Gene expression profiling of cytochromes P450, ABC transporters and their principal transcription factors in the amygdala and prefrontal cortex of alcoholics, smokers and drug-free controls by qRT-PCR.

1. Ethanol consumption and smoking alter the expression of certain drug-metabolizing enzymes and transporters, potentially influencing the tissue-specific effects of xenobiotics. 2.

Expression of CYP2E1 and CYP2U1 proteins in amygdala and prefrontal cortex: influence of alcoholism and smoking.

Background: The tissue-specific expression of cytochrome P450 enzymes (CYP, P450) in the human brain may influence the therapeutic response to, and side effects of, neuroactive drugs including alcohol. However, the distribution of many P450s, especially poorly characterized CYP2 forms, within specific regions of the brain remains obscure, partly due to the paucity of available tissue and difficulty in discriminating between related P450s with available antibodies.

Methods: In this study, we analyzed the expression of CYP2A6, CYP2B6, CYP2D6, CYP2E1, CYP2J2, CYP2S1, CYP2U1, and CYP2W1 proteins in human prefrontal cortex (PFC) and amygdala (AMG) by immunoblotting with antibodies for which the P450 form specificity had been enhanced by affinity purification.

Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain.

Cytochrome P450 enzymes from the CYP2C subfamily play a prominent role in the metabolic clearance of many drugs. CYP2C enzymes have also been implicated in the metabolism of arachidonic acid to vasoactive epoxyeicosatrienoic acids. CYP2C8, CYP2C9, and CYP2C19 are expressed in the adult liver at significant levels; however, the expression of CYP2C enzymes in extrahepatic tissues such as the brain is less well characterized.

Differential expression of human cytochrome P450 enzymes from the CYP3A subfamily in the brains of alcoholic subjects and drug-free controls.

Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40-50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically.

MALAT-1, a non protein-coding RNA is upregulated in the cerebellum, hippocampus and brain stem of human alcoholics.

Chronic alcohol intake induces neurochemical adaptative changes in the brain characterised by altered gene expression. A role for non-coding RNAs in alcoholism is beginning to emerge. PCR-differential display using total RNA extracted from brain material of human alcoholics and control cases identified a cDNA fragment corresponding to a section of a known non protein-coding RNA (ncRNA), MALAT-1, (also known as NEAT2).

Effects of exercise and antioxidant supplementation on endothelial gene expression.

Background: The molecular mechanisms of exercise training induced cardiovascular protection are poorly understood. There is growing evidence that reactive oxygen species may be involved in a number of these adaptations and that antioxidants may be used to investigate this effect.

Objective: To determine the effects of exercise training and/or antioxidant supplementation on myocardial endothelium and vascular endothelium gene expression.

Genes associated with alcohol abuse and tobacco smoking in the human nucleus accumbens and ventral tegmental area.

Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown, but interactions between these drugs have important implications for the development of and recovery from drug dependence.

Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the 2 behaviors on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity.

The effects of alcoholism on the human basolateral amygdala.

Alcohol affects gene expression in several brain regions. The amygdala is a key structure in the brain's emotional system and in recent years the crucial importance of the amygdala in drug-seeking and relapse has been increasingly recognized. In this study gene expression screening was used to identify genes involved in alcoholism in the human basolateral amygdala of male patients.

The effect of alcohol and nicotine abuse on gene expression in the brain.

Alcohol intake at levels posing an acute heath risk is common amongst teenagers. Alcohol abuse is the second most common mental disorder worldwide. The incidence of smoking is decreasing in the Western world but increasing in developing countries and is the leading cause of preventable death worldwide.

Ethanol neurotoxicity and dentate gyrus development.

Maternal alcohol ingestion during pregnancy adversely affects the developing fetus, often leading to fetal alcohol syndrome (FAS). One of the most severe consequences of FAS is brain damage that is manifested as cognitive, learning, and behavioral deficits. The hippocampus plays a crucial role in such abilities; it is also known as one of the brain regions most vulnerable to ethanol-induced neurotoxicity.

Impact of alcohol abuse on protein expression of midkine and excitatory amino acid transporter 1 in the human prefrontal cortex.

Background: Alcoholism is associated with shrinkage of brain tissue and reduction in the number of neurons and dendritic arbors particularly in the prefrontal cortex. These changes correlate with the cognitive defects common in alcoholics. A recent study investigated the mRNA expression of selected genes in the prefrontal cortex and found that the levels of mRNA encoding the neurotrophic factor, midkine (MDK), and the excitatory amino acid transporter 1 (EAAT1) were significantly higher in alcoholics compared with nonalcoholic controls.

Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.

Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain.

Cerebellar vermis proteome of chronic alcoholic individuals.

Background: Cerebellar changes are commonly associated with alcoholism and chronic alcohol consumption can produce profound impairments in motor functioning and various aspects of cognition. Although the mechanisms underlying alcohol-induced changes in the cerebellar vermis are poorly understood, observations in the alcoholic vermis are thought to be consequential to common alcohol-related factors, particularly thiamine deficiency.

