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1.
重症肌无力中枢神经系统受损模型 总被引:26,自引:2,他引:24
目的近年研究结果表明,重症肌无力(MG)病变部位并不仅仅局限于神经肌接头(NMJ)处突触后膜烟碱型乙酰胆碱受体(nAChR),烟碱型乙酰胆碱受体抗体(AChR-ab)病理作用可能波及到中枢神经系统(CNS)。因此,有必要建立模拟MG患者CNS损害的动物模型,研究MG患者脑脊液中存在的AChR-ab引起CNS损害的机制。方法从MG患者血中提取的AChR-ab经侧脑室穿刺注入到大鼠脑室系统,然后观察其症状和体征,以及用脑干听觉诱发电位仪(BAEP)检测鼠脑干听觉传导中枢功能。用免疫组化法(ABC)研究AChR-ab与CNS神经-nAChR之间免疫结合反应及其分布。结果大鼠除了出现脑干听觉传导中枢功能障碍外,还出现类似于MG动物模型表现的症状。免疫组化研究结果显示,神经-nAChR样阳性免疫反应广泛分布于CNS许多部位。结论脑室内注入的AChR-ab与神经-AChR结合引起CNS功能障碍和出现MG动物模型样症状。我们首次建立的中枢受损的MG模型将有助于阐明AChR-ab引起中枢受损和CNS下位运动神经元引起横纹肌收缩无力的机制。 相似文献
2.
In the present study, we examined the effect of intracerebroventricularly (i.c.v.) injected choline on both basal and stimulated oxytocin release in conscious rats. I.c.v. injection of choline (50–150 μg) caused time- and dose-dependent increases in plasma oxytocin levels under normal conditions. The increase in plasma oxytocin levels in response to i.c.v. choline (150 μg) was greatly attenuated by the pretreatment of rats with atropine (10 μg; i.c.v.), muscarinic receptor antagonist. Mecamylamine (50 μg; i.c.v.), a nicotinic receptor antagonist, failed to suppress the effect of 150 μg choline on oxytocin levels. Pretreatment of rats with 20 μg of hemicholinium-3 (HC-3), a specific inhibitor of choline uptake into nerve terminals, greatly attenuated the increase in plasma oxytocin levels in response to i.c.v. choline injection. Osmotic stimuli induced by either oral administration of 1 ml hypertonic saline (3 M) following 24-h dehydration of rats (type 1) or an i.c.v. injection of hypertonic saline (1 M) (type 2) increased plasma oxytocin levels significantly, but hemorrhage did not alter basal oxytocin concentrations. The i.c.v. injection of choline (50, 150 μg) under these conditions caused an additional and significant increase in plasma oxytocin concentrations beyond that produced by choline in normal conditions. These data show that choline can increase plasma oxytocin concentrations through the stimulation of central cholinergic muscarinic receptors by presynaptic mechanisms and enhance the stimulated oxytocin release. 相似文献
3.
Acute and chronic nicotine effects on measures of activity in rats: a multivariate analysis 总被引:4,自引:4,他引:0
Charles Ksir 《Psychopharmacology》1994,115(1-2):105-109
Nicotine has been reported to increase or decrease measures of activity in rats, including locomotor activity and rearing. Nicotine dose and repeated exposure to nicotine are known to be important factors in determining the effects on locomotor behavior. Less information has been gathered on rearing and other measures of activity. Rats were tested repeatedly, once per day, in Digiscan automated activity analyzers that reported 19 measures of activity. Each rat was given the same drug and dose each day, either saline or 0.1, 0.2, or 0.4 mg/kg nicotine. The 19 measures were combined or modified to produce 14 measures that were examined using factor analysis to help select the most independent measures. Four measures were selected to describe the effects of dose and to compare day 1 results with day 5 results. Total distance moved was increased in a dose-related fashion and was greater on day 5 than on day 1. Rearing was increased at low doses and decreased at high doses on both days. Stereotypy was increased approximately the same amount by all three doses, and was greater on day 5 than on day 1. Center time was increased by the highest dose on both days. These results once again point out the influences of repeated testing and repeated nicotine exposure on behavior. They may also help to clarify why some studies have reported that both ambulation and rearing are increased after nicotine whereas others find opposite effects. 相似文献
4.
本文重点介绍近年来糖尿病患者调脂治疗,主要包括临床常用的他汀类、贝特类、烟酸等药物降胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白-胆固醇(LDL-C)水平、升高高密度脂蛋白-胆固醇(HDL-C),以及减少心血管事件的疗效、不良反应等。 相似文献
5.
Xinyu D. Li Esperanza Arias Ramamohana R. Jonnala Shyamala Mruthinti Jerry J. Buccafusco 《Journal of molecular neuroscience : MN》1996,27(3):325-336
The ability of nicotine to induce a cytoprotective or neuroprotective action occurs through several down-stream mechanisms.
One possibility is that the drug increases the expression of tyrosine kinase A (TrkA) nerve growth factor (NGF) receptors.
Certain β-amyloid peptides (e.g., Aβ1–42) have been shown to bind with high affinity to α7 nicotinic receptors and thus interfere
with a potentially neurotrophic influence. Treatment of differentiated PC-12 cells with nicotine produced a concentration-dependent
increase in cell-surface TrkA receptors that occurred concomitantly with cytoprotection. The effect of nicotine was blocked
by either of the α7 receptor antagonists α-bungarotoxin (α-BTX) or methyllycaconatine. The cytoprotective action of nicotine
also was inhibited by pretreatment with 10–100 nM Aβ1–42. Nicotine also was administered (four injections of 30 μg, spaced evenly over 24 h) to rats by direct injection into
a lateral cerebral ventricle. Brain TrkA expression was increased significantly in hippocampus and entorhinal cortex (up to
32% above control), with no changes found in cerebral cortex or hypothalamus. The nicotine-induced increases in TrKA expression
in hippocampus and entorhinal cortex were significantly inhibited by 10 μg α-BTX or by 10 nmol Aβ1–42. Therefore, physiologically
relevant concentrations of Aβ1–42 can prevent nicotine-induced TrkA receptor expression in brain regions containing cholinergic
neurons susceptible to the neurotoxicity associated with Alzheimer’s disease. 相似文献
6.
Exposure of H69 small cell lung carcinoma cells to nicotinic agonists resulted in a significant increase (up to 100%) in cell number after 6 to 12 days. The effect of nicotine (10−8 M to 10−4 M) was both dose and time dependent as was that of another nicotinic agonist cytisine (10−6 M to 10−4 M). Interstingly, both the nicotine and cytisine induced increases in H69 cell number were blocked by α-bungarotoxin, as well as d-tubocurarine a nicotinic blocker which appears to interact with most nicotinic receptors. These results suggest that the nicotine induced increase in cell number is mediated through an interaction at the nicotinic α-bungarotoxin receptor. This idea is further supported by experiments which show (1) that H69 cells possess high affinity α-bungarotoxin sites (Kd = 25 nM, Bmax = 10.4 fmol/106 cells) with the characteristics of a nicotinic α-bungarotoxin receptor and (2) that the potencies of nicotinic receptor ligands in the α-bungarotoxin binding assay were similar to those observed in the functional studies. Northern analysis showed that mRNA for α7, a putative nicotinic α-bungarotoxin binding subunit, and for α5 were present in H69 cells. The present data provide further evidence that nicotine increases cell number in small cell lung carcinoma and are the first to show that this effect is mediated through an interaction at the nicotinic α-bungarotoxin receptor population. These results suggest that the α-bungarotoxin site may be involved in modulating proliferative responses in neuroendocrine derived SCLC cells. 相似文献
7.
