A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model

Do, Yun-Ju; Sul, Jee-Won; Jang, Ki-Hong; Kang, Nam Sook; Kim, Young-Hoon; Kim, Young-Gwan; Kim, Eun‐Hee

doi:10.1016/j.yexcr.2017.08.012

Cited by 37 publications

(30 citation statements)

References 36 publications

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“…In conclusion, we have demonstrated that RGC death signaling pathways are active in a regionspecific manner after blunt ocular injury, with necroptotic-dependent mechanisms likely driving a reduction in RGC numbers at the center of the impact site. The inhibition of necroptosis using pharmacological inhibitor, Nec-1s, preserved the number of RBPMS + and BRN3A + RGC compared to In line with our findings, RGC are also protected by the inhibition of necroptosis in other models of RGC death, including glaucoma [62] and retinal ischemia-reperfusion injury [63], and other models of neuronal disease and degeneration, including amyotrophic lateral sclerosis [64][65][66], Alzheimer's disease [26], Niemann-Pick disease [67], traumatic brain injury [28] and spinal cord injury [27]. The abundance of studies across multiple disease indicates the importance of necroptotic signaling in driving neuronal cell death.…”

Section: Discussionsupporting

confidence: 89%

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Thomas

Thompson

Ahmed

2019

Cells

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Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin+ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)+ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS+ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site.

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Section: Discussionsupporting

confidence: 89%

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Thomas

Thompson

Ahmed

2019

Cells

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“…Increasing evidence has demonstrated the importance of necroptosis in retinal cell death (Cai et al, 2015;Do et al, 2017;Dvoriantchikova et al, 2014;Shosha et al, 2016); therefore, we examined the effect of Epac1 deletion on necroptosis. At the molecular level, necroptosis is reported to be regulated by receptor-interacting protein 3 (RIP3), whose activation is tightly regulated by phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

Liu

Xia

et al. 2020

Journal of Experimental Medicine

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Progressive loss of retinal ganglion cells (RGCs) leads to irreversible visual deficits in glaucoma. Here, we found that the level of cyclic AMP and the activity and expression of its mediator Epac1 were increased in retinas of two mouse models of ocular hypertension. Genetic depletion of Epac1 significantly attenuated ocular hypertension–induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss, and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation. Taken together, these findings indicate that neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

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“…Having explored the cellular consequences of intravitreal TNF-α injection, we next investigated activation of pro-degenerative molecular pathways. TNF-α can trigger apoptosis or necroptosis in different contexts, including in promoting RGC death in models of glaucoma (Fuchs and Steller, 2015;Weinlich et al, 2017;Do et al, 2017;Almasieh et al, 2012). Hence, we used immunoblotting to assess molecular markers of apoptosis and necroptosis in the optic nerve following intravitreal TNF-α injection.…”

Section: Tnf-α Induces Sarm1-dependent Axon Loss and Rgc Death In A Nmentioning

confidence: 99%

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

Milbrandt

DiAntonio

2020

Journal of Cell Biology

108

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Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival factors NMNAT2 and STMN2 to activate SARM1 NADase activity, which leads to calcium influx and axon degeneration. Hence, these findings define a specialized form of axonal necroptosis. The demonstration that neuroinflammatory signals and necroptosis can act locally in the axon to stimulate SARM1-dependent axon degeneration identifies a therapeutically targetable mechanism by which neuroinflammation can stimulate axon loss in neurodegenerative disease.

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A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model

Cited by 37 publications

References 36 publications

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

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