Ethanol influences on Bax associations with mitochondrial membrane proteins in neonatal rat cerebellum.

These studies investigated interactions taking place at the mitochondrial membrane in neonatal rat cerebellum following ethanol exposure and focused on interactions between proapoptotic Bax and proteins of the permeability transition pore (PTP), voltage-dependent anion channel (VDAC) and adenine nucleotide translocator (ANT) of the outer and inner mitochondrial membranes, respectively. Cultured cerebellar granule cells were used to assess the role of these interactions in ethanol neurotoxicity. Analyses were made at the age of maximal cerebellar ethanol vulnerability (P4), compared to the later age of relative resistance (P7), to determine whether differential ethanol sensitivity was mirrored by differences in these molecular interactions.

Differential effects of ethanol on c-jun N-terminal kinase, 14-3-3 proteins, and Bax in postnatal day 4 and postnatal day 7 rat cerebellum.

These studies investigated ethanol effects on upstream cellular elements and interactions which contribute to Bax-related apoptosis in neonatal rat cerebellum at ages of peak ethanol sensitivity (postnatal day 4 [P4]), compared to later ages of relative resistance (P7). Analyses were made of basal levels of the pro-apoptotic c-jun N-terminal kinase (JNK), Bax, and the 14-3-3 anchoring proteins, as well as the responsiveness of these substances to ethanol at P4 versus P7. Dimerization of Bax with 14-3-3 was also investigated at the two ages following ethanol treatment, a process which sequesters Bax in the cytosol, thus inhibiting its mitochondrial translocation and disruption of the mitochondrial membrane potential.

Effect of bax deletion on ethanol sensitivity in the neonatal rat cerebellum.

The developing cerebellum is highly sensitive to ethanol during discrete neonatal periods. This sensitivity has been linked to ethanol-induced alterations in molecules of the Bcl-2 survival-regulatory gene family. Ethanol exposure during peak periods of cerebellar sensitivity, for example, results in increased expression of proapoptotic proteins of this family, while overexpression of the antiapoptotic Bcl-2 protein in the nervous system protects against ethanol neurotoxicity.

Ethanol-induced reduction of neurotrophin secretion in neonatal rat cerebellar granule cells is mitigated by vitamin E.

Ethanol exposure during nervous system development produces a range of abnormalities, and in humans may lead to the fetal alcohol syndrome. Among the mechanisms hypothesized to play roles in ethanol neurotoxicity are altered expression of supportive neurotrophic factors (NTFs), and cellular disturbances in oxidative processes. In this study, ethanol effects on secretion of two NTFs, brain-derived neurotrophic factor, and neurotrophin-3 were analyzed in neonatal rat cerebellar granule cells, and the potential of the antioxidant vitamin E to modulate ethanol effects was investigated.

Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of neonatal exposure.

The detrimental effects of ethanol exposure during nervous system development have been well established. The cellular mechanisms of ethanol neurotoxicity, however, have not been clearly defined. Recent studies suggest that neurotrophin signaling pathways may be involved in ethanol-mediated neuronal death.

Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of prenatal exposure.

Developmental ethanol exposure produces significant central nervous system (CNS) abnormalities. The cellular mechanisms of ethanol neurotoxicity, however, remain elusive. Recent data implicate altered neurotrophin signaling pathways in ethanol-mediated neuronal death.

Vitamin E amelioration of ethanol neurotoxicity involves modulation of apoptotis-related protein levels in neonatal rat cerebellar granule cells.

Developmental ethanol exposure leads to a variety of abnormalities in the central nervous system (CNS). Mechanisms proposed as underlying these effects include alterations of protective antioxidant support, increased generation of harmful free radicals, and altered expression of apoptosis-related proteins. In prior studies, exogenous antioxidant application has been found to reduce ethanol neurotoxicity, but the mechanisms by which this protection is afforded have not been defined.

Ethanol effects on neonatal rat cortex: comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods.

The developing central nervous system (CNS) is highly susceptible to ethanol, with acute or chronic exposure producing an array of anomalies and cell loss. Certain periods of vulnerability have been defined for various CNS regions, and are often followed by periods of relative ethanol resistance. In the present study, neonatal rats were acutely exposed to ethanol during a time when peak cell death is found in developing cerebral cortex (postnatal day 7; P7), and during a later neonatal period of ethanol resistance (P21).

The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol.

Background: Ethanol produces abnormalities in the developing nervous system, with certain regions being vulnerable during well-defined periods. Neonatal rodent cerebellum is particularly susceptible to ethanol during the early postnatal period [on postnatal days 4-5 (P4-5)], while this region is resistant to ethanol at a slightly later time (P7-9). We assessed basal levels of several substances which may be involved in differential temporal ethanol vulnerability in neonatal cerebellum, and analyzed alterations in these substances after early ethanol exposure.

Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability.

The developing central nervous system is extremely sensitive to ethanol, with well-defined temporal periods of vulnerability. Many brain regions are particularly susceptible to ethanol during the early neonatal period, corresponding to the human third trimester, which represents a dynamic period of growth and differentiation. For this study, neonatal rats were acutely exposed to ethanol or control conditions at a neonatal age when the developing striatum has been shown to be vulnerable to ethanol (postnatal day 3 [P3]), and at a later age (P14), when this developing region is relatively ethanol-resistant.

Ethanol-mediated generation of reactive oxygen species in developing rat cerebellum.

The neonatal cerebellum undergoes an early period of ethanol sensitivity in which profound neuronal loss is seen following acute exposure, while slightly later exposure produces no such loss. This study was designed to determine whether this differential susceptibility is related to differences in ethanol-induced generation of reactive oxygen species (ROS). We found that ethanol treatment on postnatal day 4 (P4), the peak period of cerebellar vulnerability, resulted in ROS increases, but slightly later exposure (on P7) produced no immediate changes in ROS, but reductions were seen at 12 and 24 h following exposure.

Influence of ethanol on neonatal cerebellum of BDNF gene-deleted animals: analyses of effects on Purkinje cells, apoptosis-related proteins, and endogenous antioxidants.

The sensitivity of the developing central nervous system (CNS) to the deleterious effects of ethanol has been well documented, with exposure leading to a wide array of CNS abnormalities. Certain CNS regions are susceptible to ethanol during well-defined critical periods. In the neonatal rodent cerebellum, a profound loss of Purkinje cells is found when ethanol is administered early in the postnatal period [on postnatal days 4 or 5 (P4-5)], while this neuronal population is much less vulnerable to similar ethanol insult slightly later in the postnatal period (P7-9).