Molecular mechanism of ADNF and ADNP peptides in neuroprotection to alcohol

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DESCRIPTION (provided by applicant): Alcohol has been known to impede the growth of the central nervous system. Previous studies have focused on the identification of antagonists for the specific actions of alcohol. In turn, these studies have investigated the possible prevention of prenatal alcohol exposure effects with peptides that were previously shown to be involved in neuroprotection in vitro and in vivo. Among these peptides, an active fragment of a nine amino acids (SALLRSIPA), SAL or ADNF-9, was the shortest sequence that mimicked the potent neuroprotective ability of activity-dependent neurotrophic factor (ADNF). Another peptide, NAP, contains eight amino acids (NAPVSIPQ) and is considered an ADNF-9-like fragment of activity-dependent neuroprotective protein (ADNP). The protective effects of NAP and SAL/ADNF-9 have been investigated particularly in vitro. The in vivo studies conducted at the NIH-NICHD using prenatal intraperitoneal injections of alcohol and peptides have demonstrated that the peptides prevented alcohol induced fetal death. In vivo studies from our laboratories that used a liquid diet paradigm as a model for moderate alcohol drinking, have demonstrated neuroprotective effects of NAP and SAL/ADNF-9 peptides by morphological analyses. The cellular mechanism of the neuroprotective effects of NAP and SAL/ADNF-9 peptides are still not fully characterized. It is unknown whether NAP and SAL/ADNF-9 act through proliferation or apoptosis in a fetal alcohol exposure model. The in vitro studies conducted in ours and others laboratories suggested that these peptides may act through the prevention of apoptosis. Based on the in vitro findings, we hypothesize that NAP and SAL/ADNF-9 peptides induce neuroprotection against the insult of prenatal alcohol exposure through apoptotic regulation. Since the molecular mechanisms of NAP and SAL/ADNF-9 against the effects of prenatal alcohol exposure are not yet elucidated, we aim in the proposed experiments to determine the precise temporal organization of the signaling outcomes and delineate pathways of neuroprotection for both NAP and SAL/ADNF-9 peptides. The data generated from the proposed experiments will provide information about NAP and SAL/ADNF-9 intracellular targets. This data will shed light on the mechanisms governing brain ontogeny and will pave the path toward potential therapeutics against developmental insults associated with prenatal alcohol exposure.