Epicatechin blocks pro-nerve growth factor (proNGF)-mediated retinal neurodegeneration via inhibition of p75 neurotrophin receptor proNGF expression in a rat model of diabetes

Abstract

Aims/hypothesis Accumulation of pro-nerve growth factor (NGF), the pro form of NGF, has been detected in neurodegenerative diseases. However, the role of proNGF in the diabetic retina and the molecular mechanisms by which proNGF causes retinal neurodegeneration remain unknown. The aim of this study was to elucidate the role of proNGF in neuroglial activation and to examine the neuroprotective effects of epicatechin, a selective inhibitor of tyrosine nitration, in an experimental rat model of diabetes. Methods Expression of proNGF and its receptors was examined in retinas from streptozotocin-induced diabetic rats, and in retinal Müller and retinal ganglion cells (RGCs). RGC death was assessed by TUNEL and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in diabetic retinas and cell culture. Nitrotyrosine was determined using Slot-blot. Activation of the tyrosine kinase A (TrkA) receptor and p38 mitogen-activated protein kinase (p38MAPK) was assessed by western blot.Results Diabetes-induced peroxynitrite impaired phosphorylation of TrkA-Y490 via tyrosine nitration, activated glial cells and increased expression of proNGF and its receptor, p75 neurotrophin receptor (p75 NTR apoptotic pathway in RGCs, leading to neuronal cell death. These effects were blocked by epicatechin, a safe dietary supplement, suggesting its potential therapeutic use in diabetic patients.Electronic supplementary material The online version of this article

MicroRNA-30b promotes axon outgrowth of retinal ganglion cells by inhibiting Semaphorin3A expression

“…Overexpression of proNGF can activate the p38MAPK signaling pathway, resulting in the phosphorylation of p38MAPK and induction of apoptosis in RGCs in diabetic rats (Al-Gayyar et al, 2011). In the ON crush model used in our study, the expression patterns of pp38MAPK and active caspase-3 were similar to that of Sema3A, suggesting that Sema3A induced apoptosis of RGCs via the p38MAPK signaling to activate caspase-3.…”

Nerve growth factor in diabetic retinopathy: beyond neurons

“…Diabetes-induced proNGF/NGF imbalance is associated with a reduction in both activity and expression of matrix metalloproteinase (MMP)-7, one of the enzymes that cleaves proNGF to form mature NGF [37,52]. Decreased MMP-7 expression and function have been observed in the vitreous and aqueous humor of humans with DR and proliferative DR, as well as in the retinal lysates of diabetic rats, and Müller glial cell cultures [31,32]. Restoration of MMP-7 activity is associated with the return of NGF and proNGF to control levels in these tissues [31].…”

“…The oxidative milieu of the diabetic retina causes increased formation of nitrotyrosine moieties including increased tyrosine nitration of the TrkA receptor. In conjunction with TrkA nitration, phosphorylation of the TrkA-Y490 site is impaired reducing the activation of downstream survival pathways [30,32,53]. In both streptozotocin-induced diabetic rat retinas, reducing nitrative stress restored TrkA-Y490 phosphorylation and RGC survival to control levels [30–32].…”

“…In conjunction with TrkA nitration, phosphorylation of the TrkA-Y490 site is impaired reducing the activation of downstream survival pathways [30,32,53]. In both streptozotocin-induced diabetic rat retinas, reducing nitrative stress restored TrkA-Y490 phosphorylation and RGC survival to control levels [30–32]. In addition to alterations in TrkA function, expression of the p75 NTR receptor is increased in diabetic retinas, which combined with increased proNGF expression, favors activation of proapoptotic and proinflammatory pathways [30,32,33].…”

“…In both streptozotocin-induced diabetic rat retinas, reducing nitrative stress restored TrkA-Y490 phosphorylation and RGC survival to control levels [30–32]. In addition to alterations in TrkA function, expression of the p75 NTR receptor is increased in diabetic retinas, which combined with increased proNGF expression, favors activation of proapoptotic and proinflammatory pathways [30,32,33]. In the diabetic retina, this shift toward proNGF/p75 NTR signaling is accompanied by neurodegeneration, evidenced by death of RGC, vascular dysfunction and activation of RhoA/p38MAPK, a common pathway implicated in both neuronal death and vascular permeability [29,31,54–59].…”