One of the most common causes of irreversible blindness worldwide is glaucoma, which is characterized by cupping or excavation of the optic disc, apoptotic degeneration of retinal ganglion cells (RGCs), and corresponding vision loss(Jonas et al., 2017; Kang and Tanna, 2021). Glaucoma is a disease in which the retina is severely damaged. Glaucoma progression is usually slowed significantly if the IOP is reduced by 30–50%. However, a reduction in IOP does not completely suppress the progression of the disease in the majority of cases(Chang and Goldberg, 2012; Jonas et al., 2017). This suggests that other factors play a role in the pathogenesis of glaucoma and may serve as targets for neuroprotection. Neuronal loss is the leading cause of vision loss, and physiological function can be maintained by slowing or preventing the death of neurons and protecting RGCs in glaucoma, thus preserving visual function and structure(Chang and Goldberg, 2012).

Neuroinflammation is a crucial process in glaucoma and involves an immune response involving astrocytes(Williams et al., 2017). Retinal astrocytes are involved in optic neuron function and metabolism and play a crucial role in retinal structure and function(Reichenbach and Bringmann, 2020). The changes in the optic nerve head in glaucoma include not only the loss of axons of RGCs but also changes in astrocytes, whose peculiar mechanism, in some aspects, may explain the pathophysiological features of glaucoma(Almasieh and Levin, 2017). When damaged to a certain extent, astrocytes activate inflammatory proteins, such as NOD-like receptor protein 3 (NLRP3), that promote RGCs death(Chen et al., 2020; Coyle et al., 2021). CD38 is a transmembrane glycoprotein with both receptor-mediated and enzyme-mediated functions and can regulate inflammation or autoimmune responses in the body. Inhibition of CD38 ameliorates astrocyte neuroinflammation(Guerreiro et al., 2020; Piedra-Quintero et al., 2020; Roboon et al., 2021). Sirtuin 1 (SIRT1) is a nuclear protein that can regulate multifarious biological functions. Numerous studies have shown that SIRT1 activators can modulate neuroinflammation by inhibiting the NLRP3 inflammasome(Jiao and Gong, 2020; Yang et al., 2022). Our team found that CD38 is highly expressed in mouse retinal astrocytes. SIRT1 protein levels were significantly reduced in retinal I/R models, while this effect was significantly attenuated by CD38 knockout(Chen et al., 2022a).

Naringenin is a natural flavonoid that is found primarily in citrus fruits and has a variety of pharmacological activities, including neuroprotective, antidiabetic, antibacterial, antioxidant, and anti-inflammatory activities(Hwang et al., 2012; Nouri et al., 2019). It targets multiple inflammatory signals involved in neuroinflammation and is a promising drug for treating inflammation-related diseases. Our previous study showed that oral naringenin can alleviate age-related retinal degeneration. The underlying mechanism may be related to the fact that naringenin improves mitochondrial dynamics and mediates the mTOR signaling pathway to promote autophagy initiation(Chen et al., 2022b). Does naringenin also protect against retinal damage caused by glaucoma? Previous studies have shown that naringenin therapy can increase the survival rate of RGCs after traumatic optic nerve injury in mice by inhibiting the JNK-JUN signaling pathway(Chen et al., 2021a). It has been shown that naringenin exerts a neuroprotective effect by inhibiting the activation of the NLRP3 inflammasome in microglia(Chen et al., 2019). Naringenin can also ameliorate homocysteine-induced endothelial injury by upregulating SIRT1 protein expression(Li et al., 2021). Furthermore, naringenin has been shown to lead to remission of nonalcoholic steatohepatitis in middle-aged mice by upregulating SIRT1(Hua et al., 2021). However, there have been no studies on the protective effect of naringenin on RGCs or its underlying mechanism in other experimental animal models related to glaucoma pathogenesis.

Acute I/R is a pathophysiological basis of glaucoma and is closely related to inflammation. IOP elevation is a leading risk factor for optic nerve damage in chronic glaucoma. In certain respects, microbead injection mimics the course of chronic glaucoma(Pang and Clark, 2020; Wang et al., 2020). In this study, we used two well-established retinal injury models, the I/R and OHT models, as tools to comprehensively assess the retinal neuroprotective effects of naringenin.