Activity-dependent neurotrophic factor-derived peptide prevents alcohol-induced apoptosis, in part, through Bcl2 and c-Jun N-terminal kinase signaling pathways in fetal brain of C57BL/6 mouse

Abstract

Fetal alcohol exposure is known to induce alteration in fetal brain development. In this study, we focused on neuroprotection against the effects of alcohol exposure using ADNF-9, a peptide derived from activity-dependent neurotrophic factor. We used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying the neuroprotective effects of ADNF-9. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet (ALC) of 25% (4.49%, v/v) ethanol derived calories; (2) pair-fed control (PF); (3) ALC combined with administration (i.p.) of ADNF-9 (ALC/ADNF-9); and (4) pair-fed combined with administration (i.p.) of ADNF-9 (PF/ADNF-9). On E13, fetal brains were collected, weighed, and apoptosis was determined using TUNEL assay. Bcl2 protein and phospho-c-Jun N-terminal kinase (JNK) levels were determined using Western blot and enzyme immunometric assay, respectively. ADNF-9 administration significantly prevented alcohol-induced reductions in fetal brain weight. In addition, ADNF-9 prevented an alcohol-induced increase in cell death in the primordium of the cerebral cortex and ganglionic eminence. Western blot analysis of the mitochondrial protein fractions revealed that ADNF-9 administration prevented an alcohol-induced reduction in the Bcl2 level. Moreover, an analysis of the proteins in the upstream signaling pathway revealed that ADNF-9 down-regulated the phosphorylation of JNK. These data indicate that the mitochondrial Bcl2 pathway and JNK upstream signaling pathway are the intracellular targets of ADNF-9. The neuroprotective mechanism of action of ADNF-9 provides a direction for potential therapeutics against alcohol-induced neural damage involving mitochondrial dysfunction.

Myocardium Protective Function of Salvianolic Acid B in Ischemia Reperfusion Rats

“…The increment in Bax expression is clearly significant, what can be an indication of apoptosis via the intrinsic pathway. The reduction of Bcl-2 factor expression can lead to a loss of survival signals (Sari et al, 2012). The results of the present study suggest that down-regulation of Bcl-2 expression may trigger activation of caspase-3 and Bax in cardiomyocytes during I/R, resulting in cell death.…”

Neurotrophic Peptides, ADNF-9 and NAP, Prevent Alcohol-Induced Apoptosis at Midgestation in Fetal Brains of C57BL/6 Mouse

“…It is noteworthy that Leker et al (2002) have showed that NAP reduced significantly the number of apoptotic cells in ischemic injury rat model. Studies from our lab demonstrated neuroprotective effects of NAP and ADNF-9 in FAE at early stage of development (Sari 2009; Sari et al 2011; Sari et al 2012). …”

“…It has been shown in in vitro study that the action of NAP in neuroprotection against alcohol-induced apoptosis might be mediated through the activation of MAPK/ERK and PI3K/Akt, and the transcription factor CREB (Pascual and Guerri 2007). On the other hand, ADNF-9 was shown to prevent alcohol-induced increases in phospho-c-Jun N-terminal kinase (JNK) and prevents alcohol-induced downregulation of the survival factor Bcl2 family (Sari et al 2012). Alternatively, colivelin, composed of ADNF-9 and humanin, was shown to prevent alcohol-induced increases in cytosolic cytochrome c and caspase-3 activity, and promote a decrease in mitochondrial cytochrome c, resulting in reduction of alcohol-induced cell death (Sari et al 2009).…”

The Fetal Alcohol Spectrum Disorders—An Overview of Experimental Models, Therapeutic Strategies, and Future Research Directions

“…ADNF-9 was shown to prevent alcohol-induced increases in phospho-c-Jun N-terminal kinase (JNK) and downregulation of the survival factor Bcl2 family. These major mitochondrial signaling pathways may be contributing factors to the neuroprotective effect [144]. Furthermore, the combination of SAL and NAP produced similar neuroprotective results [145].…”