Glaucoma and optic nerve repair

Department of Neurology, Experimental Neurology, Heinrich Heine University, Merowingerplatz 1a, 40225, Düsseldorf, Germany.
Cell and Tissue Research (Impact Factor: 3.57). 03/2013; 353(2). DOI: 10.1007/s00441-013-1596-8
Source: PubMed


Glaucoma is a leading cause of irreversible blindness worldwide and causes progressive visual impairment attributable to the dysfunction and death of retinal ganglion cells (RGCs). Progression of visual field damage is slow and typically painless. Thus, glaucoma is often diagnosed after a substantial percentage of RGCs has been damaged. To date, clinical interventions are mainly restricted to the reduction of intraocular pressure (IOP), one of the major risk factors for this disease. However, the lowering of IOP is often insufficient to halt or reverse the progress of visual loss, underlining the need for the development of alternative treatment strategies. Several lines of evidence suggest that axonal damage of RGCs occurs primary at the optic nerve head, where axons appear to be most vulnerable. Axonal injury leads to the functional loss of RGCs and subsequently induces the death of the neurons. However, the detailed molecular mechanism(s) underlying IOP-induced optic nerve injury remain poorly understood. Moreover, whether glaucoma pathophysiology is primarily axonal, glial, or vascular remains unclear. Therefore, protective strategies to prevent further axonal and subsequent soma degeneration are of great importance to limit the progression of sight loss. In addition, strategies that stimulate injured RGCs to regenerate and reconnect axons with their central targets are necessary for functional restoration. The present review provides an overview of the context of glaucoma pathogenesis and surveys recent findings regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways.

