Biomedical subjects

L Oreland

Publications and source records attributed to L Oreland.

At least 19 recordsLinked to original sources

PubMed2004

Semicarbazide-sensitive amine oxidase in transgenic mice with diabetes.

Semicarbazide-sensitive amine oxidase (SSAO) activity in plasma is increased in diabetes, and in particular, in diabetic patients with vascular complications. It has been speculated that SSAO is involved in the development of such complications due to the production of cytotoxic compounds. In this work, we have induced diabetes in a previously described mouse-model, overexpressing SSAO in smooth muscle cells. SSAO activity was estimated as well as expression of the endogenous mouse gene and human transgene using real-time PCR. Diabetes induced an increase in SSAO activity in serum, kidney, and adipose tissue of transgenic animals. An inverse correlation between SSAO activity and mouse SSAO mRNA levels was observed in transgenic animals with diabetes. These results further support the suggestion of a negative feedback control of the SSAO gene expression. The increased SSAO activity in diabetes is most likely dependent on post-transcriptional modifications or activation of existing inactive enzyme molecules.

Adipose Tissue↗

PubMed2004

Platelet MAO and personality--function and dysfunction.

Research on the association between platelet monoamine oxidase (MAO) activity and personality traits, such as sensation seeking and impulsiveness, is reviewed with an emphasis on early history and current situation. The effects of MAO-inhibiting compounds in cigarette smoke for the interpretation of this association are discussed and recent results confirming a true association between platelet MAO activity and personality and vulnerability, for e.g. type 2 alcoholism are presented. From a clinical point of view, the link between platelet MAO activity, which is highly genetically regulated and is stable in the individual, and personality traits, has had its greatest impact on the understanding of the nature of constitutional factors making individuals vulnerable, for e.g. substance abuse and other forms of sociopathic behaviour. The molecular mechanisms underlying the association between platelet MAO and behaviour are discussed and evidence that common transcriptional factors, e.g. within the AP-2 family, regulating both the expression of platelet MAO and components of the central monoaminergic systems, such as synthesising enzymes, receptors and transporters, are presented. A hypothesis is put forward, that such common transcription factors may not directly regulate platelet MAO expression, but rather mitochondrial density, or outer mitochondrial membrane surface.

Animals↗

PubMed2003

Studies on semicarbazide-sensitive amine oxidase in patients with diabetes mellitus and in transgenic mice.

Patients with diabetes mellitus and with vascular complications in particular, exhibit higher plasma activities of semicarbazide-sensitive amine oxidase (SSAO) compared to control subjects. It has been speculated that production of cytotoxic products of SSAO may cause endothelial damage and thus contribute to the development of diabetic vascular complications such as retino-, nephro-, and neuropathies as a result of SSAO activity.In order to explore the possibility that high SSAO activity contributes to the development of vascular complications in diabetes, we have performed two studies in patients with Type-2 diabetes quantifying plasma SSAO activity, HbA(1c), and urinary levels of the SSAO substrate, methylamine. We also examined the prevalence of retinopathy in these patients. Additionally, we have studied a model of transgenic mice expressing human SSAO in smooth muscle cells. The transgenic mice have an increased SSAO activity as well as mRNA expression. Histological studies revealed a specific aorta phenotype with a condensed and rigid vessel wall in some of the transgenic mice. No wild-type animals displayed this phenotype.In conclusion, we suggest that this transgenic mouse model may be of great value for increasing the knowledge about to what extent human SSAO contributes to vascular complications in diabetes, and also to which extent inhibition of SSAO can prevent the development of such complications.

Amine Oxidase (Copper-Containing)↗

PubMed2003

Enhancement of 5-hydroxytryptamine-induced head-twitch response after olfactory bulbectomy.