Methods: In the present study, we used a proteomics-based approach to compare protein expression profiles of the cerebellar vermis from human alcoholic individuals (both neurologically uncomplicated and alcoholic individuals complicated with liver cirrhosis) and healthy control brains.

Differential protein expression in the corpus callosum (splenium) of human alcoholics: a proteomics study.

It is widely accepted that the chronic use of alcohol induces metabolic abnormalities and neuronal damage in the brain, which can lead to cognitive dysfunction. Neuroimaging studies reveal that alcohol-induced brain damage is region specific and prominent damage has been observed in both gray and white matter of the prefrontal cortex, and a wide range of white matter structures including the corpus callosum. Molecular mechanisms underlying these structural changes are largely unknown.

Neuronal protein 22 colocalises with both the microtubule and microfilament cytoskeleton in neurite-like processes.

The expression of human neuronal protein 22 (hNP22) is up-regulated in the superior frontal cortex of chronic alcoholics. hNP22 shares significant homology with a number of proteins implicated in bundling of actin filaments. In addition, it contains domains similar to those found in microtubule-associated proteins.

Chronic smoking and alcoholism change expression of selective genes in the human prefrontal cortex.

Background: Alcoholism is commonly associated with chronic smoking. A number of gene expression profiles of regions within the human mesocorticolimbic system have identified potential alcohol-sensitive genes; however, the influence of smoking on these changes was not taken into account. This study addressed the impact of alcohol and smoking on the expression of 4 genes, previously identified as alcoholism-sensitive, in the human prefrontal cortex (PFC).

The novel cytoskeleton-associated protein Neuronal protein 22: elevated expression in the developing rat brain.

Neuronal development and process targeting is mediated by proteins of the cytoskeleton. However, the signaling pathways underlying these mechanisms are complex and have not yet been fully elucidated. Neuronal protein 22 (NP22) has been identified as a cytoskeleton-associated protein.

Comparative gene expression in brain regions of human alcoholics.

The mesocorticolimbic system is the reward centre of the brain and the major target for drugs of abuse including alcohol. Neuroadaptive changes in this region are thought to underlie the process of tolerance and dependence. Recently, several research groups have searched for alcohol-responsive genes using high-throughput microarrays and well-characterized human post-mortem material.

Ethanol prevents NMDA receptor reduction by maternal separation in neonatal rat hippocampus.

We measured the effects of ethanol on glutamate receptor levels in the hippocampus of neonatal Wistar rats using a vapor chamber model. Two control groups were used; a normal suckle group and a maternal separation group. Levels of NMDA receptors were not significantly altered in ethanol-treated animals compared to the normal suckle control group, as shown by [3H]MK-801 binding and Western blot analysis.

Changes in neuronal protein 22 expression and cytoskeletal association in the alcohol-dependent and withdrawn rat brain.

The action of alcohol on neuronal pathways has been an issue of increasing research focus, with numerous findings contradicting the previously accepted idea that its effect is nonspecific. The human NP22 (hNP22) gene was revealed by its elevated expression in the frontal cortex of the human alcoholic. The sequences of hNP22 and the rat orthologue rNP22 contain a number of domains consistent with those of cytoskeletal-interacting proteins.

Alcohol-responsive genes in the frontal cortex and nucleus accumbens of human alcoholics.

The molecular processes underlying alcohol dependence are not fully understood. Many characteristic behaviours result from neuroadaptations in the mesocorticolimbic system. In addition, alcoholism is associated with a distinct neuropathology.

Expression of human neuronal protein 22, a novel cytoskeleton-associated protein, was decreased in the anterior cingulate cortex of schizophrenia.

Human neuronal protein 22 (hNP22) is a novel neuron-specific protein featuring numerous motifs previously described in cytoskeleton-associating and signaling proteins. Because previous studies have supported abnormalities in neuronal cytoarchitecture and/or development in the schizophrenia brain, we examined the expression of hNP22 in the anterior cingulate cortex, the hippocampus and the prefrontal cortex of schizophrenic and normal control postmortem brains using high-sensitive immunohistochemistry. Seven schizophrenic and seven age- and sex-matched control brains were examined.

Genetic study of alcoholism and novel gene expression in the alcoholic brain.

Alcohol dependence may result from neuroadaptation involving alteration of gene expression after long-term alcohol exposure. The systematic study of gene expression profiles of the human alcoholic brain was initiated using the method of polymerase chain reaction (PCR)-differential display and was followed by DNA microarray. To date, more than 100 alcohol-responsive genes have been identified from the frontal cortex, motor cortex and nucleus accumbens of the human brain.

Effects of age and alcohol exposure during early life on pyramidal cell numbers in the CA1-CA3 region of the rat hippocampus.

We have previously shown that exposing rats to a relatively high dose of ethanol during early postnatal life can result in an alteration in spatial learning ability. The hippocampal formation is known to be involved in the control of this ability. The purpose of the present study was to determine whether exposure of rats to ethanol during early postnatal life had either immediate or delayed effects on the numbers of pyramidal cells in the CA1-CA3 subregion of the hippocampus.

Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain.

Background: Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins.