Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury

Abstract

Progressive retinal ganglion cells (RGCs) death that triggered by retinal ischemia reperfusion (IR), leads to irreversible visual impairment and blindness, but our knowledge of post-IR neuronal death and related mechanisms is limited. In this study, we first demonstrated that apart from necroptosis, which occurs before apoptosis, ferroptosis, which is characterized by iron deposition and lipid peroxidation, is involved in the whole course of retinal IR in mice. Correspondingly, all three types of RGCs death were found in retina samples from human glaucoma donors. Further, inhibitors of apoptosis, necroptosis, and ferroptosis (z-VAD-FMK, Necrostatin-1, and Ferrostatin-1, respectively) all exhibited marked RGC protection against IR both in mice and primary cultured RGCs, with Ferrostatin-1 conferring the best therapeutic effect, suggesting ferroptosis plays a more prominent role in the process of RGC death. We also found that activated microglia, Müller cells, immune responses, and intracellular reactive oxygen species accumulation following IR were significantly mitigated after each inhibitor treatment, albeit to varying degrees. Moreover, Ferrostatin-1 in combination with z-VAD-FMK and Necrostatin-1 prevented IR-induced RGC death better than any inhibitor alone. These findings stand to advance our knowledge of the post-IR RGC death cascade and guide future therapy for RGC protection.

Multiple types of programmed necrosis such as necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos contribute simultaneously to retinal damage after ischemia–reperfusion

“…The accumulation of lipid peroxides formed by free radicals has been shown in the ischemic retina 50,51 . The role of oxytosis/ferroptosis in retinal IR injury and RGC death was conveyed previously using numerous inhibitors and iron-chelating agents 32,[34][35][36][37] . Since oxytosis/ferroptosis as a type of programmed necrosis was described only after 2013 and many of these referenced articles appeared before 2013, we are only now understanding the significance of these studies.…”

Anti‐PANoptosis is involved in neuroprotective effects of melatonin in acute ocular hypertension model

“…The time points of different experiments were described in Figure 1A and selected based on many previous literature data, showing terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, 14,40,42,43 and necroptosis-related factors 14,44 were significantly increased within 1 day after AOH injury; apoptosis-and pyroptosis-related factors 40,45 were significantly increased 3 days after AOH injury; structural and functional damage in the retina was remarkable 7 days after AOH injury, 14,18,40,46 and the damage continued and aggravated, reaching a new peak at 14 days; [47][48][49] therefore, retinas were harvested on 7 and 14 days after AOH injury for histological analysis, RNA-binding protein with multiple splicing (RBPMS) immunofluorescence, spectral-domain optical coherence tomography (SD-OCT), and ERG.…”

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

“…However, glaucoma remains to have a poor prognosis, indicating that further exploration is needed to better understand RGC death in glaucoma. As such, exploring the prevention of other regulated cell death (except apoptosis) provides new therapeutic strategies for neurodegenerative diseases, such as glaucoma (Qin et al, 2022). Elucidating how molecular pathways underlying RGC death are interconnected will provide insights into future therapeutics for retinal degeneration.…”