Ethanol promotes neuronal apoptosis by inhibiting phosphatidylserine accumulation

Abstract

Prenatal and postnatal ethanol exposure induces abnormal cell death in the nervous system. We have previously reported that docosahexaenoic acid (DHA; 22:6n-3) prevents neuronal apoptosis through promoting phosphatidylserine (PS) accumulation. Previously, we have shown in C6 glioma cells that ethanol inhibits the accumulation of PS caused by DHA supplementation. In this report, we demonstrate that in vitro or in vivo exposure to ethanol inhibits DHA-dependent PS accumulation and neuronal survival. We found that Neuro 2A cells exposed to ethanol accumulated considerably less PS in response to the DHA enrichment and were less effective at phosphorylating Akt and suppressing caspase-3 activity under serum-starved or staurosporine-treated conditions. The in vivo paradigm correlated well with the in vitro findings. We found that the total PS and DHA contents in the fetal hippocampus were slightly but significantly lowered by the prenatal ethanol exposure. Fetal hippocampal cultures obtained at embryonic day 18 from ethanol-treated pregnant rats contained significantly higher apoptotic cells after 7 days in vitro under basal conditions and exhibited particular susceptibility to cell death induced by trophic factor removal in comparison with the pair-fed control group. The reduction of PS and the resulting neuronal cell death inappropriately enhanced during development may contribute to the defects in brain function often observed in fetal alcohol syndrome.

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

“…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). Our findings with Bcl-2 and caspase-3 highlight the importance of DHA in neuroprotection and zinc toxicity in apoptosis.…”

Novel Metabolism of Docosahexaenoic Acid in Neural Cells

“…Whether similar mechanisms are operative for DHA uptake in neural cells remains to be elucidated. It has been shown that long-term exposure to ethanol can decrease astroglial release (23) and neuronal incorporation of DHA (24). The inhibited neuronal DHA uptake is consistent with the loss of DHA in neural cells, particularly in brain synaptic plasma membranes after long-term ethanol exposure (13), although ethanol can also induce DHA catabolism by oxidation, as demonstrated from the liver (25).…”

“…DPAn-6 accumulated in place of DHA in n-3 fatty acid deficiency is not as effective as DHA in accumulating PS and translocating Akt and thus is less effective in supporting neuronal survival (18). Likewise, the PS reduction in neuronal membranes after long-term ethanol exposure accompanies the promotion of neuronal apoptosis (24). Considering that neurons do not regenerate easily, neuronal cells appear to employ a unique mechanism to ensure their survival, by maintaining a high level of membrane PS through DHA enrichment.…”

Maternal Alcohol Consumption Increases Sphingosine Levels in the Brains of Progeny Mice

“…Ethanol administration also leads to neuronal death by activating caspase-3 in rat cerebral cortex [72], inhibiting phosphatidyl serine accumulation [73], impairing Rho GTPase signaling [74]. Chronic ethanol also stimulates mitochndrial dysfunction and generates oxidative stress in immature CNS neurons [75].…”