino et al, 2002;Danias et al, 2003) to study and quantify this heterogeneous, specialized population of retinal neurons. FluoroGold has been the tracer of choice for such studies, and this method requires active transport mechanisms to move endocytic vesicles packed with FG back to the RGC soma (Koebbert et al, 2000); hence, FG and similar tracers do not accumulate in ganglion cells with compromised axon transport.…”

Section: Discussionmentioning

confidence: 99%

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham¹,

Inman²,

Lambert³

et al. 2008

J. Neurosci.

372

336

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Glaucoma is characterized by retinal ganglion cell (RGC) pathology and a progressive loss of vision. Previous studies suggest RGC death is responsible for vision loss in glaucoma, yet evidence from other neurodegenerative diseases suggests axonal degeneration, in the absence of neuronal loss, can significantly affect neuronal function. To characterize RGC degeneration in the DBA/2 mouse model of glaucoma, we quantified RGCs in mice of various ages using neuronal-specific nuclear protein (NeuN) immunolabeling, retrograde labeling, and optic nerve axon counts. Surprisingly, the number of NeuN-labeled RGCs did not decline significantly until 18 months of age, at which time a significant decrease in RGC somal size was also observed. Axon dysfunction and degeneration occurred before loss of NeuN-positive RGCs, because significant declines in RGC number assayed by retrograde tracers and axon counts were observed at 13 months. To examine whether axonal dysfunction/degeneration affected gene expression in RGC axons or somas, NeuN and neurofilament-heavy (NF-H) immunolabeling was performed along with quantitative reverse transcription-PCR for RGC-specific genes in retinas of aged DBA/2 mice. Although these mice had similar numbers of NeuN-positive RGCs, the expression of neurofilament light, Brn-3b, and Sncg mRNA varied; this variation in RGC-specific gene expression was correlated with the appearance of NF-H immunoreactive RGC axons. Together, these data support a progression of RGC degeneration in this model of glaucoma, beginning with loss of retrograde label, where axon dysfunction and degeneration precede neuronal loss. This progression of degeneration suggests a need to examine the RGC axon as a locus of pathology in glaucoma.

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Section: Discussionmentioning

confidence: 99%

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham¹,

Inman²,

Lambert³

et al. 2008

J. Neurosci.

372

336

View full text Add to dashboard Cite

show abstract

“…In D2 mice, high IOP causes RGC loss that can be prevented by IOP-lowering interventions (28)(29)(30)(31). Importantly, glaucoma in D2 mice is an axonopathy, as evidenced by substantial RGC protection in the presence of the Wallerian degeneration slow allele (D2.Wld s ) (20).…”

mentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

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

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…Such drugs are not expected to restore vision which has been lost prior to initiation of treatment but may very well help preserve vision Lipton [16]. Memantine, an NMDA channel blocker, has been shown to be neuroprotective in both rodent Schuettauf et al [17] and monkey Hare et al…”

Section: Bmentioning

confidence: 99%

Optimized Ophthalmic: Advances in the Treatment of Ocular Diseases in Animals

Kurup¹,

Parikh²,

Mahla³

et al. 2017

BJSTR

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Effects of anti-glaucoma medications on gangion cell survival: the DBA/2J mouse model

Cited by 96 publications

References 15 publications

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Optimized Ophthalmic: Advances in the Treatment of Ocular Diseases in Animals

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