Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum

Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development.

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The Importance of Measurement Precision and Behavioral Homologies in Evaluating the Behavioral Consequences of Fetal-Ethanol Exposure: Commentary on Williams and Colleagues (“Sensory-Motor Deficits in Children with Fetal Alcohol Spectrum Disorder Assessed

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.12328 ◽

2013 ◽

Vol 38 (1) ◽

pp. 40-43 ◽

Cited By ~ 2

Author(s):

Derek A. Hamilton

Keyword(s):

Fetal Alcohol Spectrum Disorder ◽

Ethanol Exposure ◽

Measurement Precision ◽

Spectrum Disorder ◽

Motor Deficits ◽

Fetal Alcohol ◽

Behavioral Consequences ◽

Sensory Motor ◽

Fetal Ethanol ◽

Fetal Alcohol Spectrum

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Reversal of cardiomyopathy resulting from prenatal exposure to ethanol

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100113469 ◽

1984 ◽

Vol 42 ◽

pp. 716-717

Author(s):

C. Uphoff ◽

C. Nyquist-Battie

Keyword(s):

Prenatal Exposure ◽

Heart Development ◽

Membrane Integrity ◽

Ethanol Exposure ◽

Prenatal Ethanol Exposure ◽

Pathological Changes ◽

Prenatally Exposed ◽

Inner Mitochondrial Membrane ◽

Fetal Alcohol ◽

Newborn Mice

Fetal Alcohol Syndrone (FAS) is a syndrome with characteristic abnormalities resulting from prenatal exposure to ethanol. In many children with FAS syndrome gross pathological changes in the heart are seen with septal defects the most prevalent abnormality recorded. Few studies in animal models have been performed on the effects of ethanol on heart development. In our laboratory, it has been observed that prenatal ethanol exposure of Swiss albino mice results in abnormal cardiac muscle ultrastructure when mice were examined at birth and compared to pairfed and normal controls. Fig. 1 is an example of the changes that are seen in the ethanol-exposed animals. These changes include enlarged mitochondria with loss of inner mitochondrial membrane integrity and loss of myofibrils. Morphometric analysis substantiated the presence of these alterations from normal cardiac ultrastructure. The present work was undertaken to determine if the pathological changes seen in the newborn mice prenatally exposed to ethanol could be reversed with age and abstinence.

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Role of zinc insufficiency in fetal alveolar macrophage dysfunction and RSV exacerbation associated with fetal ethanol exposure

Alcohol ◽

10.1016/j.alcohol.2018.11.007 ◽

2019 ◽

Vol 80 ◽

pp. 5-16 ◽

Cited By ~ 3

Author(s):

Juna Konomi Johnson ◽

Frank L. Harris ◽

Xiao-Du Ping ◽

Theresa W. Gauthier ◽

Lou Ann S. Brown

Keyword(s):

Alveolar Macrophage ◽

Ethanol Exposure ◽

Macrophage Dysfunction ◽

Fetal Ethanol

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Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure

Journal of Neuroinflammation ◽

10.1186/s12974-021-02243-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Victoria Macht ◽

Ryan Vetreno ◽

Natalie Elchert ◽

Fulton Crews

Keyword(s):

Cell Death ◽

High Mobility ◽

Alcohol Exposure ◽

Ethanol Exposure ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Hmgb1 Protein ◽

Immature Neurons ◽

Environmental Milieu ◽

Binge Ethanol Exposure

Abstract Background Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. Methods Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). Results Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). Conclusions Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

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The Social Consequences of Drug and Alcohol Abuse

Drug Courts ◽

10.1007/978-0-387-71433-2_7 ◽

2008 ◽

pp. 112-126 ◽

Cited By ~ 1

Author(s):

Heather R. Hayes ◽

Julie M. Queler

Keyword(s):

Alcohol Abuse ◽

Social Consequences ◽

The Social ◽

Drug And Alcohol

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Neurobiology of Fetal Alcohol Spectrum Disorders

10.1093/med/9780199937837.003.0179 ◽

2017 ◽

Author(s):

Carmen Lopez-Arvizu ◽

Carmel Bogle ◽

Harolyn M.E. Belcher

Keyword(s):

Hormonal Regulation ◽

Maternal Nutrition ◽

Fetal Alcohol Spectrum Disorders ◽

Ethanol Exposure ◽

Prenatal Ethanol Exposure ◽

Fetal Alcohol ◽

Wide Range ◽

Spectrum Disorders ◽

The Impact ◽

Fetal Alcohol Spectrum

Prenatal exposure to ethanol can result in a wide range of clinical presentations that are grouped under the term “Fetal Alcohol Spectrum Disorders” (FASD). The direct cellular teratogenic effects of ethanol on fetal neurodevelopment include damage to cell survival, proliferation, and migration mechanisms. Dysregulation of neurotransmission and alteration of genetic transcription have also been implicated in the neurotoxic effects of prenatal ethanol exposure. These deleterious events lead to brain volume reduction, corpus callosum dysgenesis, cerebellar, and other neuroanatomical anomalies that have been observed in individuals with FASD. Beyond direct ethanol-induced insults, the impact that ethanol has on maternal nutrition, metabolism, hormonal regulation, and placental physiology also adversely effects fetal development. The complex interactions between numerous neurobiological and psychosocial mechanisms that hinder optimal fetal neurodevelopment are reflected by the heterogeneous clinical presentation of FASD, including impaired growth, dysmorphic facial features, and cognitive and behavioral disorders.

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Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos

Visual Neuroscience ◽

10.1017/s0952523807070423 ◽

2007 ◽

Vol 24 (3) ◽

pp. 409-421 ◽

Cited By ~ 49

Author(s):

BHAVANI KASHYAP ◽

LOGAN C. FREDERICKSON ◽

DEBORAH L. STENKAMP

Keyword(s):

Cell Death ◽

Cell Differentiation ◽

Model Organism ◽

Cell Types ◽

Ethanol Exposure ◽

Retinal Cell ◽

Zebrafish Embryos ◽

Eye Size ◽

Organ Systems ◽

Retinal Neurogenesis

The exposure of the developing human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the visual system. One common phenotype seen in humans exposed to ethanol in utero is microphthalmia. The objective of this study was to describe the effects of ethanol during retinal neurogenesis in a model organism, the zebrafish, and to pursue the potential mechanisms by which ethanol causes microphthalmia. Zebrafish embryos were exposed to 1% or 1.5% ethanol from 24 to 48 h after fertilization, a period during which the retinal neuroepithelium undergoes rapid proliferation and differentiation to form a laminated structure composed of different retinal cell types. Ethanol exposure resulted in significantly reduced eye size immediately following the treatment, and this microphthalmia persisted through larval development. This reduced eye size could not entirely be accounted for by the accompanying general delay in embryonic development. Retinal cell death was only slightly higher in ethanol-exposed embryos, although cell death in the lens was extensive in some of these embryos, and lenses were significantly reduced in size as compared to those of control embryos. The initiation of retinal neurogenesis was not affected, but the subsequent waves of cell differentiation were markedly reduced. Even cells that were likely generated after ethanol exposure—rod and cone photoreceptors and Müller glia—were delayed in their expression of cell-specific markers by at least 24 h. We conclude that ethanol exposure over the time of retinal neurogenesis resulted in persistent microphthalmia due to a combination of an overall developmental delay, lens abnormalities, and reduced retinal cell differentiation.

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