Bilberry extract administration prevents retinal ganglion cell death in mice via the regulation of chaperone molecules under conditions of endoplasmic reticulum stress

Abstract

PurposeTo investigate the effect of bilberry extract anthocyanins on retinal ganglion cell (RGC) survival after optic nerve crush. Additionally, to determine details of the mechanism of the neuroprotective effect of bilberry extract anthocyanins and the involvement of endoplasmic reticulum stress suppression in the mouse retina.Materials and methodsAnthocyanins in bilberry extract (100 mg/kg/day or 500 mg/kg/day) were administrated orally to C57BL/6J mice. The expression levels of various molecular chaperones were assessed with quantitative reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry. RGC survival was evaluated by measuring the gene expression of RGC markers and counting retrogradely labeled RGCs after optic nerve crush.ResultsThe protein levels of Grp78 and Grp94 increased significantly in mice after bilberry extract administration. Increased Grp78 and Grp94 levels were detected in the inner nuclear layer and ganglion cell layer of the retina, surrounding the RGCs. Gene expression of Chop, Bax, and Atf4 increased in mice after optic nerve crush and decreased significantly after oral bilberry extract administration. RGC survival after nerve crush also increased with bilberry extract administration.ConclusionThese results indicate that oral bilberry extract administration suppresses RGC death. Bilberry extract administration increased Grp78 and Grp94 protein levels, an effect which may underlie the neuroprotective effect of bilberry extract after optic nerve crush. Thus, bilberry extract has a potential role in neuroprotective treatments for retinal injuries, such as those which occur in glaucoma.

Increased ER Stress After Experimental Ischemic Optic Neuropathy and Improved RGC and Oligodendrocyte Survival After Treatment With Chemical Chaperon

“…Other than our study on AION, differential regulation of GRP78 and CHOP expression, that is, reduced GRP78 and increased CHOP expression, has been found in RGCs in animal models of optic neuritis and traumatic optic neuropathy 77. Similarly, successful treatment of experimental optic neuropathies and improved RGC survival77,78 have also been associated with differential expression of GRP78 and CHOP in the opposite direction, that is, increased GRP7879 and decreased CHOP expression in cells in the RGC layer. Nakamura et al78 showed that RGC loss after optic nerve crush animal model was associated with decreased GRP78 and increased CHOP expression and that treatment with bilberry extract anthocyanins led to improved RGC survival, increased GRP78 and decreased CHOP expressions, along with reduced expression of BAX and ATF4 , which are downstream of DDIT3 (CHOP).…”

“…Similarly, successful treatment of experimental optic neuropathies and improved RGC survival77,78 have also been associated with differential expression of GRP78 and CHOP in the opposite direction, that is, increased GRP7879 and decreased CHOP expression in cells in the RGC layer. Nakamura et al78 showed that RGC loss after optic nerve crush animal model was associated with decreased GRP78 and increased CHOP expression and that treatment with bilberry extract anthocyanins led to improved RGC survival, increased GRP78 and decreased CHOP expressions, along with reduced expression of BAX and ATF4 , which are downstream of DDIT3 (CHOP). Jiang et al77 showed that transplantation of human umbilical cord cells as treatment for traumatic optic neuropathy animal model led to improved RGC survival and increase in expression of GRP78 and decrease in expression of CHOP.…”

Molecular mechanisms of optic nerve damage: the role of anthocyanozides in the prevention of retinal ganglion cell death

“…В экспериментальных исследованиях in vitrо и in vivo показано, что активация молекулярных шаперонов способствует сохранению клеток при стрессе ЭПР. В особенности это касается шаперона Grp78, который играет важную роль в ослаблении процесса апоптоза, и шаперона Grp94, подавляющего гибель нейронов при ишемии/реперфузии [9,10]. Эти данные подтверждают, что молекулярные шапероны Grp78 и Grp94 задействованы в защите поврежденных клеток при стрессе ЭПР.…”

“…В настоящее время в литературе описаны результаты экспериментального и клинического изучения влияния антоцианозидов экстракта черники на сохранение функциональной активности сетчатки и зрительного нерва при нейродегенеративных заболеваниях [10].…”

“…В связи с этим огромный интерес представляет исследование O. Nakamura и соавт. [10], которые изучали нейропротекторное действие антоци- 104 анозидов черники на ГКС при моделировании травматического повреждения зрительного нерва у мышей С57BL/6J в эксперименте in vivo. Все животные были разделены на группы: в 1-ю группу вошли мыши, получавшие буферный раствор, мыши 2-й и 3-й групп получали экстракт черники с кормом (100 и 500 мг/кг соответственно) за 3 дня до травмы и в течение 7 дней после травмы.…”