Vaudry David, Rousselle Cécile, Basille Magali, Falluel-Morel Anthony, Pamantung Tommy F, Fontaine Marc, Fournier Alain, Vaudry Hubert, Gonzalez Bruno J
European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, 76821 Mont-Saint-Aignan, France.
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6398-403. doi: 10.1073/pnas.082112699. Epub 2002 Apr 23.
Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypeptide (PACAP) can prevent the deleterious effect of ethanol on neuronal precursors. Exposure of cultured cerebellar granule cells to ethanol inhibited neurite outgrowth and provoked apoptotic cell death. Incubation of granule cells with PACAP prevented ethanol-induced apoptosis, and this effect was not mimicked by vasoactive intestinal polypeptide, suggesting that PAC1 receptors are involved in the neurotrophic activity of PACAP. Ethanol exposure induced a strong increase of caspase-2, -3, -6, -8, and -9 activities, DNA fragmentation, and mitochondrial permeability. Cotreatment of granule cells with PACAP provoked a significant inhibition of all of the apoptotic markers investigated although the neurotrophic activity of PACAP could only be ascribed to inhibition of caspase-3 and -6 activities. These data demonstrate that PACAP is a potent protective agent against ethanol-induced neuronal cell death. The fact that PACAP prevented ethanol toxicity even when added 2 h after alcohol exposure, suggests that selective PACAP agonists could have potential therapeutic value for the treatment of fetal alcohol syndrome.
发育过程中接触酒精会导致脑畸形和神经行为异常。鉴于乙醇的致畸性，鉴定能够对抗酒精神经毒性作用的分子具有高度优先性。在此，我们报告垂体腺苷酸环化酶激活多肽（PACAP）可以预防乙醇对神经元前体细胞的有害作用。将培养的小脑颗粒细胞暴露于乙醇会抑制神经突生长并引发凋亡性细胞死亡。用PACAP孵育颗粒细胞可预防乙醇诱导的凋亡，且血管活性肠肽无法模拟这种作用，这表明PAC1受体参与了PACAP的神经营养活性。乙醇暴露导致半胱天冬酶-2、-3、-6、-8和-9的活性、DNA片段化以及线粒体通透性大幅增加。用PACAP对颗粒细胞进行共处理可显著抑制所有检测的凋亡标志物，尽管PACAP的神经营养活性仅归因于对半胱天冬酶-3和-6活性的抑制。这些数据表明，PACAP是一种有效的抗乙醇诱导神经元细胞死亡的保护剂。即使在酒精暴露2小时后添加PACAP仍能预防乙醇毒性，这一事实表明选择性PACAP激动剂可能对胎儿酒精综合征的治疗具有潜在的治疗价值。
