Efeitos da administração de inibidores de fosfodiesterases na reversão da hiperatividade de camundongos expostos ao etanol no período correspondente ao terceiro trimestre de gestação em humanos

Abstract

Ethanol consumption during gestation is a serious public health problem. During development, the nervous system is particularly susceptible to the toxic effects of ethanol and, in fact, ethanol exposure during perinatal development produces a range of neurobehavioral deficits, among which hyperactivity is one of the most frequently observed. There is evidence that reduced neuronal plasticity could be associated with hiperactivity. PDE inhibitors are drugs that prevent the breakdown of intracellular second-messengers such as cAMP and cGMP, maintaining the activation of protein kinases and of the CREB transcription factor, leading to the expression of plasticity-related genes. In this study we test whether Vinpocetine or Rolipram (PDE inhibitors) treatment can improve or revert hyperactivity in Swiss exposed to alcohol during the third trimester equivalent of human gestation. To that end, two experiments were carried out: In the first one, from postnatal day (PN) 2 to PN8, litters either received ethanol (5g/Kg i.p., 25% in saline solution) or an equivalent volume of saline solution every other day. On PN30, 4 h before the open field test (which lasted for 10 min) animals received Vinpocetine (10mg/Kg or 20mg/Kg diluted in DMSO i.p.) or dimethylsulfoxide (DMSO i.p.). In the second experiment animals were treated almost as before receiving Rolipram (0.5mg/Kg diluted in DMSO i.p.), instead of Vinpocetine, or DMSO i.p. After the tests, animals were sacrificed and frontal cerebral cortices and hippocampuses were dissected and collected for the analysis of cAMP levels. Behavioral results showed that only the Vinpocetine treatment (20mg/Kg) reversed the ethanol-elicited hyperactivity, a result that was not observed for the Rolipram treatment. In this way, the dosage of cAMP levels was done only for the animals that received received Vinpocetine (20mg/Kg). Ethanol neonatal exposure significantly reduced cAMP levels both in the cortex and in the hippocampus. Vinpocentine treatment increased cAMP levels in the cortex and restored it in the hippocampus. Our results suggest that the amelioration of the ethanolinduced hyperactivity by Vinpocetine is linked to an increased neuronal plasticity induced by this drug.