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Published on: April 24, 2013
Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced
David Vaudry1, Cécile Rousselle, Magali Basille
1European 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.
Abstract:
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.
Insights
Pituitary adenylate cyclase-activating polypeptide (PACAP) protects developing brain cells from ethanol toxicity. This finding suggests PACAP may offer a therapeutic strategy for fetal alcohol syndrome.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Ethanol exposure during development can lead to severe brain malformations and neurobehavioral deficits.
- Identifying agents to counteract alcohol's neurotoxicity is crucial for preventing developmental disorders.
Purpose of the Study:
- To investigate the neuroprotective potential of pituitary adenylate cyclase-activating polypeptide (PACAP) against ethanol-induced neurotoxicity in developing neurons.
- To elucidate the mechanisms underlying PACAP's protective effects, including its role in apoptosis and receptor involvement.
Main Methods:
- Primary cultures of cerebellar granule cells were exposed to ethanol.
- Cells were treated with PACAP or vasoactive intestinal polypeptide (VIP).
- Apoptosis markers (caspase activity, DNA fragmentation, mitochondrial permeability) and neurite outgrowth were assessed.
Main Results:
- Ethanol exposure inhibited neurite outgrowth and induced apoptosis, evidenced by increased caspase activity and DNA fragmentation.
- PACAP treatment prevented ethanol-induced apoptosis and inhibited key apoptotic markers, particularly caspase-3 and -6.
- PACAP's protective effect was mediated via PAC1 receptors, as VIP did not show similar protective activity.
Conclusions:
- PACAP demonstrates significant neuroprotective properties against ethanol-induced neuronal cell death.
- PACAP's ability to counteract ethanol toxicity, even when administered post-exposure, highlights its therapeutic potential.
- Selective PACAP agonists could be valuable in treating fetal alcohol syndrome and related developmental disorders.
