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51.
Véronique Strijckmans Michel Bottlaender Humin Luo Michèle Ottavianil Daniel W. McPherson Christian Loc'h Chantal Fuseau Furn F. Knapp Bernard Mazière 《European journal of nuclear medicine and molecular imaging》1997,24(5):475-482
We studied the potential of three radiobrominated isomers of BrQNP, (Z(-,-)-[76Br]BrQNP,E(-,-)-[76Br]BrQNP andE(-,+)-[76Br]BrQNP), as suitable radioligands for imaging of central muscarinic cholinergic receptors in the human brain. These radioligands were stereospecifically prepared by electrophilic radiobromodestannylation of the respective tributylstannyl precursors using no-carrier-added [76Br]BrNH4 and peracetic acid. Preliminary pharmacological characterizations were determined by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented important specific uptakes in brain muscarinic cholinergic receptor (mAChR)-rich structures and in heart, low metabolization rates and an apparent M2 selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M1 selectivity. Reversibility of the binding was confirmed for the three radiotracers. Positron emission tomography in the living baboon brain revealed high and rapid uptake in the brain and accumulation in the mAChR-rich structures studied. At 30 min p.i., theE(-,-)-radiotracer reached a plateau in cortex, pons and thalamus with concentrations of 29%, 24% and 19% ID/l, respectively.Z(-,-)-[76Br]BrQNP also accumulated in these structures, reaching a maximal uptake (27% ID/l) in the cortex 2 h p.i. At 5 min p.i. a plateau (17% ID/l) was only observed in the cortex for theE(-,+)-[76Br]BrQNP; by contrast, the other structures showed slow washout. After 3 weeks, the (-,-)-radiotracers were studied in the same baboon pretreated with dexetimide (1 mg/kg), a well-known muscarinic antagonist. In all the mAChR structures, the highly reduced uptake observed after this preloading step indicates that these radiotracers specifically bind to muscarinic receptors.Z(-,-)-[76Br]BrQNP, which is displaced in higher amounts from M2 mAChR-enriched structures, reveals an M2 affinity. The two isomers having the (-,-)-configuration are potential probes for investigating central muscarinic receptors. The absolute configuration on the acetate chiral centre influences their muscarinic subtype selectivity and thecis-trans isomerism of the vinyl moiety affects their specific fixation. 相似文献
52.
Previous work from our laboratory showed that spontaneous contractile activity of jejunal smooth muscle increases after small
bowel transplantation. Our aim was to determine whether small bowel transplantation alters the function of nonadrenergic,
noncholinergic (NANC) nerves. Seven groups of rats, (n ≥7 in each group) were studied as follows: 1 week after sham celiotomy
and 1 week and 8 weeks after 45 minutes of ischemia/ reperfusion (IR1 and IR8), jejunal and ileal transection and reanastomosis
(TR1 and TR8), or orthotopic small bowel transplantation (TX1 and TX8). Contractility of jejunal circular muscle strips was
studied in vitro. Spontaneous contractile activity increased in the IR1, TR1, and TX1 and TX1 and TX8 groups (P<0.01). Under NANC conditions, spontaneous activity increased in TR1 and in both TX1 and TX8 (P<0.01) despite the lack of an increase in the frequency of contraction in TX1. Electrical field stimulation inhibited contractile
activity at low frequencies, but under NANC conditions this inhibition persisted at higher frequencies. The calculated equieffective
frequency (F100) that produced a response equal to baseline contractile activity was similar in all groups, but under NANC conditions was
greater in TX1 (P<0.025). Functional alterations of NANC nerves are partly responsible for the increase in spontaneous activity in rat jejunal
circular muscle strips after a limited ischemia/reperfusion injury, after selective disruption of enteric neural continuity
(transection/reanastomosis), and after small bowel transplantation. These findings may provide important insight into graft
dysfunction after small bowel transplantation in humans.
Supported by United States Public Health Service grant DK 39337 from the National Institutes of Health and by the Mayo Foundation. 相似文献
53.
Michael P Hill Erwan Bezard Steven G McGuire Alan R Crossman Jonathan M Brotchie Ann Michel Renee Grimée Henrik Klitgaard 《Movement disorders》2003,18(11):1301-1305
Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action. 相似文献
54.
55.