5-Hydroxytryptamine(2A) receptor agonists evoke the head-twitch response in mice. The head-twitch response in olfactory bulbectomized mice elicited by the administration of 5-hydroxytryptamine (40 microgram/mouse, i.c.v.) was increased about threefold as compared with controls on the 14th day after the operation. The injection of ketanserin (1 mg/kg, i.p.), a 5-hydroxytryptamine(2A) receptor antagonist, inhibited this enhancement of 5-hydroxytryptamine-induced head-twitch response after olfactory bulbectomized. On the 14th day, the number of head-twitch response induced by 5-hydroxytryptophan (40, 80 and 160 mg/kg, i.p.), a precursor of 5-hydroxytryptamine, did not differ between olfactory bulbectomized and control mice. Monoamine oxidase-B activity in the forebrain of olfactory bulbectomized mice was higher than that in controls while monoamine oxidase-A activities were unchanged. The 5-hydroxytryptamine uptake into synaptosomes in the forebrain homogenates of olfactory bulbectomized mice was lower than that in controls. These findings indicate that olfactory bulbectomized causes the enhancement of head-twitch response by a supersensitivity of 5-hydroxytryptamine(2A) receptors in cerebral cortex derived from degeneration of neurons projecting from the olfactory bulb.

5-Hydroxytryptophan↗

PubMed2003

Chronic citalopram treatment induces time-dependent changes in the expression and DNA-binding activity of transcription factor AP-2 in rat brain.

Imbalances in the midbrain monoaminergic systems have been implicated to play a role in neuropsychiatric conditions. Several genes in these systems have binding sites for transcription factor activating protein-2 (AP-2) in their regulatory regions. Thus, AP-2 may be a factor controlling the expression of genes in the monoaminergic systems important for maintaining normal psychiatric functions. The present study indicates that subchronic treatment with the antidepressant citalopram induces time-dependent changes in DNA-binding activity and levels of transcription factor AP-2 in rat whole brain. Rats were treated with citalopram (10 mg/kg) for 1, 3, 7 and 21 days. Animals treated for 7 days had significantly decreased DNA-binding activity and levels of AP-2 alpha and AP-2 beta isoforms when compared to saline-treated animals. There was no observed difference between citalopram- and saline-treated animals after 21 days. Elucidation of the molecular mechanisms underlying mental disorders is important for future drug development, where transcription factors might be important drug targets.

Animals↗

PubMed2003

Further evidence for suicide inhibition of semicarbazide-sensitive amine oxidase in guinea pig lung by 2-bromoethylamine.

The inhibitory effects of 2-bromoethylamine (2-BEA), a derivative of ethylamine, on guinea pig lung semicarbazide-sensitive amine oxidase (SAO) have been studied. Preincubation with 2-BEA time-dependently inhibited SSAO activity. The mode of the initial phase of inhibition was competitive, with a Ki value of 52 microM. After preincubation at 37 degrees C for 2 h, the inhibition was noncompetitive and irreversible, as there was no recovery of SSAO activity by dilution of the inhibited samples. Kinetic analyses confirmed previous results with rat lung SSAO that 2-BEA is a suicide SSAO inactivator with a dissociation constant of 42 microM. This latter value is similar to that of the Ki value (52 microM) for the reversible phase of inhibition by 2-BEA. Addition of the nucleophilic compound 2-mercaptoethanol could not reduce the SSAO inhibition, indicating that inactivation could not be prevented by trapping the enzymatic reaction product from 2-BEA. This finding clearly indicates that the reaction product should not diffuse away from its site of genesis and agrees with one of the characteristics of suicide inhibitors. This conclusively excludes the possibility of an affinity-labeling mechanism.

Amine Oxidase (Copper-Containing)↗

PubMed2002

Smoking only explains part of the associations between platelet monoamine oxidase activity and personality.

Platelet monoamine oxidase (MAO) activity has been shown to be inversely associated with personality traits such as sensation seeking, impulsiveness and extraversion. Those personality traits have also been linked to vulnerability for substance abuse, e.g. tobacco smoking and early onset or "type 2" alcoholism. Compounds in cigarette smoke have been shown to be inhibitors of MAO, which has led several authors to claim that there is no association between alcoholism, which is the most studied psychiatric condition, and platelet MAO if the effect of smoking is removed. With regard to the association between personality and platelet MAO, authors have in general been cautious. In the present paper we describe a number of results which show that there is such an association, both in clinical series if the effect of smoking is removed and in series where smoking have never taken place. A cornerstone in this regard is the significant association between platelet MAO activity and both behaviour/personality, voluntary alcohol intake and biochemical measures of CNS serotonergic activity in non-human primates. Strong evidence that the regulation of platelet MAO activity takes place on a transcriptional level with an involvement of transcription factors, likely to also regulate central monoaminergic activity, are presented.

