Biomedical subjects

A Nordberg

Publications and source records attributed to A Nordberg.

At least 19 recordsLinked to original sources

PubMed2001

Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla.

Neuronal nicotinic receptors (nAChRs) are expressed in the brain but also in the peripheral tissues including the adrenal medulla. However, it is unclear which nAChRs are present in the human adrenal medulla. In the study, receptor binding assay, Western blot and RT-PCR have been performed to investigate the expression of nAChRs in adrenal medulla from human, rat and mouse. The results showed that in human adult adrenal medulla, mRNAs for nAChR alpha3, alpha4, alpha5, alpha7, beta2, beta3, and beta4 subunits but not beta2 in the fetal human adrenal medulla were expressed. Saturation binding of [3H]epibatidine showed two binding sites in human aged adrenal medulla. The specific binding of [3H]epibatidine (0.1 nM) was significantly higher in human fetal compared to human aged adrenal medulla. mRNAs for the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 subunits but not the beta3 were detectable in adult rat and mouse adrenal medulla. No differences in gene-expression of the nAChRs were observed between new born, adult and aged rat adrenal medulla. Saturation binding of [3H]epibatidine showed only one binding site in rat adrenal medulla. Lower protein levels for the nAChR subunits were observed in the rat adrenal medulla compared to rat brain. There was lower protein levels of the nAChRs in aged rat adrenal medulla compared to the young rats. Sub-chronic treatment of nicotine to rats did not influence level of the nAChRs in the adrenal medulla. In conclusion, the expression of nAChRs in adrenal medulla is age- related and species dependent.

Adrenal Medulla↗

PubMed2001

Reduced expression of neuronal nicotinic acetylcholine receptors during the early stages of damage by oxidative stress in PC12 cells.

The mechanism for a large loss of neuronal nicotinic acetylcholine receptors (nAChRs) in brains with neurodegenerative diseases remains unclear. Based on our previous results of [(3)H]epibatidine binding influenced by lipid peroxidation, we suggest that nAChR deficit in neurodegenerative diseases might be related to the neurons attacked by free radicals. To further understand how free radicals influence the expression of nAChRs, we detected [(125)I]alpha-bungarotoxin binding, nAChR subunit protein and mRNA during the early stage of damage by oxidative stress in PC12 cells in the present study. The results showed that free radical insult (FeSO(4)) within the concentration range (1 -100 microM) used in the study induced dose-dependent increases in lipid peroxidation and toxicity to PC12 cells, but did not result in apoptosis or necrosis. Significant reductions in [(125)I]alpha-bungarotoxin binding site, protein level for the alpha3 and alpha7 subunits, and mRNA level for the alpha7 subunit were observed in PC12 cells treated by FeSO(4) at the concentrations without inducing cell death compared to control. Pretreatment of cultural cells with antioxidant such as Vitamin E and reduced glutathione prevented the inhibiting effect of free radicals on [(125)I]alpha-bungarotoxin and [(3)H]epibatidine bindings. The present results further demonstrate that oxidative stress might reduce the number of [(125)I]alpha-bungarotoxin binding site and selectively suppress the expression of the nAChR subunits at protein and mRNA levels during the early stages of damage in PC12 cells.

Animals↗

PubMed2001

Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment.

The objective of this study was to assess whether reduced glucose metabolism (rCMRGlu) and cognitive functioning could predict development of Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Twenty MCI patients underwent baseline and follow-up investigations of rCMRGlu, as measured by PET, and cognitive function measured by neuropsychological test assessments. Subjects were clinically followed up with an average interval of 36.5 months. Two groups were obtained after the second clinical assessment. Nine patients were diagnosed as AD and classified as progressive MCI (P-MCI), whereas 11 patients remained clinically stable and were classified as stable MCI (S-MCI). There were no differences in demographic variables or baseline MMSE between the two subgroups. Logistic regression indicated the two variables that most effectively predicted future development of AD were rCMRGlu from the left temporoparietal area and performance on the block design. These combined measures gave an optimal 90% correct classification rate, whereas only rCMRGlu or neuropsychology alone gave 75% and 65% correct classification, respectively. Measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to AD for patients with MCI.

Aged↗

PubMed2001

Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications.

