Adenovirus-Mediated Expression of Ciliary Neurotrophic Factor (CNTF) Rescues Axotomized Rat Retinal Ganglion Cells But Does Not Support Axonal Regeneration in Vivo

Weise, Jens; Isenmann, Stefan; Klöcker, Nikolaj; Kügler, Sebastian; Hirsch, Sabine; Gravel, Claude; Bähr, Mathias

doi:10.1006/nbdi.2000.0285

Cited by 106 publications

(67 citation statements)

References 47 publications

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“…CNTF was found to stimulate macrophage activation, and its effects on regeneration were suppressed when macrophages were eliminated (27). It remains possible, however, that CNTF could contribute to the effects of intraocular inflammation in enhancing RGC survival (20,28). The combination of NGF, NT3 and FGF2 has also been reported to promote axon regeneration in the optic nerve (18), although the cellular mechanisms and physiological significance of these findings are presently unknown.…”

Section: Discussionmentioning

confidence: 99%

Oncomodulin links inflammation to optic nerve regeneration

Yin¹,

Cui

Gilbert³

et al. 2009

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

177

186

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The inflammatory response that accompanies central nervous system (CNS) injury can affect neurological outcome in both positive and negative ways. In the optic nerve, a CNS pathway that normally fails to regenerate when damaged, intraocular inflammation causes retinal ganglion cells (RGCs) to switch into an active growth state and extend lengthy axons down the nerve. The molecular basis of this phenomenon is uncertain. A prior study showed that oncomodulin (Ocm), a Ca 2؉ -binding protein secreted by a macrophage cell line, is a potent axon-promoting factor for RGCs. However, it is not known whether Ocm contributes to the physiological effects of intraocular inflammation in vivo, and there are conflicting reports in the literature regarding its expression and significance. We show here that intraocular inflammation causes infiltrative cells of the innate immune system to secrete high levels of Ocm, and that agents that prevent Ocm from binding to its receptor suppress axon regeneration. These results were verified in different strains, species, and experimental models, and establish Ocm as a potent growth-promoting signal between the innate immune system and neurons in vivo.retina ͉ trophic factor

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Section: Discussionmentioning

confidence: 99%

Oncomodulin links inflammation to optic nerve regeneration

Yin¹,

Cui

Gilbert³

et al. 2009

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

177

186

View full text Add to dashboard Cite

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“…16,17 In addition, neuroprotective effects of several neurotrophic factors on axotomized RGCs seem to be partially due to mechanisms other than inhibition of intracellular caspase activity. 20,47 In the present study, we therefore examined the role of PARP, which has been identified as an important mediator of a necrotic-type cell death, in axotomy-induced RGC death. Following ON transection, we observed an RGC-specific, transient increase in PARP activity as shown by GCLspecific enhancement of poly(ADP-ribose) polymer formation.…”

Section: Discussionmentioning

confidence: 99%

“…The optic nerve (ON) was exposed and transected as described previously leaving the retinal blood supply intact. 20,47 To determine RGC densities in lesioned animals, cells were retrogradely labeled with Fast Blue (FB; Dr Illing Chemie, Gross-Umstadt, Germany). For FB staining, a small piece of gel foam soaked in a 2% aqueous FB solution was placed at the ocular nerve stump after ON axotomy.…”

Section: Animal Surgery and Intravitreal Injectionsmentioning

confidence: 99%

“…For exact evaluation of survival-promoting effects due to the specific treatment, we defined an effective RGC rescue (ERR): ERR=(N ther -N con )/(N tot -N con )6100 (N tot : RGC number in unlesioned retinae, N con : RGC number surviving axotomy without therapy, N ther : RGC number surviving after a given therapy. 47 )…”

Section: Assessment Of Rgc Survival: Cell Densities and Statistical Amentioning

confidence: 99%

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Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

2001

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Excessive activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by free-radical damaged DNA mediates necrotic cell death in injury models of cerebral ischemiareperfusion and excitotoxicity. We recently reported that secondary retinal ganglion cell (RGC) death following rat optic nerve (ON) transection is mainly apoptotic and can significantly but not entirely be blocked by caspase inhibition. In the present study, we demonstrate transient, RGC-specific PARP activation and increased retinal PARP expression early after ON axotomy. In addition, intravitreal injections of 3-aminobenzamide blocked PARP activation in RGCs and resulted in an increased number of surviving RGCs when compared to control animals 14 days after ON transection. These data indicate that secondary degeneration of a subset of axotomized RGCs results from a necrotic-type cell death mediated by PARP activation and increased PARP expression. Furthermore, PARP inhibition may constitute a relevant strategy for clinical treatment of traumatic brain injury. Cell Death and Differentiation (2001) 8, 801 ± 807.

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“…29 The CNTF vector was efficient in rescuing RGCs after optic nerve axotomy and subsequent intraocular vector injection, which leads to transduction mainly of Mu È ller glia cells and some amacrine and bipolar cells in the retina. 35 After application on the nerve stump, however, Ad.CNTF administration did not rescue more ganglion cells than either the Ad.Xiap and Ad.p35 vectors, both of which code for intracellular proteins. This surprising result might either be due to the fact that CNTF acts only as a ligand for receptors on transduced cells or that not enough protein is secreted to be protective on larger cell numbers.…”

Section: Discussionmentioning

confidence: 99%

The X-linked inhibitor of apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo

et al. 2000

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The inhibition of neuronal apoptosis in acute traumatic and ischemic injuries as well as in long term neurodegenerative disorders like spinal muscular atrophy and possibly Alzheimer's disease is a fundamental requirement for a therapeutic strategy. In this study we used an established in vivo model system of induction of neuronal apoptosis in the CNS to evaluate the properties of the X-linked inhibitor of apoptosis protein (XIAP) to inhibit secondary cell death after axonal lesions. We used adenoviral vectors to transduce retinal ganglion cells after axotomy of the optic nerve of adult rats. Vector application was performed at the optic nerve stump so that only the lesioned retinal neurons could be transduced. We found XIAP to be as effective as the viral broad spectrum caspase inhibitor protein p35. These findings suggest that axotomized RGCs degenerate through class II caspase activity and furthermore offer the possibility of using mammalian XIAP protein to inhibit neuronal apoptosis as a basis for a regenerative therapy in the CNS. Cell Death and Differentiation (2000) 7, 815 ± 824.

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Adenovirus-Mediated Expression of Ciliary Neurotrophic Factor (CNTF) Rescues Axotomized Rat Retinal Ganglion Cells But Does Not Support Axonal Regeneration in Vivo

Cited by 106 publications

References 47 publications

Oncomodulin links inflammation to optic nerve regeneration

Oncomodulin links inflammation to optic nerve regeneration

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

The X-linked inhibitor of apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo

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