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Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.

ABSTRACT: Glaucoma is a common neurodegenerative disorder characterized by retinal ganglion cell death, astrocyte reactivity in the optic nerve, and vision loss. Currently, lowering the intraocular pressure (IOP) is the first-line treatment, but adjuvant neuroprotective approaches would be welcome. Vitamin C possesses neuroprotective activities that are thought to be related to its properties as a co-factor of enzymes and its antioxidant effects. Here, we show that vitamin C promotes a neuroprotective phenotype and increases gene expression related to neurotropic factors, phagocytosis, and mitochondrial ATP production. This effect is dependent on the up-regulation of secreted phosphoprotein 1 (SPP1) in reactive astrocytes via the transcription factor E2F1. SPP1⁺ astrocytes in turn promote retinal ganglion cell survival in a mouse model of glaucoma. In addition, oral administration of vitamin C lowers the IOP in mice. This study identifies an additional neuroprotective pathway for vitamin C and suggests a potential therapeutic role of vitamin C in neurodegenerative diseases such as glaucoma.

SUBMITTER: Li S

PROVIDER: S-EPMC10172762 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.

Li Song S Jakobs Tatjana C TC

Life science alliance 20230509 8

Glaucoma is a common neurodegenerative disorder characterized by retinal ganglion cell death, astrocyte reactivity in the optic nerve, and vision loss. Currently, lowering the intraocular pressure (IOP) is the first-line treatment, but adjuvant neuroprotective approaches would be welcome. Vitamin C possesses neuroprotective activities that are thought to be related to its properties as a co-factor of enzymes and its antioxidant effects. Here, we show that vitamin C promotes a neuroprotective phe ...[more]

PMID: 37160307

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Project description:Removal of the Bax gene from mice completely protects the somas of retinal ganglion cells (RGCs) from apoptosis following optic nerve injury. This makes BAX a promising therapeutic target to prevent neurodegeneration. In this study, Bax+/- mice were used to test the hypothesis that lowering the quantity of BAX in RGCs would delay apoptosis following optic nerve injury. RGCs were damaged by performing optic nerve crush (ONC) and then immunostaining for phospho-cJUN, and quantitative PCR were used to monitor the status of the BAX activation mechanism in the months following injury. The apoptotic susceptibility of injured cells was directly tested by virally introducing GFP-BAX into Bax-/- RGCs after injury. The competency of quiescent RGCs to reactivate their BAX activation mechanism was tested by intravitreal injection of the JNK pathway agonist, anisomycin. Twenty-four weeks after ONC, Bax+/- mice had significantly less cell loss in their RGC layer than Bax+/+ mice 3 weeks after ONC. Bax+/- and Bax+/+ RGCs exhibited similar patterns of nuclear phospho-cJUN accumulation immediately after ONC, which persisted in Bax+/- RGCs for up to 7 weeks before abating. The transcriptional activation of BAX-activating genes was similar in Bax+/- and Bax+/+ RGCs following ONC. Intriguingly, cells deactivated their BAX activation mechanism between 7 and 12 weeks after crush. Introduction of GFP-BAX into Bax-/- cells at 4 weeks after ONC showed that these cells had a nearly normal capacity to activate this protein, but this capacity was lost 8 weeks after crush. Collectively, these data suggest that 8-12 weeks after crush, damaged cells no longer displayed increased susceptibility to BAX activation relative to their naïve counterparts. In this same timeframe, retinal glial activation and the signaling of the pro-apoptotic JNK pathway also abated. Quiescent RGCs did not show a timely reactivation of their JNK pathway following intravitreal injection with anisomycin. These findings demonstrate that lowering the quantity of BAX in RGCs is neuroprotective after acute injury. Damaged RGCs enter a quiescent state months after injury and are no longer responsive to an apoptotic stimulus. Quiescent RGCs will require rejuvenation to reacquire functionality.

Project description:Background: Low-intensity pulsed ultrasound (LIPUS) has been used in clinical studies. But little is known about its effects on the central nervous system (CNS), or its mechanism of action. Retinal ganglion cells (RGCs) are CNS neuronal cells that can be utilized as a classic model system to evaluate outcomes of LIPUS protection from external trauma-induced retinal injury. In this study, we aim to: (1) determine the pulse energy and the capability of LIPUS in RGC viability, (2) ascertain the protective role of LIPUS in optic nerve (ON) crush-induced retinal injury, and 3) explore the cellular mechanisms of RGC apoptosis prevention by LIPUS. Methods: An ON crush model was set up to induce RGC death. LIPUS was used to treat mice eyes daily, and the retina samples were dissected for immunostaining and Western blot. The expression of yes-associated protein (YAP) and apoptosis-related proteins was detected by immunostaining and Western blot in vitro and in vivo. Apoptosis of RGCs was evaluated by TUNEL staining, the survival of RGCs and retained axons were labeled by Fluoro-gold and Tuj1 antibody, respectively. Rotenone was used to set up an in vitro cellular degenerative model and siYAP was used to interfering the expression of YAP to detect the LIPUS protective function. Results: LIPUS protected RGC from loss and apoptosis in vivo and in vitro. The ratio of cleaved/pro-caspase3 also decreased significantly under LIPUS treatment. As a cellular mechanical sensor, YAP expression increased and YAP translocated to nucleus in LIPUS stimulation group, however, phospho-YAP was found to be decreased. When YAP was inhibited, the LIPUS could not protect RGC from caspase3-dependent apoptosis. Conclusion: LIPUS prevented RGCs from apoptosis in an ON crush model and in vitro cellular degenerative model, which indicates a potential treatment for further traumatic ON injury. The mechanism of protection is dependent on YAP activation and correlated with caspase-3 signaling.

Dataset Information

Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.

Publications

Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage.

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