Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway

Abstract

Identifying the trophic factors for retina photoreceptors and the intracellular pathways activated to promote cell survival is crucial for treating retina neurodegenerative diseases. Docosahexaenoic acid (DHA), the major retinal polyunsaturated fatty acid, prevents photoreceptor apoptosis during early development in vitro, and upon oxidative stress. However, the signaling mechanisms activated by DHA are still unclear. We investigated whether the extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) or the phosphatidylinositol-3-kinase (PI3K) pathway participated in DHA protection. 1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophynyltio) butadiene (U0126), a specific MEK inhibitor, completely blocked the DHA anti-apoptotic effect. DHA rapidly increased ERK phosphorylation in photoreceptors, whereas U0126 blocked this increase. U0126 hindered DHA prevention of mitochondrial depolarization, and blocked the DHA-induced increase in opsin expression. On the contrary, PI3K inhibitors did not diminish the DHA protective effect. DHA promoted the early expression of Bcl-2, decreased Bax expression and reduced caspase-3 activation in photoreceptors. These results suggest that DHA exclusively activates the ERK/MAPK pathway to promote photoreceptor survival during early development in vitro and upon oxidative stress. This leads to the regulation of Bcl-2 and Bax expression, thus preserving mitochondrial membrane potential and inhibiting caspase activation. Hence, DHA, a lipid trophic factor, promotes photoreceptor survival and differentiation by activating the same signaling pathways triggered by peptidic trophic factors.

Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats

“…EC rodents exhibit improved spatial memory [8], while administration of DHA improves cognitive impairment in mouse models of mild cognitive dysfunction or in AD [51]. C57BL/6 learning-impaired mice [52] show increased survival of hippocampal cells if exposed to an EC, while DHA prolongs cell survival in retinal photoreceptors [53]. Brains of EC rodents exhibit increased NGF (nerve growth factor) expression [54]; likewise DHA administration can increase the expression of NGF [55].…”

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

“…In the present study, administration of DHA increased Bcl-2 levels in MPTP-induced + DHA-treated dopaminergic neurons compared to the MPTP-induced group. It has been demonstrated that DHA administration correlates with an increase in Bcl-2 levels in the brain [84,85] and in retina tissues [84,86]. In a cell study, German et al [86] found that DHA treatment induced Bcl-2 expression in neurons.…”

“…It has been demonstrated that DHA administration correlates with an increase in Bcl-2 levels in the brain [84,85] and in retina tissues [84,86]. In a cell study, German et al [86] found that DHA treatment induced Bcl-2 expression in neurons. DHA protection in cells in culture and in in vivo models may involve neuroprotection D1 (NPD1) synthesis [87].…”

“…It has been shown that DHA activates positive regulators of cell survival by up-regulating Akt, extracellular-signal-regulated kinase (ERK) and/or Bcl-2 [85]. Besides, DHA also has a negative effect on damaging factor production such as inflammatory cytokines and free radicals [20,86,118,119]. The mechanism of activation of Akt is still controversial, even though it has been widely investigated.…”

Effect of Zinc and DHA on Expression Levels and Post-Translational Modifications of Histones H3 and H4 in Human Neuronal Cells

“…An increase in zinc levels causes up-regulation of caspase-3 and down-regulation of Bcl-2 expression, suggesting the potential occurrence of apoptosis of zinc-induced M17 cells, which is representative of neurodegenerative conditions such as AD where intracellular zinc ion is elevated while DHA level is reduced. Conversely, DHA treatment of M17 cells increased expression levels of Bcl-2 and reduced caspase-3, which suggest that DHA exclusively activates the extracellular signal regulated kinase/mitogen-activated protein kinases (ERK/MPK) pathway to promote cell survival that lead to the up-regulation of Bcl-2 and inhibition of caspase-3 activation (German, Insua et al 2006). Our observation was supported by Akbar et al (2006), which showed the involvement of DHA in neuronal cell survival by driving Akt translocation resulting in activation of Bcl-2 and subsequent suppression of caspase-3 activity leading to inhibition of apoptosis in neuronal cells (Akbar, Baick et al 2006).…”