The neuronal nicotinic acetylcholine receptors (nAChRs) in the brain are important for functional processes, including cognitive and memory functions. The nAChRs acting as neuromodulators in communicative processes regulated by different neurotransmitters show a relatively high abundance in the human cortex, with a laminar distribution of the nAChRs of superhigh, high, and low affinity in the human cortex. The regional pattern of messenger RNA (mRNA) for various nAChR subtypes does not strictly follow the regional distribution of nAChR ligand-binding sites in the human brain. Consistent losses of nAChRs have been measured in vitro in autopsy brain tissue of Alzheimer's disease patients (AD), as well as in vivo by positron emission tomography (PET). Measurement of the protein content of nAChRs showed reduced levels of the alpha4, alpha3, and alpha7 nAChR subtypes. The finding that the alpha4 and alpha3 mRNA levels were not changed in AD brains suggests that the losses in high-affinity nicotinic-binding sites cannot be attributed to alterations at the transcriptional level of the alpha4 and alpha3 genes and that the causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of the alpha7 nAChR subtyep in the hippocampus indicates that subunit-specific changes in gene expression of the alpha7 nAChR might be associated with AD. The PET studies reveal deficits in nAChRs as an early phenomena in AD, stressing the importance of nAChRs as a potential target for drug intervention. PET ligands measuring the alpha4 nAChRs are under development. Studies of the influence of beta-amyloid on nAChRs in brain autopsy tissue from patients with the amyloid precursor protein 670/671 mutation have shown that there is no direct relationship between nAChR deficits and pathology. Treatment with cholinergic drugs in AD patients indicate improvement of the nAChRs in the brain, as visualized by PET. Further studies on neuroprotective mechanisms mediated via nAChR subtypes are exciting new avenues.

Aged↗

PubMed2001

Suppressed expression of nicotinic acetylcholine receptors by nanomolar beta-amyloid peptides in PC12 cells.

A line of evidence has shown that a link between the common pathological features of beta-amyloid peptide (Abeta) deposition and cholinergic degeneration observed in Alzheimer's disease (AD) may exist, however, no experimental evidence has shown that exposure to Abeta can decrease expression of nicotinic acetylcholine receptors (nAChRs), which have been shown to play roles in brain cognitive functions. Here, we report that treatment with Abeta1-40 and Abeta25-35 at nanomolar concentrations significantly decreased the [3H]epibatidine and [125I]alpha-bungarotoxin binding sites, the protein and mRNA levels of nAChR alpha3, alpha7 and beta2 subunits in PC12 cells. Abeta1-40 and Abeta25-35 at the concentrations used in the treatment study neither bound to nAChRs nor induced apoptosis, but significantly inhibited the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromide) reduction. These data suggest that the decreased biosynthesis of nAChRs induced by Abeta may be attributable partially to perturbances of some intracellular signal transduction pathways. The results presented in this study lead to a hypothesis that Abeta can degenerate nAChRs early in the course of AD before the formation of abundant Abeta fibrils.

Acetylcholine↗

PubMed2001

Nicotine-induced alterations in the expression of nicotinic receptors in primary cultures from human prenatal brain.

The nicotinic receptor proteins and gene transcripts for the different nicotinic receptor subunits exist in human prenatal brain already at 4-5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [(3)H]epibatidine (labelling both the alpha3 and alpha4 subtype) and [(3)H]cytisine (labelling the alpha4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5-11 weeks of gestation), the highest specific binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The effects of nicotine exposure were studied in primary cultures of prenatal brain (7.5-11 weeks of gestation). Treatment with nicotine (1-100 microM) for 3 days significantly increased the specific binding of [(3)H]epibatidine and [(3)H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-specific differences in the sensitivity to nicotine exposure. Relative quantification of mRNA showed that the expression of the nicotinic receptor subunits alpha3 and alpha7, but not alpha4, was increased in cortical cells after nicotine treatment. These findings support the assumption of a potential risk of disturbance in the functional role of nicotinic receptors during brain development as a consequence of maternal smoking during pregnancy.

Alkaloids↗

PubMed2001

Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia.

The laminar cortical distribution of the [125I]alpha-bungarotoxin, [3H]cytisine and [3H]epibatidine nicotinic acetylcholine receptor ligands was investigated by quantitative autoradiography in autopsy tissue from the cingulate, orbitofrontal and temporal cortices of control and schizophrenia subjects matched for age and smoking history. Different laminar binding patterns were observed for the various nicotinic ligands both in schizophrenic and control brains. [125I]alpha-Bungarotoxin binding was distributed homogeneously across all cortical layers in all three brain regions, with highest binding densities in the cingulate cortex. [3H]Cytisine and [3H]epibatidine binding varied across the cortical ribbon, with high binding in layers I, III, V and VI, within the three cortical regions. A significantly reduced [125I] alpha-bungarotoxin binding (-54%) was observed in the cingulate cortex of schizophrenia subjects, in comparison with normal individuals who smoked tobacco. In the same brain region also a significantly higher [3H]cytisine binding (48-77%) was observed in nearly all layers, except for layer I of the schizophrenia subjects, when compared to normal individuals with a history of tobacco use. No significant changes in [3H]epibatidine binding was observed within the individual cortical layers between control subjects and patients with schizophrenia, but when calculated as a whole region (i.e. measurements performed across the whole cortical ribbon), the temporal cortex showed a significant increase in [3H]epibatidine binding in schizophrenia subjects compared to control subjects. The results suggest opposite changes of the alpha4beta2 and alpha7 nicotinic receptor subtypes in the cingulate cortex of patients with schizophrenia which might reflect involvement of two different nicotinic receptor mechanisms in schizophrenia brain.

Acetylcholine↗

PubMed2001

Mechanisms of alcohol-nicotine interactions: alcoholics versus smokers.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Bo Söderpalm. The presentations were (1) Nicotinic mechanisms and ethanol reinforcement: Behavioral and neurochemical studies, by Bo Söderpalm, M. Ericson, P. Olausson, and J. A. Engel; (2) Chronic nicotine and ethanol: Differential regulation in gene expression of nicotinic acetylcholine receptor subunits, by X. Zhang and A. Nordberg; (3) Nicotine-ethanol interactions at neuronal nicotinic acetylcholine receptors, by Toshio Narahashi, William Marszalec, and Gary L. Aistrup; (4) Relapse prevention in alcoholics by cigarette smoking? Treatment outcome in an observational study with acamprosate, by L.G. Schmidt, U. Kalouti, M. Smolka, and M. Soyka; and (5) Effect of nicotine on voluntary ethanol intake and development of alcohol dependence in male rats, by L. Hedlund and G. Wahlström.

Acamprosate↗

PubMed2000

Preface.

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Journal Article↗

PubMed2000

Influence of lipid peroxidation on the nicotinic acetylcholine receptors in PC12 cells.

The expression of neuronal nicotinic acetylcholine receptors (nAChRs) influenced by lipid peroxidation has been investigated. The results showed that exposure of PC12 cells to a free radical insult (FeSO(4)) induced concentration-dependent increase in level of MDA (malondialdehyde), and a significant decline in MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] reduction. In cultured cells exposed to FeSO(4), a significant dose-dependent decrease in [(3)H] epibatidine binding sites was detected and a significant reduction in B(max) value was observed in the high affinity epibatidine binding site. These results demonstrate that lipid peroxidation in cellular membranes can induce a reduction in numbers of neuronal nAChRs.

Animals↗

PubMed2000

Rats exhibiting acute behavioural tolerance to nicotine have more [125I]alpha-bungarotoxin binding sites in brain than rats not exhibiting tolerance.

