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1.
Acetylcholinesterase (AChE) which catalyzes the hydrolysis of the neurotransmitter acetylcholine has been recognized as one of the major regulators of stress responses after traumatic brain injury (TBI). Repeated blast exposure induces TBI (blast TBI) with a variable neuropathology at different brain regions. Since AChE inhibitors are being used as a line of treatment for TBI, we sought to determine the time course of AChE activity in the blood and different brain regions after repeated blast exposures using modified Ellman assay. Our data showed that repeated blast exposures significantly reduced AChE activity in the whole-blood and erythrocytes by 3-6 h, while plasma AChE activity was significantly increased by 3 h post-blast. In the brain, significant increase in AChE activity was observed at 6 h in the frontal cortex, while hind cortex and hippocampus showed a significant decrease at 6 h post-blast, which returned to normal levels by 7 days. AChE activity in the cerebellum and mid brain showed a decrease at 6 h, followed by significant increase at 3 days and that was decreased significantly at 14 days post-blast. Medulla region showed decreased AChE activity at 24 h post-blast, which was significantly increased at 14 days. These results suggest that there are brain regional and time-related changes in AChE activity after tightly coupled repeated blast exposures in mice. In summary, acute and chronic regional specific changes in the AChE activity after repeated blast exposures warrant systematic evaluation of the possibility of AChE inhibitor therapeutics against blast TBI. 相似文献
2.
Experimental manipulations suggest that in vivo administration of cholinergic agonists or inhibitors of acetylcholinesterase (AChE) increases the concentration of acetylcholine. Biochemical studies have proposed a role for AChE in brain mechanisms responsible by development to status epilepticus (SE) induced by pilocarpine. The present study was aimed at investigating the changes in AChE activities in hippocampus, striatum and frontal cortex of adult rats after pilocarpine-induced SE. The control group was treated with 0.9% saline (s.c., control group) and another group received pilocarpine (400 mg/kg, s.c.). Both groups were sacrificed 1 h after treatment. The results have shown that pilocarpine administration and resulting SE produced a significant decrease in the AChE activity in the hippocampus (63%), striatum (35%) and frontal cortex (27%) of adult rats. Our results demonstrated a direct evidence of a decrease in the activity of the AChE in rat brain regions during seizure activity that could be responsible by regulation of acetylcholine levels during the establishment of SE induced by pilocarpine. 相似文献
3.
S A Soliman A Curley J Farmer R Novak 《Journal of environmental pathology, toxicology and oncology》1986,7(1-2):211-224
An equimolal single dose (1 mmole/kg) of leptophos or cyanofenphos was given orally to chickens to assay the clinical and biochemical neurotoxic effects of these two organophosphorus insecticides. Parathion and TOCP at 2 and 1000 mg/kg of chicken body weight were tested in the same manner as negative and positive neurotoxicants, respectively. Three birds of each of five groups tested were sacrificed 1,2,3,7,14,21 and 28 days after treatment and the brains were taken for the biochemical tests. Acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activities were determined in the brain microsomal fractions. In addition, the AChE activity in the brain soluble fractions was measured. Clinical observations indicated that leptophos-, cyanofenphos- and parathion-treated chickens became acutely poisoned but recovered from the typical cholinergic signs in a day or two. However, about 10 to 15 days later leptophos- and cyanofenphos-treated chickens developed the characteristic leg weakness and unrecoverable ataxia seen in birds given TOCP. The biochemical results indicated that cyanofenphos followed by leptophos and parathion produced more in vivo AChE inhibition than that produced by TOCP in both chicken brain soluble and microsomal fractions. Results suggested that there are no correlations between the in vivo effect of TOCP, leptophos and cyanofenphos on AChE and phenyl valerate-total hydrolyzing activities and the ability of these chemicals to produce neuropathy in hens. The results obtained from this study of the in vivo effect of the tested compounds on chicken brain NTE activity present an acceptable correlation between the inhibition of this enzyme and the ability of these chemicals to induce neuropathy. The mechanism and explanation for this correlation are presented. The in vivo effect of the tested compounds on the chicken brain NTE activity was determined using the indirect and a new direct method. The data presented in this report suggested that the new direct technique of assaying NTE activity using 4-nitrophenyl valerate (4-NPV) as substrate, can be useful in the in vivo screening studies of organophosphates for their ability to induce neuropathy in hens. 相似文献
4.
