Regional selectivity in ethanol-induced pro-oxidant events within the brain

doi:10.1016/0006-2952(94)00442-O

Biochemical Pharmacology

Volume 49, Issue 1, 6 January 1995, Pages 69-72

https://doi.org/10.1016/0006-2952(94)00442-O Get rights and content

Abstract

Several biochemical parameters that reflect the presence of excess levels of reactive oxygen species were modulated in the brains of rats exposed acutely or subchronically to ethanol. These parameters included depression of cytosolic glutathione (GSH) concentration and of glutamine synthetase levels. However, using these indices, there was a significant difference in susceptibility to ethanol in different brain regions. After dietary exposure to ethanol for 12 days, these indices were selectively depressed in the striatum but not in the cerebral cortex or cerebellum. Eighteen hours after a single acute dose of ethanol (4.5 g/kg body wt), the striatum was also the only one of these areas in which proteolytic activity was elevated by ethanol treatment. Two injections of acetaldehyde (300 mg/ kg), given 18 and 2 hr prior to tissue preparation, caused a specific reduction of glutamine synthetase in the striatum and a decrease of GSH levels in both striatum and cerebellum. Taken together, the results suggest a distinctive vulnerability of the striatum to ethanol-promoted oxidative events. Rather than ethanol exerting effects directly, the metabolite acetaldehyde may be the primary agent responsible for these changes.

References (32)

HSK Anandatheerthavarada et al.
Induction of brain cytochrome P-450IIEI by chronic ethanol treatment
Brain Res
(1993)
SC Phillips
Cytoprotective value of lysine, penicillamine and pyridoxal phosphate against the neurotoxicity of acetaldehyde
Toxicol Appl Pharmacol
(1989)
H Rouach et al.
Effect of acute ethanol administration upon the subcellular distribution of iron in rat liver and cerebellum
Biochem Pharmacol
(1990)
NF Schor
Inactivation of mammalian brain glutamine synthetase by oxygen radicals
Brain Res
(1988)
PR Dodd et al.
A rapid method for preparing synaptosomes: Comparison with alternative procedures
Brain Res
(1981)
DC Shrieve et al.
Heterogeneity of cellular glutathione among cells derived from a murine fibrosarcoma or a human renal cell carcinoma detected by flow cytometric analysis
J Biol Chem
(1988)
MM Bradford
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of dye-binding
Anal Biochem
(1976)
GS Vince et al.
Is enhanced free radical flux associated with increased intracellular proteolysis?
FEBS Lett
(1987)
S Shaw et al.
Acetaldehyde-mediated lipid peroxidation: Role of Superoxide and ferritin
Biochem Biophys Res Commun
(1987)
JY Westcott et al.
In vivo acetaldehyde in the brain of the rat treated with ethanol
Biochem Pharmacol
(1980)

A Zuddas et al.

Acetaldehyde directly enhances MPP⁺ neurotoxicity and delays its elimination from the striatum

Brain Res

(1989)

V Jackson-Lewis et al.

Partial attenuation of chronic fluphenazine-induced changes in regional monoamine metabolism by d-α-tocopherol

Brain Res Bull

(1991)

JD Adams et al.

Biochemical mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Could oxidative stress be involved in the brain?

Biochem Pharmacol

(1991)

G Pezzoli et al.

n-Hexane induces Parkinsonism in rats

Brain Res

(1990)

V Steffen et al.

The effect of a vitamin E deficient diet on amino acid levels in the substantia nigra, striatum and hippocampus of rats

Life Sci

(1994)

R Nordmann et al.