Blood Platelets↗

PubMed2001

Investigation of the functional effect of monoamine oxidase polymorphisms in human brain.

Monoamine oxidase A and monoamine oxidase B ( MAOA and MAOB) have been suggested to play a role in psychiatric disorders and/or behavioral traits. We have investigated whether different polymorphisms can account for variations in enzyme activity and/or mRNA levels in human brain. Whereas several association studies have been reported previously, this is the first study of the functional effect of MAO DNA variants in human brain. Four polymorphic changes were analyzed: a VNTR located in the MAOA promoter, a VNTR located in the first intron of the MAOA gene, and two single nucleotide polymorphisms located in exon 8 of MAOA and in intron 13 of MAOB. We studied the association of the variants and the resulting haplotypes, with expression levels and enzyme activities of both monoamine oxidases in human cortical brain autopsies. We did not find a significant association of any single MAOA polymorphism with expression levels or enzyme activity in human brain. We did, however, find an association of a particular haplotype with MAOA enzyme levels ( P=0.03). Our results suggest that a novel functional polymorphism that affects enzyme activity in human brain may exist in MAOA. For MAOB, we found a significant association ( P=0.02) between the MAOB intron 13 alleles and different levels of MAOB enzyme activity in human brain. We postulate that there may be a cis-regulatory element in linkage disequilibrium with the B-SNP13 polymorphisms that alters MAOB enzyme activity in human brain.

Autopsy↗

PubMed2001

Levels of transcription factors AP-2alpha and AP-2beta in the brainstem are correlated to monoamine turnover in the rat forebrain.

The transcription factors AP-2alpha and AP-2beta are implicated to play an important role during embryonic development of different parts of the brain, and in targeted regulation of gene expression in the adult brain. Several monoaminergic genes have binding sites for AP-2 in regulatory regions. We have in the present study, analysed the association between AP-2 levels in the brainstem of rats (n=9) and monoamine levels in the frontal cortex, septum and hippocampus. Several regionally specific correlations were found between AP-2alpha and AP-2beta and specific monoamines in the rat forebrain. The data support our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.

Animals↗

PubMed2001

Release of dopamine by perfusion with 1-methyl-4-phenylpyridinium ion (MPP(+)) into the striatum is associated with hydroxyl free radical generation.

In Parkinson's disease (PD), the dopamine (DA) neuronal cell death in the nigrostriatal system has been proposed to be mediated by reactive oxygen radicals such as hydroxyl radicals (.OH). This.OH production may cause lipid peroxidation of cell membranes leading to neuronal cell death. This paper report that the DA-selective neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), (1 nmol/microl per min for 1 h) infusion into the striatum of rats induces elevation of extracellular DA and.OH formation. These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases in non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. To test the involvement of DA release in the.OH generation and lipid peroxidation, the rats were pretreated with reserpine (5 mg/kg, i.v., 24 h before MPP(+) or without MPP(+)) to deplete presynaptic DA. Reserpine treatment alone did not change the levels of DA or 2,3-DHBA, while the combined treatment with both MPP(+) and reserpine clearly decreased 2,3-DHBA, as well as DA levels, compared to those in the group treated with MPP(+) alone. After injection into reserpinized rats, DA at various doses (2, 5 and 10 microM) small increased 2,3-DHBA levels dose-dependently, as compared to the MPP(+) alone-treated group. These results clearly indicate that MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as.OH free radicals. These events may contribute, at least in part, to the nigrostriatal neurons cell death after MPP(+).

1-Methyl-4-phenylpyridinium↗

PubMed2001

Effects of histamine H3-receptor ligands on brain monoamine oxidase in various mammalian species.

The effects of an H3 agonist, R-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in the hypothalamus of rat, monkey and human brains were compared in vitro. The histamine H(3)-receptor ligands competitively inhibited MAO-B, but noncompetitively inhibited MAO-A in all three mammalian species. However, alpha-MeHA inhibited MAO-A more potently than MAO-B at high concentrations in all three species. The K(i) values for MAO-A of alpha-MeHA in hypothalamic homogenates of rat, monkey and human brains were estimated to be 1.1, 1.2 and 1.9 mM, respectively, suggesting that alpha-MeHA cannot behave as a substrate for the MAO inhibitor. In contrast, rat, monkey and human brain MAO-B activities were inhibited by thioperamide, with respective K(i) values of 174.6, 8.2 and 10.8 microM, more potently than MAO-A activity. These results indicate that thioperamide, which elicits a strong activation of histamine release and turnover to N-tele-methylhistamine from histamine, competitively inhibits the conversion of N-tele-methylhistamine to N-tele-methylimidazoleacetic acid in human and monkey brains where MAO-B predominates.

