The peptide NAP promotes neuronal growth and differentiation through extracellular signal-regulated protein kinase and Akt pathways, and protects neurons co-cultured with astrocytes damaged by ethanol.

We have previously shown that glial cells are a target of ethanol toxicity during brain ontogeny, since ethanol affects glial development and impairs the release of neurotrophic factors which are important for neuronal outgrowth and synaptic plasticity. Activity-dependent neuroprotective protein (ADNP) is a glial factor with anti-apoptotic and neuroprotective actions. We proposed that some ethanol effects on brain development and synaptic formation are, in part, mediated by the ethanol-induced impairment of the synthesis and release of ADNP by astroglial cells. We show a reduction in the ADNP mRNA levels in the cerebral cortex and astrocytes from prenatal ethanol exposed (PEE) foetuses. Furthermore, co-cultures of PEE astrocytes with control neurons cause a marked decrease in neuronal growth, differentiation and synaptic connections relative to the co-cultures with control astrocytes, effects that were reverted by the addition of NAP, the active peptide of ADNP. We further show that one mechanism by which NAP could exert its actions is the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, the phosphatidylinositol-3-kinase (PI-3K)/Akt pathways and the transcription factor cAMP response element-binding protein. These results indicate that the protective actions of NAP are mediated by triggering signalling pathways which are important in neuronal growth and differentiation contributing to the restoration of PEE-associated neuronal plasticity.