The Protective Effects of n-Butylidenephthalide on Retinal Ganglion Cells during Ischemic Injury

Abstract

Clinically, acute ischemic symptoms in the eyes are one of the main causes of vision loss, with the associated inflammatory response and oxidative stress being the key factors that cause injury. Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common type of ischemic optic neuropathy (ION); however, there are still no effective or safe treatment options to date. In this study, we investigated the neuroprotective effects of n-butylidenephthalide (BP) treatment in an experimental NAION rodent model (rAION). BP (10 mg/kg) or PBS (control group) were administered on seven consecutive days in the rAION model. Rats were evaluated for visual function by flash visual evoked potentials (FVEPs) at 4 weeks after NAION induction. The retina and optic nerve were removed for histological examination after the rats were euthanized. The molecular machinery of BP treatment in the rAION model was analyzed using Western blotting. We discovered that BP effectively improves retinal ganglion cell survival rates by preventing apoptotic processes after AION induction and reducing the inflammatory response through which blood-borne macrophages infiltrate the optic nerve. In addition, BP significantly preserved the integrity of the myelin sheath in the rAION model, demonstrating that BP can prevent the development of demyelination. Our immunoblotting results revealed the molecular mechanism through which BP mitigates the neuroinflammatory response through inhibition of the NF-κB signaling pathway. Taken together, these results demonstrate that BP can be used as an exceptional neuroprotective agent for ischemic injury.

Literature Commentary

“…Nonarteritic anterior ischemic optic neuropathy (NAION) is a vexing problem for neuro-ophthalmologists because there is no effective prevention or treatment for it. Numerous unsuccessful therapeutic approaches include antiplatelet treatment, anticoagulation, calcium channel blockers, levodopa, memantine, anti-inflammatory agents, corticosteroids, growth factors, neuroprotective agents, optic nerve sheath fenestration, and hyperbaric oxygen (1). A greater understanding of the mechanisms leading to retinal ganglion cell death after an attack of NAION may open avenues for new treatments.…”

“…This elegant study provides strong evidence that the TAF9 pathway is an important component of GCSF-induced neuroprotection of RGC. It takes its place alongside multiple other studies that demonstrate neuroprotective effects involving the inhibition of apoptosis by various molecules, including n-butylidenephthalide (1) and bardoxolone methyl (2) in rat models of NAION. The results provide hope for targeted antiapoptosis therapy for patients with NAION through upregulation of TAF9 at a time when vision-saving treatments are still desperately needed.…”

Natural products: protective effects against ischemia-induced retinal injury

“…Huang demonstrated that Epimedium exerts anti-inflammatory effects in a rodent anterior ischemic optic neuropathy (rAION) model, inhibits nuclear factor-kappa B kinase to phosphorylate phosphatase and alleviate tensin homolog and activate threonine protein kinase (Akt) in response to ischemic stress ( Huang et al, 2020a ). Further research found that butylens benzonitrile can effectively prevent the apoptosis induced by rAION and that the inhibition of NF-κB signaling can reduce the inflammatory response of blood-derived macrophages infiltrating the optic nerve, thereby alleviating neuroinflammation and facilitating the improvement of RGCs ( Chou et al, 2022 ). The administration of Houttuynia cordata after retinal I/R injury has been found to inhibit the upregulation of TNF-α, inducible nitric oxide synthase (iNOS), and IL-1β in the treatment of ischemic events by activating microglia to promote the survival of RGCs ( Ren and Zhang, 2020 ).…”