Involvement of Caspase-6 and Caspase-8 in Neuronal Apoptosis and the Regenerative Failure of Injured Retinal Ganglion Cells

Monnier, Philippe P.; D'Onofrio, Philippe M; Magharious, Mark; Hollander, Adam C.; Tassew, Nardos G.; Szydłowska, Kinga; Tymianski, Michael; Koeberle, Paulo D.

doi:10.1523/jneurosci.0148-11.2011

Cited by 93 publications

(100 citation statements)

References 82 publications

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“…We also observed that PEDF in vivo was more neuroprotective than CNTF. 45,62,63 PEDF can protect RGC from death after glutamate toxicity, ischemia, trophic factor withdrawal, and in mouse models of glaucoma and inherited retinal degeneration. 35,38,[64][65][66][67] In vitro and in vivo, optimal RGC neuroprotective dosages of PEDF were 2.5 3 10 À5 lg/lL and 1 lg/lL, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…[71][72][73][74][83][84][85] Other commonly used RGC neuroprotective factors include BDNF, GDNF, NT-3, NT-4/5, TrkB gene transfer, as well as caspase inhibitors. 45,53,59,[75][76][77][78][79][80][83][84][85][86] Although we showed that BDNF administration in our ONC model supported nearly 100% survival of RGC at 7 days, 53 long-term studies with BDNF peptide or gene transfer showed that BDNF supported approximately 60% of RGC survival at 2 weeks after ON transection. 77,78 Most neuroprotective strategies including other NTF and caspase inhibitors commonly support 60% of RGC survival at 2 weeks.…”

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confidence: 98%

“…34,[38][39][40][41] In this present study, we evaluated, in vitro and in vivo, the RGC neuroprotective and axogenic properties of PEDF and compared the results with the effects of CNTF, a neurotrophic factor with well documented RGC survival and neurite/axon growth promoting properties. [42][43][44][45][46] We also studied the effects of combining PEDF with cAMP (which raises the intrinsic ability of RGC to grow their neurites and axons), [47][48][49][50] predicting that PEDF-induced RGC axon regeneration would be enhanced by cAMP. We confirm that PEDF is RGC neuroprotective after axotomy and also promotes RGC neuritogenesis/axon regeneration both in vitro and in vivo.…”

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confidence: 99%

“…77,78 Most neuroprotective strategies including other NTF and caspase inhibitors commonly support 60% of RGC survival at 2 weeks. 45,76,83,84 However, combinations of neurotrophic agents such as GDNFþBDNF and BDNFþTrkB support nearly 80% RGC from death at 2 weeks after ON transection suggesting that combinations of neurotrophic factors may support synergistic RGC protection. 77 Despite this optimism, very few of these strategies promote RGC axon regeneration.…”

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Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Traditionally, the primary caspases involved in the apoptotic degeneration of RGCs after axotomy have been caspase-3 and caspase-9 [67][68][69][70][71][72] . While neither caspase-3 nor caspase-9 was found to be involved in axonal degeneration [73,74] , it now appears that caspase-6 and caspase-8 both play prominent roles in this process, as well as in RGC apoptosis [75,76] . As well, caspase-2 has recently been shown to be involved in RGC apoptosis following optic nerve damage, most likely at the stage of apoptosis initiation [77] .…”

Section: Mechanisms Of Cell Death During Retinal Ischemiamentioning

confidence: 99%

What can we learn about stroke from retinal ischemia models?

D'Onofrio

Koeberle

2012

Acta Pharmacol Sin

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Retinal ischemia is a very useful model to study the impact of various cell death pathways, such as apoptosis and necrosis, in the ischemic retina. However, it is important to note that the retina is formed as an outpouching of the diencephalon and is part of the central nervous system. As such, the cell death pathways initiated in response to ischemic damage in the retina reflect those found in other areas of the central nervous system undergoing similar trauma. The retina is also more accessible than other areas of the central nervous system, thus making it a simpler model to work with and study. By utilizing the retinal model, we can greatly increase our knowledge of the cell death processes initiated by ischemia which lead to degeneration in the central nervous system. This paper examines work that has been done so far to characterize various aspects of cell death in the retinal ischemia model, such as various pathways which are activated, and the role neurotrophic factors, and discusses how these are relevant to the treatment of ischemic damage in both the retina and the greater central nervous system.

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