NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neural cell survival.

Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

Alcohol-induced neuronal death in central extended amygdala and pyriform cortex during the postnatal period of the rat.

Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome defined as fetal alcohol spectrum disorder (FASD) in their offspring. This disorder is characterized by reduction in brain size, cognitive deficits and emotional/social disturbances. These alterations are thought to be caused by an alcohol-induced increase in apoptosis during neurodevelopment. Little is known about neuroapoptosis in the central extended amygdala and the pyriform cortex, which are key structures in emotional/social behaviors. The goal of this study was to determine the vulnerability of neuroapoptotic alcohol effects in those areas. Rats were administered alcohol (2.5g/kg s.c. at 0 and 2h) or saline on postnatal day (PND) 7, 15 and 20. The Amino-cupric-silver technique was used to evaluate neurodegeneration and immunohistochemistry to detect activated caspases 3-8 and 9 at 2h, 4, 6, 8, 12 and 24h after drug administration. We measured blood alcohol levels each hour, from 2 to 8h post second administration of alcohol in each of the ages studied. Results showed alcohol induced apoptotic neurodegeneration in the central extended amygdala on PND 7 and 15, and pyriform cortex on PND 7, 15 and 20. These structures showed activation of caspase 3 and 9 but not of caspase 8 suggesting that alcohol-induced apoptosis could occur by the intrinsic pathway. The pharmacokinetic differences between ages did not associate with the neurodegeneration age dependence. In conclusion, these limbic areas are damaged by alcohol, and each one has their own window of vulnerability during the postnatal period. The possible implications in emotional/social features in FASD are discussed.