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Available from: Dietmar Fischer
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    • "In the year 2020 it is estimated that more than 80 million people will suffer from a glaucomatous disease worldwide [1]. The molecular pathophysiology of glaucoma is poorly understood, reflecting its complex multifactorial etiology [2]. In regard to their etiology, glaucomas can be sub grouped into primary and secondary glaucomas. "
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    ABSTRACT: The aqueous humor (AH) component transforming growth factor (TGF)-β2 is strongly correlated to primary open-angle glaucoma (POAG), and was shown to up-regulate glaucoma-associated extracellular matrix (ECM) components, members of the ECM degradation system and heat shock proteins (HSP) in primary ocular cells. Here we present osteopontin (OPN) as a new TGF-β2 responsive factor in cultured human optic nerve head (ONH) astrocytes. Activation was initially demonstrated by Oligo GEArray microarray and confirmed by semiquantitative (sq) RT-PCR, realtime RT-PCR and western blot. Expressions of most prevalent OPN receptors CD44 and integrin receptor subunits αV, α4, α 5, α6, α9, β1, β3 and β5 by ONH astrocytes were shown by sqRT-PCR and immunofluorescence labeling. TGF-β2 treatment did not affect their expression levels. OPN did not regulate gene expression of described TGF-β2 targets shown by sqRT-PCR. In MTS-assays, OPN had a time- and dose-dependent stimulating effect on the metabolic activity of ONH astrocytes, whereas TGF-β2 significantly reduced metabolism. OPN signaling via CD44 mediated a repressive outcome on metabolic activity, whereas signaling via integrin receptors resulted in a pro-metabolic effect. In summary, our findings characterize OPN as a TGF-β2 responsive factor that is not involved in TGF-β2 mediated ECM and HSP modulation, but affects the metabolic activity of astrocytes. A potential involvement in a protective response to TGF-β2 triggered damage is indicated, but requires further investigation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Diseases like glaucoma or mechanical stress impair axonal transport, lead to synapse retraction and dying back degeneration of the axon (Raff et al., 2002). As a consequence cell soma and dendrites may shrink and apoptosis is initiated (Jakobs et al., 2005; Whitmore et al., 2005; Diekmann and Fischer, 2013). In rodents RGCs start to undergo apoptotic cell death 1 week after intraorbital optic nerve injury (Berkelaar et al., 1994; Fischer et al., 2004; Fischer and Leibinger, 2012; Germain et al., 2013) Degeneration of the different cellular compartments (axon, soma, dendrites) might not occur simultaneously but rather independently and compartmentalized. "
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    ABSTRACT: Axonal injury in the optic nerve is associated with retinal ganglion cell (RGC) degeneration and irreversible loss of vision. However, inflammatory stimulation (IS) by intravitreal injection of Pam3Cys transforms RGCs into an active regenerative state enabling these neurons to survive injury and to regenerate axons into the injured optic nerve. Although morphological changes have been well studied, the functional correlates of RGCs transformed either into a de- or regenerating state at a sub-cellular level remain unclear. In the current study, we investigated the signal propagation in single intraretinal axons as well as characteristic activity features of RGCs in a naive, a degenerative or a regenerative state in ex vivo retinae 1 week after either optic nerve cut alone (ONC) or additional IS (ONC + IS). Recordings of single RGCs using high-density microelectrode arrays demonstrate that the mean intraretinal axonal conduction velocity significantly decreased within the first week after ONC. In contrast, when ONC was accompanied by regenerative Pam3Cys treatment the mean intraretinal velocity was undistinguishable from control RGCs, indicating a protective effect on the proximal axon. Spontaneous RGC activity decreased for the two most numerous RGC types (ON- and OFF-sustained cells) within one post-operative week, but did not significantly increase in RGCs after IS. The analysis of light-induced activity revealed that RGCs in ONC animals respond on average later and with fewer spikes than control RGCs. IS significantly improved the responsiveness of the two studied RGC types. These results show that the transformation into a regenerative state by IS preserves, at least transiently, the physiological functional properties of injured RGCs.
    Full-text · Article · Feb 2014 · Frontiers in Cellular Neuroscience
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    • "Research in the past two decades indicates that neutralization of myelin inhibition alone might be insufficient to promote significant RGC regeneration (Fischer et al., 2004a, 2004b; Liu et al., 2011; Sengottuvel et al., 2011). However, several experimental approaches have been discovered to markedly delay RGC apoptosis and/or to promote regeneration of lengthy axons into the inhibitory environment of an injured optic nerve (Berry et al., 1999; Diekmann and Fischer, 2013; Fischer et al., 2001; Heskamp et al., 2013; Leaver et al., 2006; Moore et al., 2009; Park et al., 2008; Pernet et al., 2013; Smith et al., 2009; Sun et al., 2011; Yin et al., 2003). "
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    ABSTRACT: Retinal ganglion cells (RGCs) do not normally regenerate injured axons. However, several strategies to transform RGCs into a potent active regenerative state have been developed in recent years. Intravitreal CNTF application combined with conditional PTEN and SOCS3 deletion or zymosan-induced inflammatory stimulation together with cAMP analogue injection and PTEN-deletion in RGCs induce long-distance regeneration into the optic nerve of adult mice. A recent paper by the Benowitz group (de Lima et al.) claimed that the latter treatment enables full-length regeneration, with axons correctly navigating to their central target zones and partial recovery of visual behaviors. To gain a more detailed view of the extent and the trajectories of regenerating axons, Luo et al. applied a tissue clearing method and fluorescent microscopy to allow the tracing of naïve and regenerating RGC axons in whole ON and all the way to their brain targets. Using this approach, the authors found comparable axon regeneration in the optic nerve after both above-mentioned experimental treatments, which was accompanied by prevalent aberrant axon growth in the optic nerve and significant axonal misguidance at the optic chiasm. Less than 120 axons per animal reached the optic chiasm and only few entered the correct optic tract. Importantly, no axons reached visual targets in the olivary pretectal nucleus, the lateral geniculate nucleus or the superior colliculus, thereby contradicting and challenging previous claims by the Benowitz group. The data provided by Luo et al. rather suggest that potent stimulation of axonal growth per se is insufficient to achieve functional recovery and underscore the need to investigate regeneration-relevant axon guidance mechanisms in the mature visual system.
    Full-text · Article · Jun 2013 · Experimental Neurology
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