Darreh-Shori T Kadir A Almkvist O Grut M Wall A Blomquist G Eriksson B Långström B Nordberg A 《Neurobiology of aging》2008,29(2):168-184
The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients. 相似文献
5.
Tsakiris S 《Mechanisms of ageing and development》2001,122(5):491-501
The effect of different L-phenylalanine (Phe) concentrations (0.12-1.8 mM) on acetylcholinesterase (AChE), (Na(+), K(+))-ATPase and Mg(2+)-ATPase activities was investigated in homogenates of adult and aged rat whole brain at 37 degrees C. Adult and aged rat experiments were necessary in relation to phenylketonuria (PKU) since phenylketonuric patients usually discontinue their therapeutic special diet when they reach adulthood. Diet discontinuation results in the pathological increase of Phe concentration in plasma and consequently in brain. AChE activity in adult brain homogenates showed a decrease up to 18% (P<0.01) with 0.48--1.8 mM Phe preincubated for 1 h. Adult brain Na(+), K(+)-ATPase was stimulated by 30--35% (P<0.01) in the presence of 0.48--1.8 mM Phe. However, high Phe concentrations were not able to affect the activities of AChE and Na(+), K(+)-ATPase, when preincubated with aged brain homogenate for 3 h. Moreover, high Phe concentrations appeared unable to affect the activity of eel E. electricus pure AChE inhibited about 30% (P<0.001) by the free radical system H(2)O(2)/Fe(2+). Also, the antagonists of alpha- and beta-adrenergic receptors (phenoxybenzamine and propranolol, respectively) inhibited adult rat brain Na(+), K(+)-ATPase activity about 30--40% (P<0.01) and Phe was unable to change this action. It is suggested that: (a) The inhibitory effect of Phe on brain AChE and its stimulatory effect on brain Na(+), K(+)-ATPase are decreased with age; (b) These effects may be influenced by aging factors, such as free radical action and/or reduced density of alpha- and beta-adrenergic receptors in the tissue. 相似文献
6.
Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide 总被引:11,自引:0,他引:11
Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer's disease (AD) patient's brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide Abeta(25-35) on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with Abeta(25-35) (25 microM, 24 h) and antioxidants such as alpha-tocopherol acetate and nitric oxide synthase (NOS) inhibitors were capable of preventing this effect. Despite Abeta(25-35) did not affect cell membrane integrity, the redox capacity of cells decreased. The incubation with this amyloidogenic peptide led to an increment of reactive oxygen species formation (20%), of lipid peroxidation (65%), and basal intracellular calcium levels (40%). The data obtained show that the enhancement of AChE activity induced by Abeta(25-35) is mediated by oxidative stress, and that vitamin E and NOS inhibitors, by preventing the compromise of the enzyme activity, can have an important role in the maintenance of acetylcholine synaptic levels, thus preventing or improving cognitive and memory functions of AD patients. 相似文献
7.
Vanadium improves brain acetylcholinesterase activity on early stage alloxan-diabetic rats 总被引:1,自引:0,他引:1
The present study is designed to screen the possible effects of sodium orthovanadate therapy on the kinetic parameters of brain membrane-bound and soluble acetylcholinesterase (AChE) forms in alloxan-induced diabetic rats. The diabetic rats were treated with 300 mg/kg sodium orthovanadate orally for 45 days. While diabetes significantly decreased the brain specific activity (V(max)) of AChE soluble form by 42%, it caused a fivefold increase of the K(m) of the membrane-bound form. Furthermore, the activity of brain glutathione-S-transferase (GST) was significantly decreased and this was associated with a remarkable increase in brain lipid peroxidative parameter, thiobarbituric acid reactive substances (TBARS), as compared to sham control. The alterations of both AChE forms observed in diabetic state could be attributed to hyperglycemia and lipid peroxidation that triggered brain dysfunction by disturbing the neurotransmitter acetylcholine level. Administration of sodium orthovanadate reversed the diabetic conditions by lowering the blood glucose level and normalized the blood Hb(A1C) level. It also normalized the levels of brain AChE, GST and TBARS as compared to diabetic state and control. Therefore, vanadate administration could protect against direct action of lipid peroxidation on brain AChE and in this way, it might be useful in the prevention of cholinergic neural dysfunction, which is one of the major complications in diabetes. 相似文献
8.