Ethanolinduced lipid peroxidation and oxidative stress in extrahepatic tissues

Alcohol Alcohol

(1990)

Cited by (34)

Alcohol and IL-6 Alter Expression of Synaptic Proteins in Cerebellum of Transgenic Mice with Increased Astrocyte Expression of IL-6
2020, Neuroscience
Citation Excerpt :
One limitation of our studies is that it is unknown if/how the changes in Glu Syn levels would translate into changes in Glu Syn activity. Effects of alcohol on Glu Syn activity has been measured in several studies and show brain region dependent changes, typically a reduction, or no effect (Bell et al., 2016; Bondy and Guo, 1995; Das et al., 2016; Hemmingsen and Jørgensen, 1980). Glu Syn activity was reduced in the cerebellum of rats that drank alcohol (10% v/v in water) as the only liquid for 8 weeks, but this effect was not observed with 4 weeks of drinking, perhaps because of the low BALs (BALs at 4 weeks were 36 mg/dl) (Rouach et al., 1997).
Recent studies indicate that neuroimmune factors, including the cytokine interleukin-6 (IL-6), play a role in the CNS actions of alcohol. The cerebellum is a sensitive target of alcohol, but few studies have examined a potential role for neuroimmune factors in the actions of alcohol on this brain region. A number of studies have shown that synaptic transmission, and in particular inhibitory synaptic transmission, is an important cerebellar target of alcohol. IL-6 also alters synaptic transmission, although it is unknown if IL-6 targets are also targets of alcohol. This is an important issue because alcohol induces glial production of IL-6, which could then covertly influence the actions of alcohol. The persistent cerebellar effects of both IL-6 and alcohol typically involve chronic exposure and, presumably, altered gene and protein expression. Thus, in the current studies we tested the possibility that proteins involved in inhibitory and excitatory synaptic transmission in the cerebellum are common targets of alcohol and IL-6. We used transgenic mice that express elevated levels of astrocyte produced IL-6 to model persistently elevated expression of IL-6, as would occur in alcohol use disorders, and a chronic intermittent alcohol exposure/withdrawal paradigm (CIE/withdrawal) that is known to produce alcohol dependence. Multiple cerebellar synaptic proteins were assessed by Western blot. Results show that IL-6 and CIE/withdrawal have both unique and common actions that affect synaptic protein expression. These common targets could provide sites for IL-6/alcohol exposure/withdrawal interactions and play an important role in cerebellar symptoms of alcohol use such as ataxia.
Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings
2016, Progress in Molecular Biology and Translational Science
Citation Excerpt :
A more recent preclinical study found decreased GAD-67 expression levels, in the BLA, 2 months after 3 weeks of ethanol-diet initiated in adulthood, but not adolescence.170 Another study reported that chronic ethanol consumption decreased glutamine synthetase in the striatum (dorsal vs. ventral was not delineated) but not cortex of rats.171 A contemporary study also reported reduced glutamine synthetase in the brain, although the area of the brain was not identified, after chronic ethanol consumption, which started at the beginning of adolescence.172
Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.
Oxidative stress in anxiety and comorbid disorders
2010, Neuroscience Research
Anxiety disorders, depression, and alcohol use disorder are common neuropsychiatric diseases that often occur together. Oxidative stress has been suggested to contribute to their etiology. Oxidative stress is a consequence of either increased generation of reactive oxygen species or impaired enzymatic or non-enzymatic defense against it. When excessive it leads to damage of all major classes of macromolecules, and therefore affects several fundamentally important cellular functions. Consequences that are especially detrimental to the proper functioning of the brain include mitochondrial dysfunction, altered neuronal signaling, and inhibition of neurogenesis. Each of these can further contribute to increased oxidative stress, leading to additional burden to the brain. In this review, we will provide an overview of recent work on oxidative stress markers in human patients with anxiety, depressive, or alcohol use disorders, and in relevant animal models. In addition, putative oxidative stress-related mechanisms important for neuropsychiatric diseases are discussed. Despite the considerable interest this field has obtained, the detailed mechanisms that link oxidative stress to the pathogenesis of neuropsychiatric diseases remain largely unknown. Since this pathway may be amenable to pharmacological intervention, further studies are warranted.