Adult male Sprague-Dawley rats trained to discriminate nicotine (0.4 mg/kg, s.c. vs vehicle) using a two-lever food-reinforced operant discriminative stimulus (DS) paradigm were tested as to the ability of each subject to develop acute tolerance to nicotine. Nicotine (0.8 mg/kg, s.c.) was administered to nicotine-trained rats in their home cage and each rat tested as to its ability to detect a 2nd dose of nicotine (0.4 mg/kg, s.c.) injected at 30 min intervals thereafter (90-180 min). Tolerance was determined by evaluating nicotine-correct responding during a 2 min test session. The results of this experiment indicated that 8 out of 31 rats (26%) displayed acute tolerance (desensitizers); 18 rats (58%) did not exhibit acute tolerance (non-desensitzers) and five rats (16%) fell into a middle group and were designated as neither desensitizers or non-desensitizers. The mode time for acute tolerance was 150 min, with each desensitizer rat displaying a unique temporal profile which was replicable 4-5 weeks later. Receptor autoradiographic analysis indicated no significant differences in [3H]epibatidine binding sites in the brains of desensitizers and non-desensitizers. In contrast, [125I]alpha-bungarotoxin binding was significantly higher in a number of brain regions in desensitizers. In situ hybridization analysis revealed no difference in alpha7 nAChR subunit mRNA levels between desensitizers and non-desensitizers. These observations can be interpreted to suggest that the ability to display acute tolerance to nicotine is contingent upon the ability to upregulate alpha7 nAChRs. These data may also be central to understanding the variability of tobacco use in humans, which may be contingent on the ability of the receptors binding to alpha-bungarotoxin to be responsive to nicotine-induced desensitization.

Animals↗

PubMed2000

Development of ligands for in vivo imaging of cerebral nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(-)-nicotine, radiolabeled with 11C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs.

Animals↗

PubMed2000

Apolipoprotein E varepsilon4 allele has an impact on vascular reactivity in Alzheimer's disease.

Seventeen otherwise healthy, non-smoking patients with probable Alzheimer's disease (AD) and 11 healthy, non-smoking, age-matched controls participated in a study of vascular reactivity. Three substances were iontophoresed into the skin: sodium nitroprusside (SNP) delivered at the cathode, and acetylcholine chloride and isoprenaline sulphate delivered at the anode. The resultant vasodilation was mapped through a laser Doppler perfusion imager. The patients harbouring the Apolipoprotein E varepsilon4 allele (ApoE4) (n=9) showed significantly greater vasodilation compared both with patients without the ApoE4 and with controls (one control possessed the ApoE4) when SNP was delivered at the cathode. An additional study of ten of the AD patients and ten controls suggested that the enhanced reactivity in the patients with the ApoE4 depended on a greater sensitivity to the iontophoretic current itself at the cathode rather than to SNP. The quotient between total cholesterol and high-density lipoprotein-cholesterol was higher in the patients with the ApoE4 compared both with patients without the ApoE4 and with controls. A dysfunction of voltage-dependent ion channels and/or other membrane abnormalities in AD patients possessing the ApoE4 is suggested.

Journal Article↗

PubMed2000

Neuronal nicotinic receptors in the human brain.

Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand gated ion channels which are widely distributed in the human brain. Multiple subtypes of these receptors exist, each with individual pharmacological and functional profiles. They mediate the effects of nicotine, a widely used drug of abuse, are involved in a number of physiological and behavioural processes and are additionally implicated in a number of pathological conditions such as Alzheimer's disease, Parkinson's disease and schizophrenia. The nAChRs have a pentameric structure composed of five membrane spanning subunits, of which nine different types have thus far been identified and cloned. The multiple subunits identified provide the basis for the heterogeneity of structure and function observed in the nAChR subtypes and are responsible for the individual characteristics of each. A substantial amount of information on human nAChR structure and function has come from studies on neuroblastoma cell lines which naturally express nAChRs and from recombinant nAChRs expressed in Xenopus oocytes. In vitro brain nAChR distribution can be mapped with a number of appropriate agonist and antagonist radioligands and subunit distribution may be mapped by in situ hybridization using subunit specific mRNA probes. Receptor distribution in the living human brain can be studied with noninvasive imaging techniques such as PET and SPECT, with a significant reduction in nAChRs in the brains of Alzheimer's patients having been identified with [11C] nicotine in PET studies. Despite the significant body of knowledge now accumulated about nAChRs, much remains to be elucidated. This review will attempt to describe the current knowledge on the nAChR subtypes in the human brain, their functional roles and neuropathological involvement.

Animals↗

PubMed2000

Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer's disease.

