Mechanisms of Ethanol-Induced Death of Cerebellar Granule Cells

Abstract

Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system (CNS) underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that is most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of NMDA receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis.

Autophagy and ethanol neurotoxicity

“…These potential mechanisms include interference with neurotrophic factor-and retinoid acid-mediated signaling, induction of oxidative stress, DNA damage and ER stress, increased proinflammatory proteins, disruption of the neurotransmitter system, and inhibition of translational regulation. [28][29][30][31][32][33] As mentioned above, autophagy can be activated by various types of cellular stress including deprivation of nutrients, hypoxia, oxidative stress, ER stress, DNA damage, and protein aggregates, as well as by the presence of intracellular pathogens. 16,34 We have recently shown that ethanol activates autophagy in neurons in vitro and in the developing brain.…”

“…ER stress can activate autophagy by disrupting intracellular Ca 2C homeostasis or activating kinases and transcription factors that regulate autophagy; these include ERN1, MAPK/JNK, DDIT4/REDD1, AKT, DDIT3/CHOP, XBP1, DAPK1, and NFE2L1/NFE2L2. 52,61,62 Since ethanol induces ER stress in cultured neurons and in the brain, 31,33 it may trigger autophagy by inducing ER stress in neurons.…”

Alcohol and thiamine deficiency trigger differential mitochondrial transition pore opening mediating cellular death

“…Neurotoxic effects of neonatal alcohol exposure on cellular death depend on brain region, neuronal population and treatment period [56][57][58]. Alcohol-induced neuronal death is mainly mediated by the mitochondrial apoptotic pathway also known as intrinsic apoptotic pathway [59,60].…”

“…Alcohol-induced neuronal death is mainly mediated by the mitochondrial apoptotic pathway also known as intrinsic apoptotic pathway [59,60]. The Bcl-2 family proteins are critical factors triggering intrinsic apoptotic pathway [58]. Indeed, ethanol exposure up-regulates pro-apoptotic Bax and Bad, but down-regulates anti-apoptotic Bcl2 in neonatal rat brain [61,62].…”

Original article Alcohol-induced changes in the developing cerebellum. Ultrastructural and quantitative analysis of neurons in the cerebellar cortex

“…The Purkinje cells in a more advanced state of differentiation are more vulnerable to ethanol-induced cell death than those less matured [4]. It is known that the rat cerebellum is particularly sensitive to ethanol during the first period after birth [19], which is considered to be equivalent to the third trimester of human pre -…”