Abstract
We found that hesperidin, a plant-derived bioflavonoid, may be a candidate agent for neuroprotective treatment in the retina, after screening 41 materials for anti-oxidative properties in a primary retinal cell culture under oxidative stress. We found that the intravitreal injection of hesperidin in mice prevented reductions in markers of the retinal ganglion cells (RGCs) and RGC death after N-methyl-D-aspartate (NMDA)-induced excitotoxicity. Hesperidin treatment also reduced calpain activation, reactive oxygen species generation and TNF-α gene expression. Finally, hesperidin treatment improved electrophysiological function, measured with visual evoked potential, and visual function, measured with optomotry. Thus, we found that hesperidin suppressed a number of cytotoxic factors associated with NMDA-induced cell death signaling, such as oxidative stress, over-activation of calpain, and inflammation, thereby protecting the RGCs in mice. Therefore, hesperidin may have potential as a therapeutic supplement for protecting the retina against the damage associated with excitotoxic injury, such as occurs in glaucoma and diabetic retinopathy.
Highlights
Oxidative stress is a major cause of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis[1]
We found that 24 h after NMDA injury, the number of RBPMS-positive retinal ganglion cells (RGCs) was lower in the NMDA-treated group than the PBS-treated group (PBS: 109.1 ± 37.2 cells/mm vs. NMDA: 34.4 ± 6.7 cells/ mm)
We found that the intravitreal injection of NMDA increased the gene expression of TNF-α to 183% of its expression in animals injected with PBS, and increased the gene expression of Ddit[3] to 169%
Summary
Oxidative stress is a major cause of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis[1]. If oxidative stress directly induces RGC death in human glaucoma patients, antioxidant molecules may have neuroprotective effects in glaucoma. We performed a follow-up in vivo experiment to assess the neuroprotective effect of the most promising compound, hesperidin, in the RGCs after NMDA injury in mice. We chose this animal model because of the well-known ability of NMDA to promote cellular oxidative stress via the NMDA receptors and cause calcium overload in cells[1, 26]
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