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Neuroprotective effects of PACAP against ethanol-induced toxicity in the developing rat cerebellum
Béatrice Botia1, Valérie Jolivel, Delphine Burel
1INSERM U982, DC2N, University of Rouen, Mont-Saint-Aignan, France.
Insights
Pituitary adenylate cyclase-activating polypeptide (PACAP) protects developing rat cerebellum from alcohol toxicity. PACAP counteracts ethanol
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The developing cerebellum is vulnerable to alcohol during early neurogenesis.
- Pituitary adenylate cyclase-activating polypeptide (PACAP) shows neuroprotective effects in vitro.
Purpose of the Study:
- To investigate PACAP's ability to counteract ethanol toxicity in vivo in young rats.
- To explore PACAP's effects on alcohol-induced gene expression and cell survival.
Main Methods:
- 8-day-old rats were administered ethanol and/or PACAP.
- Behavioral tests (negative geotaxis) were performed.
- Gene expression (c-jun, caspase-3, α6 GABA A, neuroD2) and cell counts were analyzed.
Main Results:
- PACAP improved locomotor activity in ethanol-exposed rats.
- Ethanol-induced pro-apoptotic gene expression was partially blocked by PACAP.
- PACAP counteracted ethanol's inhibition of neuronal differentiation markers and prevented granule cell loss.
Conclusions:
- PACAP effectively counteracts the in vivo neurotoxic effects of ethanol on the developing cerebellum.
- PACAP's beneficial effects on locomotor activity precede its impact on cell survival, suggesting it blocks detrimental actions on neuronal differentiation.
Abstract:
The developing rat cerebellum is particularly sensitive to alcohol at the end of the first postnatal week, a period of intense neurogenesis. The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) has previously been shown to prevent the death of cultured neurons in vitro. We have thus investigated the capacity of PACAP to counteract ethanol toxicity in 8-day-old rats. Behavioral studies revealed that PACAP reduces the deleterious action of alcohol in the negative geotaxis test. Administration of ethanol induced a transient increase of the expression of pro-apoptotic genes including c-jun or caspase-3 , which could be partially blocked by PACAP. Alcohol inhibited the expression of the α6 GABA ( A ) subunit while PACAP increased neuroD2 mRNA level, two markers of neuronal differentiation. Although gene regulations occurred rapidly, a third injection of ethanol was required to strongly reduce the number of granule cells in the internal granule cell layer, an effect which was totally blocked by PACAP. The action of PACAP was mimicked by D-JNKi1 and Z-VAD-FMK, indicating the involvement of the jun and caspase-3 pathways in alcohol toxicity. The present data demonstrate that PACAP can counteract in vivo the deleterious effect of ethanol. The beneficial action of PACAP on locomotor activity precedes its activity on cell survival, indicating that PACAP can block the detrimental action of ethanol on cell differentiation.