Aged↗

PubMed2001

Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat: effects on behavior and monoamine neurochemistry.

Chronic variable stress (CVS) and manipulations of 5-HT-ergic neurotransmission are increasingly used as animal models of depression. In the present study, CVS for 2 weeks and a partial lesion of 5-HT projections by a small dose of parachloroamphetamine (PCA, 2 mg/kg) were applied independently or in combination. CVS reduced significantly the gain in body weight and increased the number of defecations in the open field test. PCA reduced body weight only within the first 24 h after its administration. Consumption of sucrose solution and its preference to water in non-deprived rats were significantly higher in PCA-pretreated rats 2 weeks after CVS compared to control animals. In the forced swimming test, both PCA and CVS treatments reduced immobility on the first but not the second session. Both treatments reduced significantly the time rats spent in social interaction. CVS also elicited an increase in the weight of the right adrenal, but this effect was not present in the PCA-pretreated group. PCA reduced 5-HT and 5-HIAA levels in the frontal cortex, hippocampus, and septum by approximately 20%. CVS increased HVA levels in the frontal cortex. Applied together, PCA pretreatment and CVS increased dopamine turnover in the frontal cortex. Conclusively, this study has provided evidence that chronic variable stress, which elicited expected physiological and neurochemical changes, does not reduce sucrose intake or preference in non-deprived animals, but, instead, may increase it after partial 5-HT-ergic denervation; and that partial 5-HT-ergic denervation by a low dose PCA treatment has a long-lasting effect on forced swimming and social behavior similar to chronic stress.

Animals↗

PubMed2001

Inhibition of tissue-bound semicarbazide-sensitive amine oxidase by two haloamines, 2-bromoethylamine and 3-bromopropylamine.

Various mammalian tissues contain membrane-bound amine oxidase termed semicarbazide-sensitive amine oxidase (SSAO). A variety of compounds has been identified as relatively selective SSAO inhibitors, but those inhibitors currently available also inhibit monoamine oxidase (MAO). In the present study, inhibitory properties of 2-bromoethylamine (2-BEA) and 3-bromopropylamine (3-BPA) toward rat lung-bound SSAO have been studied. Regardless of preincubation, 2-BEA could not appreciably inhibit MAO-A and MAO-B activity, but 3-BPA at relatively high concentrations inhibited only MAO-B activity. 3-BPA was a competitive and reversible SSAO inhibitor with a Ki value of 17 microM regardless of preincubation. In contrast, without preincubation, 2-BEA competitively inhibited SSAO activity with the Ki value of 2.5 microM and after preincubation, the mode of inhibition changed to be noncompetitive, indicating irreversible inhibition after the preincubation. Dialysis experiments with 2-BEA-pretreated homogenate resulted in no recovery of SSAO activity even after overnight dialysis. A decreased rate of SSAO inhibition under N2 atmosphere to that obtained under O2 was produced upon preincubation of enzyme with 2-BEA, suggesting that oxidized intermediate was necessary for its inhibitory activity. Thus, 2-BEA first interacts with SSAO to form a reversible complex with a subsequent reaction, leading this complex to the covalently bound enzyme-inhibitor adduct. The data analyzed by the plot of 1/k' vs 1/2-BEA concentrations intersected on the y-axis indicate that the inhibition by 2-BEA is not mediated by a bimolecular reaction; thus it is not an affinity-labeling agent, but a suicide SSAO inhibitor. 2-BEA may be employed as a useful compound in the studying SSAO.

Alkylating Agents↗

PubMed2001

Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus.

A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.

Animals↗

PubMed2001

Platelet monoamine oxidase in healthy 9- and 15-years old children: the effect of gender, smoking and puberty.

