Abstract
Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.
Highlights
Introduction published maps and institutional affilTraumatic neural injuries always lead to immediate neural degeneration and subsequent neuronal death
We investigated the roles of three important components of Citrus flavanones—naringenin, hesperidin, and nobiletin, in the neuroprotection of retinal ganglion cells (RGCs) in traumatic optic nerve crush (ONC) injury mouse models, and revealed the underlying molecular mechanisms of their neuroprotective effects in regulating the JNK-JUN pathway
To identify whether the JNK-JUN pathway is activated after traumatic ONC injury, we generated traumatic ONC injury mouse models and verified the phosphorylation level of JUN
Summary
Traumatic neural injuries always lead to immediate neural degeneration and subsequent neuronal death. There are no available neuroprotectants for the treatment of traumatic neural injuries. Naringenin, hesperidin, and nobiletin are flavanones that are widely detected in most citrus species, including Zhishi. Naringenin (40 ,5,7-trihydroxyflavanone, with the molecular formula C15 H12 O5 and a molecular weight of 272.25 g/mol) is a plant bioflavonoid that is naturally found in citrus fruits (up to 10% of its dry weight) [4], it contains two benzene rings linked together with a heterocyclic pyrone ring [5,6]. Hesperidin (hesperetin 7-rutinoside), a flavanone glycoside, is isolated from citrus fruit with a content of about 3%, and has the molecular formula C28 H34 O15 and a molecular weight of 610.56 g/mol [7,8].
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