Non-contractile Ca2+ mobilization (not accompanied by muscle contraction) occurs by the prolonged activation of nicotinic acetylcholine receptor in mouse diaphragm muscles treated with anticholinesterase. To elucidate the regulation properties of non-contractile Ca2+ mobilization by nicotinic receptor, the modes of action of competitive and depolarizing neurmuscular blockers were investigated. (+)-Tubocurarine (0.07–0.1 μM), pancuronium (0.05 μM) and -bungarotoxin (0.03–0.06 μM) decreased decay time (T2, duration of inactivation phase) without changes in rise time (T1, duration of activation phase) of non-contractile Ca2+ transients. These competitive antagonists also suppressed their peak amplitude at higher concentrations than those affectingT2. Contractile Ca2+ transients were not inhibited by these antagonists at the concentrations used. Decamethonium (1 μM), a depolarizing blocker, suppressed the peak amplitude of non-contractile Ca2+ transients without affecting their duration. In contrast, succinylcholine (0.3 μM) suppressed both peak amplitude andT1 without changingT2, presumably via the receptor desentization. Succinylcholine but not decamthonium inhibited contractile Ca2+ transients at the concentrations used. These results demonstrate that the activation and inactivation phase in non-contractile Ca2+ transients are independently regulated by nicotinic acetylcholine receptor. 相似文献
8.
The aim of this study was to investigate the relationship between the cells possessing the alpha3 or alpha5 nicotinic acetylcholine receptor subunits and the enzyme acetylcholinesterase, with respect to tyrosine hydroxylase immunoreactive dopaminergic neurons in the rat substantia nigra. Most, but certainly not all, acetylcholinesterase immunoreactive cells were located in the pars compacta. In the substantia nigra pars compacta there were in turn two populations of acetylcholinesterase containing neurons: those that were tyrosine hydroxylase reactive and those that were not. Double label studies, that included an antibody immunoreactive against a common immunogen on alpha1 of muscle and alpha3 and alpha5 neuronal nicotinic acetylcholine receptor subunits, revealed that nearly all nicotinic receptor positive cells were also tyrosine hydroxylase neurons. However, a minority non-tyrosine hydroxylase population was alpha3- and/or alpha5-nAChR positive and these were always AChE-immunoreactive. In summary, there appears to be a close correlation between nicotinic receptors and acetylcholinesterase in the substantia nigra, irrespective of the transmitter phenotype in different neuronal subpopulations. 相似文献
9.
Agneta Nordberg Anders Lilja Hans Lundqvist Per Hartvig Kaarina Amberla Matti Viitanen Ulrika Warpman Monika Johansson Ewa Hellstrm-Lindahl Peter Bjurling Karl-Johan Fasth Bengt Lngstrm Bengt Winblad 《Neurobiology of aging》1992,13(6):747-758
Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(−)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(−)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(−)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement. 相似文献
10.
Ken Nakazawa 《Pflügers Archiv : European journal of physiology》1994,427(1-2):129-135
Modulation by protein phosphorylation of the relation between acetylcholine (ACh)-activated current (I
ACh) and adenosine triphosphate-(ATP)-activated current (I
ATP) was investigated with the whole-cell voltage-clamp technique in rat sympathetic neurons. During simultaneous activation by 100 M ATP of an inward current, the current evoked by 100 M ACh was reduced to 60–70% of that in the absence of ATP. Effects of compounds that are known to modulate protein phosphorylation were tested by including them in the intracellular solution. The reduction ofI
ACh by ATP was not observed when K252a (1 M), a non-selective protein kinase inhibitor, adenosine 5-O-(3-thiotriphosphate) (ATP[S], 1 mM) or,-methylene ATP (1 mM) were included in the intracellular solution. Activators of protein kinases, adenosine 3,5-cyclic monophosphate (cAMP, 100 M), guanosine 3,5-cyclic monophosphate (cGMP, 100 M), phorbol 12-myristate 13-acetate (PMA, 1 M), also abolished the reduction by ATP ofI
ACh. The effects of okadaic acid, a protein phosphatase inhibitor, were paradoxical: okadaic acid (2 M) itself abolished the reduction by ATP ofI
ACh but it antagonized the abolishment by cAMP or cGMP of the reduction ofI
ACh. Okadaic acid did not affect the disappearance of the reduction ofI
ACh by ATP in the presence of intracellular PMA. The results suggest that the interaction betweenI
ACh andI
ATP is regulated by protein phosphorylation/dephosphorylation. Possible mechanisms underlying the effects of these modulators of protein phosphorylation are discussed. 相似文献