Peptidases inactivating thyrotrophin-releasing hormone (TRH) were found to be present in two subcellular fractions prepared from the hypothalamus, thalamus, cortex and cerebellum of male rats, with the highest enzyme activity being detected in the cortex. TRH immunoreactivity was also measured in the two fractions from the 4 brain areas, after peptidase activity had first been removed by heat denaturation: the particulate fraction had a significantly higher TRH content than the supernatant fraction; of the regions investigated, the hypothalamus had the highest content, although TRH was detected in all the 4 brain regions. These findings provide further evidence that TRH may be one of several brain peptides having either a neuro transmitter function of a role as modulators of neuronal activity. 相似文献
9.
Manikandan S Padma MK Srikumar R Jeya Parthasarathy N Muthuvel A Sheela Devi R 《Neuroscience letters》2006,399(1-2):17-22
Spatial memory is coordinated with different brain regions especially hippocampus (HIP) and medial prefrontal cortex (mPFC). Influence of noise stress on working and reference memory error in rats was evaluated by radial eight-arm maze experiment. Changes in the dendritic count were observed in the brain regions such as CA1, CA3 regions of HIP and layers II, III of mPFC. In order to understand the possible mechanism behind noise stress-induced changes, free radical status and acetylcholinesterase (AChE) activity in HIP and mPFC were evaluated. Plasma corticosterone level was also evaluated. Results obtained in this study showed that after noise-stress exposure, 100 dBA/4h per day for 30 days, working and reference memory error increased significantly (P < 0.05) when compared to control animals. Neuronal dendritic count in the HIP was reduced in the 2nd and 3rd order dendrites but not in the mPFC. Superoxide dismutase, lipid peroxidation, plasma corticosterone level and AChE activity were significantly increased in the 1 day, 15 days and 30 days stress groups animal significantly. Catalase and glutathione peroxidase activity were increased in the 1 day and 15 days noise-stress groups but decreased in the 30 days noise-stress group and GSH level was decreased in all the stress exposed animals. In conclusion, oxidative stress, increased AChE activity, reduced dendritic count in HIP, mPFC regions and elevated plasma corticosterone level which develops in long-term noise-stress exposed rats, might have caused the impairment of spatial memory. 相似文献
10.
The AChE activity was demonstrated in some brain regions of adult rats after intoxication with DFP ( (di-isopropyl-fluorophosphate). Within these nuclear areas (Caudate-Putamen-Complex, Globus pallidus, Nucleus accumbens septi, Substantia nigra, Locus coeruleus) various proportions of the neuron population could be shown to be AChE positive. There is a characteristic morphology of the AChE containing neurons. Comparing them with staining and silver impregnation, cytological attributability appears feasible. 相似文献
11.
Distribution of DT diaphorase in the rat brain: biochemical and immunohistochemical studies 总被引:4,自引:0,他引:4
DT diaphorase [NAD(P)H:quinone oxidoreductase] activity was measured in subcellular fractions from homogenates of striatum, frontal cortex, hippocampus, cerebellum, hypothalamus and substantia nigra. This flavoprotein, which by definition oxidizes dihydronicotinamide adenine dinucleotide and dihydronicotinamide adenine dinucleotide phosphate at equal rates and is completely inhibited by 10(-5) M dicoumarol, was found to constitute 80-90% of the total dihydronicotinamide adenine dinucleotide- and dihydronicotinamide adenine dinucleotide phosphate-reductase activities in all brain regions studied. Antibodies raised against purified cytosolic DT diaphorase from the rat liver cross-reacted with the brain enzyme and inhibited soluble DT diaphorase from striatum and cerebellum to 80-90%. Immunohistochemical studies with the same antibodies demonstrated the occurrence of DT diaphorase immunoreactivity in a population of neurons in the substantia nigra and ventral tegmental area. In some neurons there was a colocalization of DT diaphorase and tyrosine hydroxylase-like immunoreactivity. The dense network of DT diaphorase-immunoreactive fibres in the striatum disappeared along with the dopaminergic innervation after 6-hydroxydopamine lesion. DT diaphorase immunoreactivity was also found in Bergmann glia, astrocytes and tanycytes. No correlation appeared to exist between the localization of neuronal DT diaphorase immunoreactivity and the dihydronicotinamide adenine dinucleotide phosphate-diaphorase-like activity, as defined by tetrazolium salt staining, used as a marker for certain peptidergic and cholinergic neurons. However, in, for example, glial cells in the cerebellum, DT diaphorase might contribute or be responsible for the histochemical dihydronicotinamide adenine dinucleotide phosphate-diaphorase activity. 相似文献
12.
