Virally delivered, constitutively active <scp>NF</scp>κB improves survival of injured retinal ganglion cells

Dvoriantchikova, Galina; Pappas, Steve; Luo, Xueting; Ribeiro, Márcio; Danek, Dagmara; Pelaez, Daniel; Park, Kevin K.; Ivanov, Dmitry

doi:10.1111/ejn.13383

Cited by 9 publications

(5 citation statements)

References 50 publications

(121 reference statements)

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“…Optic nerve crush (ONC) injury was performed on either male C57BL/6J WT or male Thy1-GFP mice at 2 months of age. The ONC procedure was performed as previously described [72]. Briefly, all mice were anesthetized via intraperitoneal injection of ketamine (80 mg/kg) / xylazine (10 mg/kg); their optic nerves were exposed intraorbitally and crushed with jeweler's forceps (Dumon #5; tip dimension, 0.1 x 0.6 mm) for 10 seconds approximately 1 to 2 mm behind the optic disk, pupillary response using indirect illumination from the side was used to indicate a successful injury.…”

Section: Optic Nerve Crush Model (Onc)mentioning

confidence: 99%

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Strong

Esquivel

Wang

et al. 2023

Preprint

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Background: Optic neuropathy (ON) is a major cause of irreversible blindness, yet the molecular determinants that contribute to neuronal demise have not been fully elucidated. Several studies have identified ephrin signaling as one of the most dysregulated pathways in the early pathophysiology of ON with varied etiologies. Developmentally, gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes. Little is known about the role ephrin signaling played in the post-natal visual system and its correlation with the onset of optic neuropathy. Methods: Postnatal mouse retinas were collected for mass spectrometry analysis for Eph receptors. Optic nerve crush (ONC) model was employed to induce optic neuropathy, and proteomic changes during the acute phase of neuropathic onset were analyzed. Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury. Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation. Results: Mass spectrometry revealed expression of seven Eph receptors (EphA2, A4, A5, B1, B2, B3, and B6) in postnatal mouse retinal tissue. Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 hours after ONC. Confocal microscopy demonstrated the presence of both subclasses of Eph receptors in the inner retinal layers. STORM super-resolution imaging combined with optimal transport co-localization analysis revealed a significant co-localization of activated Eph receptors with injured neuronal processes, compared to uninjured neuronal and/or injured glial cells, 48 hours post-ONC. Eph receptor inhibitors displayed notable neuroprotective effects after 6 days of ONC injury. Conclusions: Our findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina, capable of modulating multiple biological processes. Pan-Eph receptor activation contributes to the onset of neuropathy in ONs, with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury. Notably, Eph receptor activation precedes neuronal loss. We observed neuroprotective effects upon inhibiting Eph receptors. Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice, relevant to both homeostasis and disease processes.

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Section: Optic Nerve Crush Model (Onc)mentioning

confidence: 99%

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Strong

Esquivel

Wang

et al. 2023

Preprint

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“…In previous report, we suggested that Wnt/β-catenin signaling and Nf-κb protein are involved in the neuroprotection of R28 by MSCs [27,28]. In this study, we also examined whether Wnt/β-catenin signaling may be involved with NPC in the recovery mechanisms of damaged R28 cells.…”

Section: Wnt/β-catenin Signal Is Involved During Recovery Of Retinal Ganglion Cells By Npcsmentioning

confidence: 85%

“…The mechanisms by which MSCs directly regulate neuroprotection remain unclear. PSCs have neuroprotective effects via the moderation of Hif-1α and GAP43 [22] and mediation of NF-κb pathways [27,28]. These results suggest that MSC-based therapy may be useful for treating optic nerve disorders, but the critical pathway for optic nerve recovery is unclear.…”

Section: Discussionmentioning

confidence: 98%

Human Pluripotent Stem Cell-Derived Neural Progenitor Cells Promote Retinal Ganglion Cell Survival and Axon Recovery in an Optic Nerve Compression Animal Model