BACKGROUND: Since the measurement of human cerebral glucose metabolism (GluM) by positron emission tomography (PET) and that of human cerebral electrical activity by EEG reflect synaptic activity, both methods should be related in their cerebral spatial distribution. Healthy subjects do indeed demonstrate similar metabolic and neuroelectric spatial patterns. OBJECTIVE: The aim of the study was to show that this similarity of GluM and EEG spatial patterns holds true in a population with a high variability of glucose metabolism. METHODS: We investigated healthy control subjects and patients with varying degrees of cognitive dysfunction and varying GluM patterns by applying [18F]FDG PET and EEG. RESULTS: We demonstrated that the localization of intracerebral generators of EEG correlates with spatial indices of GluM. CONCLUSION: These results indicates that EEG provides similar spatial information about brain function as GluM-PET. Since EEG is a non-invasive technique, which is more widely available and can be repeated more often than PET, this may have important implications both for neuropsychiatric research and for clinical diagnosis. However, further studies are required to determine whether equivalent EEG dipole generators can yield a diagnostic specificity and sensitivity similar to that of GluM-PET.

Aged↗

PubMed2000

Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain.

The neuronal nicotinic acetylcholine receptors (nAChR) are involved in functional processes in brain including cognitive function and memory. A severe loss of the nAChRs has been detected in brain of patients with Alzheimer's disease (AD). There is a great interest to image nAChRs noninvasive for detection of receptor impairments even at a presymptomatic stage of AD as well for monitoring outcome of drug treatment. (S) [11C]Nicotine, has so far been the only nAChR ligand used in positron emission tomography (PET) studies for visualizing nAChRs in human brain. In order to develop PET/SPECT nAChRs ligands for detection of subtypes of nAChRs nicotine analogues, epibatidine and A-85380 compounds have been characterized in vitro and investigated in vivo. Epibatidine and A-85380 have been found to have higher specific signals and more favorable kinetic parameters than nicotine and its analogues. The epibatidine and A-85380 compounds can also be radiolabeled with high specific radioactivity, show affinities for the nAChRs in the pM range and readily cross the blood-brain barrier. In addition they reversibly bind to the nAChRs and show low non-specific binding and moderately fast metabolism. Due to a probably high alpha4beta2 nAChR selectivity combined with low toxicity, the A-85380 analogs presently seem to be the most promising nAChR ligand imaging of subtypes of nAChRs in human brain.

Alzheimer Disease↗

PubMed2000

Decreased protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer's disease.

Deficits of cortical nicotinic acetylcholine receptors (nAChRs) have been observed in Alzheimer's disease (AD) by receptor binding assays. Little is known about the receptor subunit specificity influenced by AD, and it might be of importance for therapeutic strategies. In the present study, the protein levels of nAChR alpha3, alpha4, alpha7, and beta2 subunits were investigated using western blot analysis on postmortem brains of patients with AD and age-matched controls. The results showed that in human postmortem brain samples, bands with molecular masses of 52, 42, and 50 kDa were detected by anti-alpha4, anti-alpha7, and anti-beta2 antibodies, respectively. When anti-alpha3 antibody was used, one major band of 49 kDa and two minor bands of 70 and 38 kDa were detected. In AD patients, as compared with age-matched controls, the alpha4 subunit was reduced significantly by approximately 35 and 47% in the hippocampus and temporal cortex, respectively. A significant reduction of 25% in the alpha3 subunit was also observed in the hippocampus and a 29% reduction in the temporal cortex. For the alpha7 subunit, the protein level was reduced significantly by 36% in the hippocampus of AD patients, but no significant change was detected in the temporal cortex. In neither the hippocampus nor the temporal cortex was a significant difference observed in the beta2 subunit between AD patients and controls. These results reveal brain region-specific changes in the protein levels of the nAChR alpha3, alpha4, and alpha7 subunits in AD.

Aged↗

PubMed2000

Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists.

Several cholinesterase inhibitors used in the treatment of Alzheimer's disease (AD) have been shown to interact with an allosteric site on the nicotinic acetylcholine receptor (nAChR). A possible linkage between the phosphorylation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72 h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M), and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M) increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The increased tau immunoreactivity induced by tacrine was not prevented by atropine, indicating that in terms of cholinergic receptors, tacrine modulates tau levels mainly through interactions with nAChRs and not with muscarinic receptors. Additional work is needed to determine the exact mechanism by which cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and levels of tau protein.

Alkaline Phosphatase↗