Louise Nadon Jack Siemiatycki Ron Dewar Daniel Krewski Michel Grin 《American journal of industrial medicine》1995,28(3):303-324
Polycyclic aromatic hydrocarbons (PAHs) demonstrate carcinogenic activity in animal models. Although some epidemiologic studies have implicated PAHs as risk factors for human cancer, the evidence reported to date has not been consistent. The purpose of this report is to describe the associations between occupational exposure to PAHs in the workplace and each of 14 types of cancer. A population-based, case-control study was carried out in Montreal to investigate associations between a large variety of environmental and occupational exposures on the one hand, and several types of cancer on the other. A detailed job history was obtained from each subject along with information on a number of potential confounders. Each job history was reviewed by a team of experts, who used this information to construct a corresponding history of occupational exposures. Among the PAH exposures considered were benzo(a)pyrene (B(a)P) and five categories of PAHs defined on the basis of the source material, namely, wood, petroleum, coal, other sources, and any source. Altogether, 3,730 cancer patients and 533 population controls were interviewed and their job exposure histories coded. For each of 14 types of cancer analyzed, three control groups were available: other cancer patients, population controls, and the pooled set of cancer and population controls. The associations between 14 cancer types and 6 PAH exposures were analyzed using logistic regression methods. For most types of cancer evaluated, there was no evidence of excess risk due to PAHs at the levels encountered in the occupations in which PAH exposure has been prevalent in the Montreal area. For a few cancer sites–the esophagus, the pancreas, and the prostate gland–there were suggestions of excess risk; these observations are noteworthy hypotheses for further investigation. For lung cancer, there appeared to be an increased risk due to PAHs among nonsmokers and light smokers, but not among heavy smokers. 相似文献
56.
Patrick P. A. Humphrey Gary Buell Ian Kennedy Baljit S. Khakh Anton D. Michel Annmarie Surprenant Derek J. Trezise 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(6):585-596
Significant advances in understanding of P2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P2X receptor heterogeneity, from data with agonists, has recently been reported.A number of new antagonists at P2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P2X purinoceptor.Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents. 相似文献
57.
Markus Kohler Hans M. Eppenberger Imogen Cordt-Riehle Christian Michel 《Acta oncologica (Stockholm, Sweden)》1992,31(6):673-677
Urination frequency and cystic pressure resistance have been used as end-points to assess x-ray-induced changes of bladder function. Whole or half bladders of adult male rabbits were irradiated, caudally or cranially. The absorbed dose was 33 Gy, 36 Gy or 39 Gy, given in 5 daily fractions. Animals which received a whole bladder dose of 39 Gy or 36 Gy showed increased urination frequency and enhanced bladder pressure resistance during the whole follow-up time of 100 weeks, compared with the sham-irradiated controls. At half bladder irradiation, only the highest doses (39 Gy to the cranial part of the bladder and 39 Gy or 36 Gy to the caudal part) gave rise to a slight increase in frequency at about 20 weeks after exposure. 相似文献
58.
Dusica Maysinger Mario Herrera-Marschitz Michel Goiny Urban Ungerstedt A. Claudio Cuello 《Brain research》1992,577(2):300-305
The effects of intraventricular nerve growth factor (NGF) or saline treatments on extracellular acetylcholine (ACh), dopamine (DA) and adenosine (Ade) levels in the cortex and striatum of rats with unilateral devascularizing cortical lesions were studied in vivo with microdialysis. The devascularizing cortical lesion produced a decrease in extracellular ACh levels in both cortex and striatum as compared to those in normal rats, while the NGF treatment produced a significant increase in ACh levels in both regions. NGF could even increase cortical ACh levels in normal rats. The cortical lesion produced a decrease in extracellular DA in the cortex, while the NGF treatment appeared to reverse this effect. No significant changes in DA were observed in the striatum. The present study gives evidence that a unilateral cortical devascularizing lesion leads to changes in extracellular ACh and DA levels in cortex and striatum and that these changes could be reversed with intraventricular NGF treatment. 相似文献
59.
J C Marshall C Lee J L Meakins R P Michel N V Christou 《Archives of surgery (Chicago, Ill. : 1960)》1987,122(2):191-196
The effects of global hepatic injury and of Kupffer cell activation on systemic immunity were studied in an in vivo rat model, using the diameters of the delayed-type hypersensitivity (DTH) response to keyhole limpet hemocyanin and of a subcutaneous Staphylococcus aureus abscess as measures of systemic immunoresponsiveness. Hepatic injury with carbon tetrachloride resulted in significant suppression of the DTH score (5.5 +/- 0.7 vs 8.8 +/- 0.8 mm). Kupffer cell activation with intraportal Escherichia coli was likewise suppressive (DTH score, 4.4 +/- 0.5 vs 6.1 +/- 0.4 mm for animals receiving systemic E coli); the magnitude of this suppression correlated with the numbers of organisms extracted by the liver. Conversely, Kupffer cell ablation with carrageenan lessened the immunosuppressive effects of anesthesia and surgery (DTH score, 8.5 +/- 0.9 vs 6.8 +/- 0.6 mm for controls; S aureus abscess, 4.1 +/- 0.4 vs 5.7 +/- 0.4 mm for controls). These results indicate that Kupffer cells can modulate the systemic immune response and suggest that gram-negative portal bacteremia with resultant Kupffer cell activation may contribute to the immunologic derangements characteristic of trauma and critical surgical illness. 相似文献
60.