Park

Kim

Shin

et al. 2021

IJMS

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Human pluripotent stem cell-derived neural progenitor cells (NPCs) have the potential to recover from nerve injury. We previously reported that human placenta-derived mesenchymal stem cells (PSCs) have neuroprotective effects. To evaluate the potential benefit of NPCs, we compared them to PSCs using R28 cells under hypoxic conditions and a rat model of optic nerve injury. NPCs and PSCs (2 × 106 cells) were injected into the subtenon space. After 1, 2, and 4 weeks, we examined changes in target proteins in the retina and optic nerve. NPCs significantly induced vascular endothelial growth factor (Vegf) compared to age-matched shams and PSC groups at 2 weeks; they also induced neurofilaments in the retina compared to the sham group at 4 weeks. In addition, the expression of brain-derived neurotrophic factor (Bdnf) was high in the retina in the NPC group at 2 weeks, while expression in the optic nerve was high in both the NPC and PSC groups. The low expression of ionized calcium-binding adapter molecule 1 (Iba1) in the retina had recovered at 2 weeks after NPC injection and at 4 weeks after PSC injection. The expression of the inflammatory protein NLR family, pyrin domain containing 3 (Nlrp3) was significantly reduced at 1 week, and that of tumor necrosis factor-α (Tnf-α) in the optic nerves of the NPC group was lower at 2 weeks. Regarding retinal ganglion cells, the expressions of Brn3a and Tuj1 in the retina were enhanced in the NPC group compared to sham controls at 4 weeks. NPC injections increased Gap43 expression from 2 weeks and reduced Iba1 expression in the optic nerves during the recovery period. In addition, R28 cells exposed to hypoxic conditions showed increased cell survival when cocultured with NPCs compared to PSCs. Both Wnt/β-catenin signaling and increased Nf-ĸb could contribute to the rescue of damaged retinal ganglion cells via upregulation of neuroprotective factors, microglial engagement, and anti-inflammatory regulation by NPCs. This study suggests that NPCs could be useful for the cellular treatment of various optic neuropathies, together with cell therapy using mesenchymal stem cells.

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“…In prior work on RGC neuroprotection in vivo (Guo et al, 2021), the transcription factor CREB was implicated as necessary for CaMKIIα's neuroprotective effect, although the role of CREB in RGC neuroprotection is controversial (Pita-Thomas et al, 2021). Another potentially relevant CaMKII effector is the transcription factor nuclear factor-κB (NF-κB; Dvoriantchikova et al, 2016), as suggested by studies showing that the in vitro neuroprotective effects of CaMKIIγ and CaMKIIδ during oxygen/glucose deprivation and reoxygenation correlated with the activation of the NF-κB pathway (Ye et al, 2019). CREB is not likely the CaMKII effector responsible for the observed RGC axon growth suppression, as CaMKII inhibition blocked RGC axon outgrowth in vitro stimulated by oncomodulin and elevated cAMP, a treatment that also activates CREB (Yin et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Ca²⁺/Calmodulin-Dependent Protein Kinase II Enhances Retinal Ganglion Cell Survival But Suppresses Axon Regeneration after Optic Nerve Injury

Xia,

Shi,

Tsien

et al. 2024

eNeuro

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Neuroprotection after injury or in neurodegenerative disease remains a major goal for basic and translational neuroscience. Retinal ganglion cells (RGCs), the projection neurons of the eye, degenerate in optic neuropathies after axon injury, and there are no clinical therapies to prevent their loss or restore their connectivity to targets in the brain. Here we demonstrate a profound neuroprotective effect of the exogenous expression of various Ca2+/calmodulin-dependent protein kinase II (CaMKII) isoforms in mice. A dramatic increase in RGC survival following the optic nerve trauma was elicited by the expression of constitutively active variants of multiple CaMKII isoforms in RGCs using adeno-associated viral (AAV) vectors across a 100-fold range of AAV dosing in vivo. Despite this neuroprotection, however, short-distance RGC axon sprouting was suppressed by CaMKII, and long-distance axon regeneration elicited by several pro-axon growth treatments was likewise inhibited even as CaMKII further enhanced RGC survival. Notably, in a dose-escalation study, AAV-expressed CaMKII was more potent for axon growth suppression than the promotion of survival. That diffuse overexpression of constitutively active CaMKII strongly promotes RGC survival after axon injury may be clinically valuable for neuroprotection per se. However, the associated strong suppression of the optic nerve axon regeneration demonstrates the need for understanding the intracellular domain- and target-specific CaMKII activities to the development of CaMKII signaling pathway-directed strategies for the treatment of optic neuropathies.

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Virally delivered, constitutively active NFκB improves survival of injured retinal ganglion cells

Cited by 9 publications

References 50 publications

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Human Pluripotent Stem Cell-Derived Neural Progenitor Cells Promote Retinal Ganglion Cell Survival and Axon Recovery in an Optic Nerve Compression Animal Model

Ca²⁺/Calmodulin-Dependent Protein Kinase II Enhances Retinal Ganglion Cell Survival But Suppresses Axon Regeneration after Optic Nerve Injury

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Virally delivered, constitutively active NFκB improves survival of injured retinal ganglion cells

Cited by 9 publications

References 50 publications

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

Human Pluripotent Stem Cell-Derived Neural Progenitor Cells Promote Retinal Ganglion Cell Survival and Axon Recovery in an Optic Nerve Compression Animal Model

Ca2+/Calmodulin-Dependent Protein Kinase II Enhances Retinal Ganglion Cell Survival But Suppresses Axon Regeneration after Optic Nerve Injury

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Ca²⁺/Calmodulin-Dependent Protein Kinase II Enhances Retinal Ganglion Cell Survival But Suppresses Axon Regeneration after Optic Nerve Injury