Ibotenic acid was injected into the nucleus basalis magnocellularis region of rat brain in order to study whether an elevation of lipase activities was associated with the degeneration of cholinergic neurons in this potential animal model of Alzheimer's disease. Two plasma membrane fractions were prepared from different regions of ibotenate injected (right hemisphere) and non-injected (left hemisphere) rat brain. One plasma membrane fraction was from synaptosomes (SPM) and the other from glial and neuronal cell bodies (PM). Activities of mono- and diacylglycerol lipases in these plasma membrane fractions were markedly increased (3- to 5-fold) in hippocampus, midbrain and frontal cortical regions of rat brain at 10 days after the injection of ibotenate. The activity of choline acetyltransferase was decreased in frontal cortex but unchanged in hippocampus and midbrain. Our results suggest that the increase in lipase activity is much more widespread and non-specific than is the decrease in cholinergic function. 相似文献
13.
KA-672, a lipophilic benzopyranone derivative which is currently under development as a cognitive enhancer and antidementia drug, has previously been shown to have facilitatory effects on learning and memory in rats at doses of 0.1-1 mg/kg. We now report that KA-672 inhibited the activity of acetylcholinesterase (AChE), measured in vitro in rat brain cortical homogenate, with an IC50 value of 0.36 microM indicating that KA-672 may improve cognitive functions as a consequence of AChE inhibition. However, when we employed the microdialysis procedure to monitor acetylcholine (ACh) release from rat hippocampus, no effect of KA-672 (0.1-10 mg/kg) was found, indicating a lack of inhibition of brain AChE under in vivo-conditions. [14C]-labelled KA-672 was found to easily penetrate the blood-brain barrier, and an apparent concentration of 0.22 nmol/g brain (equivalent to 0.39 microM tissue concentration) was calculated following an i.p. injection of 1 mg/kg KA-672. However, no labelled substance could be detected in hippocampal microdialysates or in cerebrospinal fluid (CSF) taken from the cisterna magna, indicating that the concentration of KA-672 in brain extracellular fluid must have been below 0.01 microM. We conclude that KA-672 is a potent AChE inhibitor, an activity which, however, does not contribute to its behavioural effects in vivo because the lipophilic drug does not reach sufficient concentrations in the extracellular fluid, apparently due to cellular sequestration. 相似文献
14.
Major localization of aminopeptidase M in rat brain microvessels 总被引:3,自引:0,他引:3
The localization of two enkephalin-hydrolysing aminopeptidases i.e. aminopeptidase M (aminopeptidase N, EC 3.4.11.2) relatively insensitive to puromycin (Ki = 78 microM), and a puromycin-sensitive aminopeptidase (Ki = 1 microM) was studied in rat brain. The two aminopeptidases were differentially identified and/or localized using polyclonal anti-aminopeptidase M antibodies displaying anticatalytic activity and the inhibitors puromycin, bestatin and amastatin. Microvessels represent a major localization of cerebral aminopeptidase M as shown by the intense immunostaining of their walls in sections from various regions as well as in a fraction isolated from cerebral cortex homogenates by a sieving procedure. As compared to the starting homogenate, aminopeptidase M activity was enriched about twenty fold in this microvascular fraction. Aminopeptidase M was identified in this fraction by comparing the inhibitory potencies of antibodies and peptidase inhibitors towards the hydrolysis of [tyrosyl-3,5-3H, Met5]enkephalin to those found for the purified enzyme. A rather high aminopeptidase M activity was also localized in choroid plexuses. Following differential and gradient centrifugation analysis of cerebral cortex homogenates, aminopeptidase M activity was also enriched (by five to six fold) in fractions containing synaptic membranes. No significant soluble aminopeptidase M activity could be detected. These data suggest a dual localization of cerebral aminopeptidase M in microvessels and synaptic membranes consistent with its roles in preventing the access of circulating peptides to brain as well as in inactivating neuropeptides released from cerebral neurones. In comparison, puromycin-sensitive aminopeptidase activity, which is about 100 fold higher than aminopeptidase M activity in brain, was relatively low in microvessels and non-detectable in fractions enriched in synaptic membranes, being almost entirely restricted to soluble fractions. 相似文献
15.