1. The effect of gender, smoking and pubertal development on platelet monoamine oxidase (MAO) activity was described in a randomly selected, large sample of 9- and 15-years old healthy children. 2. Platelet MAO activity was measured in 1129 children by a radioenzymatic method with beta-phenylethylamine as the substrate. Smoking habits were reported in an anonymous questionnaire. Pubertal status was assessed visually using Tanner's stages. 3. Boys, younger children and smokers had significantly lower platelet MAO activity than girls, older children and non-smokers, respectively. Girls in Tanner's stage V for breast and pubic hair development had significantly lower MAO than girls in stage IV. 4. Differences in gender, age, pubertal status and smoking habits must be taken into account if the relationship between platelet MAO activity, personality and psychiatric disorders is studied in children.

Adolescent↗

PubMed2001

Genetic mechanisms of behavior--don't forget about the transcription factors.

Major changes in psychiatric phenotypes due to genetic factors are seldom the result of single gene polymorphisms, but more often the result of several genetic mechanisms. In this millennium article we discuss the notion that the expression of numerous candidate genes could be regulated by the same transcription factors, and that polymorphisms in transcription factor genes might explain some phenotypes. We describe recent results of studies on the biological marker thrombocyte monoamine oxidase (trbc MAO) and the transcription factor AP-2beta. Low levels of trbc MAO is associated with temperamental characteristics such as sensation seeking and impulsiveness, and the enzyme is genetically regulated by specific transcriptional mechanisms. Transcription factor AP-2beta is important for the development of midbrain structures and AP-2beta has several binding sites in the regulatory regions of genes encoding key proteins in the monoamine transmitter systems. We have recently shown AP-2beta to be linked to personality, binge-eating disorder, treatment with antidepressant drugs, and also to trbc MAO. Regardless of whether transcriptions factors, such as AP-2beta, regulate the expression of eg, the number of monoamine neurons or a variety of candidate genes within the monoamine systems, or both, we would like to emphasize the role of transcription factors, besides polymorphisms in monoaminergic candidate genes, when explaining inter-individual differences in temperament and psychiatric vulnerability.

Animals↗

PubMed2001

Human fear conditioning is related to dopaminergic and serotonergic biological markers.

Biological markers for acquisition and extinction of fear conditioning were studied in 40 individuals selected for displaying either good or poor acquisition of fear conditioning. as estimated by the skin conductance response. Participants with a short serotonin transporter (5-HTT) promoter allele or low monoamine oxidase activity in platelets (trbc-MAO) displayed better acquisition than those with only long alleles or high trbc-MAO, whereas participants with a long dopamine D4 receptor (D4DR) exon III allele showed delayed extinction compared with those with only short alleles. The findings, that D4DR exon III and 5-HTT promoter genotypes and trbc-MAO activity are related to human fear conditioning, a basic form of associative learning, are consistent with animal studies suggesting a genetic contribution to fear conditioning. The authors suggest that in humans these genetic mechanisms are partly dopaminergic and serotonergic in origin.

Alleles↗

PubMed2000

Chronic pharmacological treatment with certain antidepressants alters the expression and DNA-binding activity of transcription factor AP-2.

Several of the genes in the serotonergic and the dopaminergic systems have consensus binding sites for the AP-2 transcription factor family in their regulatory regions. Imbalances in these systems have been implicated in many psychiatric disorders, including depression and bipolar affective disorder. We have made an effort to further elucidate the molecular mechanisms of drugs used for affective disorders. Recently, we analyzed the effects of chronic treatment with certain antidepressants on AP-2 in rat brain. The present study demonstrates that chronic administration of three different classes of antidepressants modulates the DNA-binding activity of AP-2 in the rat brain. Chronic administration of citalopram (10 mg/kg), imipramin (10 mg/kg) and lithium-chloride (40 mg/kg) significantly decreased DNA-binding activity of AP-2. Furthermore, citalopram (10 mg/kg) and imipramin (10 mg/kg) significantly decreased the amount of AP-2alpha protein as determined by ELISA. In addition, citalopram (10 mg/kg) significantly decreased the amount of AP-2beta protein. In contrast, chronic administration of lithium-chloride (40 mg/kg) did not affect the amount of the two AP-2 isoforms. An increased understanding of the function of transcription factors and their involvement in human disease, such as depression, could make it possible in the future to selectively modulate relevant target genes directly.

Animals↗