Retinal neurodegeneration, especially the impairment of retinal ganglion cells (RGCs), is an early and critical event in several blinding diseases, including diabetic retinopathy and glaucoma.
1,2 Although the underlying mechanism is not fully elucidated, it is known that excessive glutamate receptor activation plays an important role in the pathological process.
3,4 In many instances, the neurotoxic effect of glutamate has been predominantly attributed to excessive stimulation of N-methyl-D-aspartic (NMDA) receptors.
5,6 In NMDA receptor-mediated cell death, increase of intracellular Ca
2+ concentration is thought to be the key event.
7 In addition, upregulation of proinflammatory cytokines
8,9 and accumulation of amyloid β (Aβ) in the retina are involved in this process.
10 Thus, excessive activation of NMDA receptors appears to affect retinal neuronal cell survival by direct as well as indirect mechanisms. A single intravitreal injection of NMDA is commonly used in vivo to induce experimental RGC degeneration.
11,12 By using the NMDA-induced neurotoxic model, we attempted to investigate whether activation of liver X receptors (LXRs) protects the neurotoxicity and to elucidate the possible molecular mechanisms.
A hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD), is the deposition of Aβ,
13 and Aβ is also the major constituent of drusen from eyes of patients with AMD.
14 The formation of Aβ is from a two-step proteolytic processing of the amyloid precursor protein (APP) by β- then γ-secretase. The APP is widely expressed in the central nervous system, including RGCs.
15 Studies have shown that patients with AD present RGC loss similar to typical glaucomatous changes.
16 In addition, Aβ has recently been reported to be implicated in the development of RGC apoptosis in glaucoma, with evidence of caspase-3–mediated abnormal APP processing and increased expression of Aβ in RGCs in experimental glaucoma.
17 Furthermore, Aβ colocalizes with apoptotic RGCs in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner, and neutralizing Aβ with antibodies significantly attenuates RGC apoptosis.
18 It also has been reported that sublethal NMDA receptor activation increased the production and secretion of Aβ.
10 Thus, Aβ could be involved in the pathological process of NMDA-induced retinal neurotoxicity.
Liver X receptors are known for their important roles in modulating cholesterol homeostasis.
19 There are two isoforms (LXRα, LXRβ) of LXRs, which belong to the nuclear receptor superfamily of ligand-activated transcription factors. The LXRα is expressed predominantly in liver, kidney, intestine, and adrenal gland, whereas LXRβ is expressed ubiquitously. Our previous research has shown that both LXRα and LXRβ are expressed in mouse retina.
20 The LXR target genes, including the ATP-binding cassette (ABC) transporters, ABCA1, ABCG1 and apolipoprotein E (ApoE), are associated with lipid metabolism and reverse cholesterol transport.
19 In recent years, studies have described new functions of LXRs and their ligands, including regulation of inflammation and different aspects of the acquired immune response.
20,21 The anti-inflammatory effect of LXRs has been attributed to inhibition of the transcription factor nuclear factor–κB (NF-κB) signaling.
20,22 Previous study also demonstrated that NF-κB participates in NMDA-induced retinal neuronal cell death.
23 Notably, LXRs and their ligands also have been proposed to prevent neurodegeneration in the adult nervous system,
24 and LXR agonists reduce Aβ formation in neurons.
25,26 Thus, we hypothesize that an LXR agonist may be a novel class of drug for retinal neurodegenerative diseases as it not only inhibits Aβ formation but also suppresses neuroinflammation and alleviates the pathology changes.
In this study, we investigated the protective effect of systemic administration of an LXR agonist, TO901317 (TO90), on NMDA-induced retinal neurotoxicity and its potential mechanism.