Ethanol modifies differently aspartyl- and glutamyl-aminopeptidase activities in mouse frontal cortex synaptosomes
2002, Brain Research Bulletin
Aminopeptidase A activity (aspartyl aminopeptidase (AspAP) and glutamyl aminopeptidase (GluAP) exerts angiotensinase activity due to its relation to the metabolism of angiotensins in the regional brain renin-angiotensin system (RAS). This activity may also modify the free amino acid pool through the release of N-terminal acidic amino acids. Ethanol (EtOH) exerts profound effects on the brain, inducing important neurological damages. Our purpose is to study the influence of EtOH on AspAP and GluAP activities on basal and K⁺-stimulated conditions, at the synapse level. We used mouse frontal cortex synaptosomes and their incubation supernatant in a Ca²⁺-containing or Ca²⁺-free artificial cerebrospinal fluid. We evaluate the possible contribution of these enzymatic activities on brain blood pressure regulation through RAS and/or the free acidic amino acid pool. The results obtained are correlated with several parameters of oxidative stress, such as free radical generation, lipid peroxidation, and protein oxidation. Under basal conditions, in synaptosomes, EtOH inhibits AspAP and GluAP activities independently of Ca²⁺. In the supernatant, however, EtOH differently modulates the two enzyme activities under the various concentrations. Under K⁺-stimulated conditions, EtOH inhibits the K⁺-stimulated increase on AspAP and GluAP differently depending on the presence or absence of Ca²⁺ and the concentration of EtOH used. These results invalidate the idea that excess free acidic amino acids could be released by AspAP and GluAP to induce neurodegeneration. The changes in AspAP and GluAP activities as a consequence of EtOH administration and their role in the brain RAS are discussed.
Glutamate-mediated transmission, alcohol, and alcoholism
2000, Neurochemistry International
Glutamate-mediated neurotransmission may be involved in the range of adaptive changes in brain which occur after ethanol administration in laboratory animals, and in chronic alcoholism in human cases. Excitatory amino acid transmission is modulated by a complex system of receptors and other effectors, the efficacy of which can be profoundly affected by altered gene or protein expression. Local variations in receptor composition may underlie intrinsic regional variations in susceptibility to pathological change. Equally, ethanol use and abuse may bring about alterations in receptor subunit expression as the essence of the adaptive response. Such considerations may underlie the regional localization characteristic of the pathogenesis of alcoholic brain damage, or they may form part of the homeostatic change that constitutes the neural substrate for alcohol dependence.
Acetaldehyde cytotoxicity in cultured rat astrocytes
1999, Brain Research
The effect of acetaldehyde on astrocytes have been investigated because not only do they play an important role in brain maturation but also recent reports have shown their delayed proliferation following both `in vivo' and `in vitro' ethanol exposure. Biochemical parameters related to apoptotic and necrotic processes were examined in primary cultures of rat astrocytes exposed for 4 days to acetaldehyde generated from ethanol by co-cultured alcohol dehydrogenase-transfected Chinese hamster ovary cells. Acetaldehyde levels in the culture media attained concentrations of approximately 450 μM. To study ethanol effects, alcohol oxidation was inhibited by 4-methylpyrazole (an inhibitor of alcohol dehydrogenase). Acetaldehyde but not ethanol increased intracellular calcium levels by 155%. Moreover, significant DNA fragmentation was detected using a random oligonucleotide primed synthesis assay, by flow cytometry and when using agar gel electrophoresis. Transglutaminase activity was elevated in the cells treated with acetaldehyde but when acetaldehyde formation was inhibited by 4-methylpyrazole the enzyme activity was unaffected. Nitrate levels in the culture media were unchanged. Additionally, microscopic examination of cell nuclei revealed chromatin condensation in astrocytes exposed to acetaldehyde. It can be concluded, that in `in vitro' acetaldehyde exposed rat astrocytes apoptotic pathways are activated.

View all citing articles on Scopus

View full text

Research paperRegional selectivity in ethanol-induced pro-oxidant events within the brain

Abstract

Brain Res

Toxicol Appl Pharmacol

Biochem Pharmacol

Brain Res

Brain Res

J Biol Chem

Anal Biochem

FEBS Lett

Biochem Biophys Res Commun

Biochem Pharmacol

Brain Res

Brain Res Bull

Biochem Pharmacol

Brain Res

Life Sci

Ethanolinduced lipid peroxidation and oxidative stress in extrahepatic tissues

Alcohol Alcohol

Research paper
Regional selectivity in ethanol-induced pro-oxidant events within the brain