Long-term neuroprotection of retinal ganglion cells by inhibiting caspase-2

Vigneswara, Vasanthy; Ahmed, Zubair

doi:10.1038/cddiscovery.2016.44

Cited by 21 publications

(19 citation statements)

References 7 publications

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“…Indeed, we have shown that RGC exclusively activate cleaved caspase-2 after ONC injury and suppression of caspase-2 with a siRNA (siCASP2) protects >95% RGC in the rat retina. 46,62,63 However, despite the survival of >95% of RGC, siCASP2 treatment did not cause RGC axon regeneration. 62 In conclusion, our results showed that the BMP4/Smad1 pathway is activated in surviving and regenerating RGC.…”

Section: Discussionmentioning

confidence: 97%

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

Thompson

Berry

Logan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Thompson A, Berry M, Logan A, Ahmed Z. Activation of the BMP4/ Smad1 pathway promotes retinal ganglion cell survival and axon regeneration. Invest Ophthalmol Vis Sci. 2019;60:1748-1759. https://doi.org/ 10.1167 PURPOSE. We investigate if the BMP4/Smad1 intracellular signaling pathway is neuroprotective and axogenic in adult rodent retinal ganglion cells (RGC) in vivo and in vitro. METHODS.Adult retinal cultures were prepared from intact and after optic nerve crush (ONC) injured rats that have been stimulated to survive and regenerate using an intravitreal peripheral nerve (PN) graft. Laser capture microdissection (LCM) then was used to isolate RGC with and without neurites. Quantitative RT-PCR determined changes in BMP4/Smad1 signaling pathway mRNA. Immunohistochemistry confirmed localization of BMP4 and activation of Smad1 in ONCþPN-stimulated RGC in vivo. BMP4 peptide was used to stimulate RGC survival and neurite/axon regeneration in vitro and in vivo. Finally, the rapamycin sensitivity of the effects was determined in BMP4-stimulated RGC in vitro and in vivo. RESULTS.In retinal cultures prepared from intact and ONCþPN-stimulated rats, RGC with neurites had upregulated regeneration-related and BMP4/Smad1 signaling pathway mRNA levels, while low levels of these mRNAs were present in RGC isolated without neurites. An optimal dose of 200 ng/mL BMP4 peptide in vitro promoted approximately 30% RGC survival and disinhibited RGC neurite outgrowth, despite the presence of inhibitory CNS myelin extracts. BMP4 also promoted approximately 30% RGC survival in vivo and stimulated significant RGC axon regeneration at 100, 200, and 400 lm beyond the lesion site. Finally, the response of RGC to BMP4 treatment in vitro and in vivo was rapamycin-insensitive.CONCLUSIONS. Activation of the BMP4/Smad1 pathway promotes survival and axon regeneration independent of mTOR and, therefore, may be of therapeutic interest.

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Section: Discussionmentioning

confidence: 97%

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

Thompson

Berry

Logan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Here we show that caspase-2 is immunolocalized to injured RGC and that levels of the active form, cleaved caspase-2, increased over 48 hours after blunt ocular trauma. Activated caspase-2 induces RGC death in diverse models of RGC degeneration, including ONC (direct TON), [33][34][35] glaucoma, and optic neuritis. 37 Inhibition of caspase-2 protects >95% of RGCs from death after ONC.…”

Section: Discussionmentioning

confidence: 99%

“…For example, axotomized RGC activate caspase-2, whereas pharmacological inhibition protects~60% of RGC for up to 21 days after ONC and a chemically modified synthetic short interfering RNA (siRNA) against caspase-2 (siCASP2) protects >95% of RGCs for up to 12 weeks. [33][34][35][36] siCASP2 also protects RGC in a mouse optic neuritis model. 37 siCASP2 (also known as QPI-1007) is currently in clinical trials for nonarteritic ischemic optic neuropathy (NAION) (protocol: QRK007 NCT01064505) and acute primary angle-closure glaucoma (protocol: QRK208 NCT01965106) with Quark Pharmaceuticals (Ness Ziona, Israel).…”

mentioning

confidence: 99%

Caspase-2 Mediates Site-Specific Retinal Ganglion Cell Death After Blunt Ocular Injury

Thomas

Thompson

McCance

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“… 91 , 95 , 96 For example, intravitreal administration of either siCASP2 91 or the pharmacological inhibitor z-VDVAD-fmk 95 protect 98% and 60% of RGC, respectively, for up to 30 days and >95% of RGC are protected from death for 12 weeks if siCASP2 is injected every 8 days. 116 Pharmacological inhibition with z-VDVAD-fmk also inhibits caspase-3 and -7, 59 though activation of these caspases was not affected. The siCASP2 is being developed by Quark Pharmaceuticals Inc. and is currently in Phase III clinical trials for ischaemic optic neuropathy and glaucoma.…”

Section: Caspases and Rgc Deathmentioning

confidence: 99%

“…Recent studies have indicated a pivotal role of caspase-2 in apoptotic RGC injury. 91 , 95 , 96 , 116 , 117 After ON axotomy and crush, active caspase-2 is exclusively localised to RGC, and its inhibition using siRNA provides significant neuroprotection. 91 , 95 , 96 For example, intravitreal administration of either siCASP2 91 or the pharmacological inhibitor z-VDVAD-fmk 95 protect 98% and 60% of RGC, respectively, for up to 30 days and >95% of RGC are protected from death for 12 weeks if siCASP2 is injected every 8 days.…”

Section: Caspases and Rgc Deathmentioning

confidence: 99%

Caspases in retinal ganglion cell death and axon regeneration

et al. 2017

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Retinal ganglion cells (RGC) are terminally differentiated CNS neurons that possess limited endogenous regenerative capacity after injury and thus RGC death causes permanent visual loss. RGC die by caspase-dependent mechanisms, including apoptosis, during development, after ocular injury and in progressive degenerative diseases of the eye and optic nerve, such as glaucoma, anterior ischemic optic neuropathy, diabetic retinopathy and multiple sclerosis. Inhibition of caspases through genetic or pharmacological approaches can arrest the apoptotic cascade and protect a proportion of RGC. Novel findings have also highlighted a pyroptotic role of inflammatory caspases in RGC death. In this review, we discuss the molecular signalling mechanisms of apoptotic and inflammatory caspase responses in RGC specifically, their involvement in RGC degeneration and explore their potential as therapeutic targets.

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Long-term neuroprotection of retinal ganglion cells by inhibiting caspase-2

Cited by 21 publications

References 7 publications

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

Activation of the BMP4/Smad1 Pathway Promotes Retinal Ganglion Cell Survival and Axon Regeneration

Caspase-2 Mediates Site-Specific Retinal Ganglion Cell Death After Blunt Ocular Injury

Caspases in retinal ganglion cell death and axon regeneration

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