Tsuguto Nakamura Takayoshi Ikeda Isao Shimokawa Yasuhisa Inoue Takashi Suematsu Hiroyuki Sakai Keisuke Iwasaki Takeshi Matsuo 《Anatomy and embryology》1994,190(4):367-373
Acetylcholinesterase (AChE) activity was topographically investigated in the presumptive cardiac conduction tissue regions visualized by HNK-1 immunoreactivity in rat embryos, and AChE-positive cells were examined with the electron microscope. On embryonic day (ED) 14.5, when HNK-1 was most intensely visualized, AChE activity could not be detected enzyme-histochemically in the conduction tissue regions, except in the ventricular trabeculae and part of the AV node. On ED 16.5, however, the AChE activity was clearly demonstrated in some parts of the developing conduction tissue. One exception was the AV node region, where an AChE-positive area was in close proximity to an area showing HNK-1 immunoreactivity but did not overlap. Furthermore, AChE activity was demonstrated predominantly in the ventricular trabeculae, including cardiac myocytes, but was rather weak in the atrium. With the electron microscope, AChE reaction products were observed predominantly intracellulary in both developing conduction tissue cells and developing ordinary myocytes, and no reactivity was found in neuronal components. From ED 18.5 until birth, both AChE activity and HNK-1 immunoreactivity faded away in the conduction tissue. Thus, transient AChE activity in the embryonic heart seems to be different from the developing adult form and may be related to a morphogenetic function in embryonic tissues, as proposed by other authors. 相似文献
16.
Soluble and membrane-bound forms of brain acetylcholinesterase in Alzheimer''s disease 总被引:1,自引:0,他引:1
Kathleen M. Schegg Leslie S. Harrington Surl Neilsen Richard M. Zweig John H. Peacock 《Neurobiology of aging》1992,13(6):697-704
In order to determine the effect of Alzheimer's disease on the relative distribution of soluble and membrane-bound molecular forms of acetylcholinesterase (AChE) in the brain, postmortem samples (delay interval less than 12 h) were obtained from parietal cortex (Brodmann area 40) and hippocampus as well as the areas containing their respective projection nuclei, i.e., substantia innominata and septal nucleus, in 9 patients with Alzheimer's disease (AD) and 4 normal controls. The monomer (G1), dimer (G2), and tetramer (G4) forms of AChE were examined. In AD compared to controls, significant changes occurred in area 40 and hippocampus but not in the areas containing projection nuclei, and included loss of mean total AChE activity, decrease in the relative percentage of membrane-bound G4, and increase in the relative percentage of soluble G1---G2. Percent of soluble G4 was unaffected in AD brain. In area 40 but not hippocampus a large increase in percent membrane-bound G1-G2 occurred. Thus, these results emphasize that the selective decrease in membrane-bound G4 accounts for the decrease in total G4 activity in AD brain. 相似文献
17.
Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex 总被引:17,自引:0,他引:17
Studies in vitro have suggested that acetylcholinesterase (AChE) may interact with beta-amyloid to promote deposition of amyloid plaques in the brain of patients with Alzheimer's disease. To test that hypothesis in vivo, we crossed Tg2576 mice, which express human amyloid precursor protein and develop plaques at 9 months, with transgenic mice expressing human AChE. The resulting F1 hybrids (FVB/N x [C57B6 x SJL/J]) expressed both transgenes in brain. By 6 months of age, their cerebral cortex showed authentic plaques that stained both by thioflavin S and by beta-amyloid 1-40 and 1-42 immunohistochemistry. The plaques also stained positively for other components including Cd11b, GFAP, and AChE. Plaque onset in the hybrids occurred 30-50% sooner than in the parental lines. Plaque numbers increased with age and plaques remained more numerous in the doubly transgenic animals at 9 and 12 months. Quantitative immunoassay via ELISA also showed an increase of total amyloid content in brain at 9-12 months. These histological and biochemical results support the conclusion that AChE may play a role in pathogenesis of Alzheimer's disease 相似文献
18.
19.
Herink J Krejcová G Bajgar J Svoboda Z Kvĕtina J Zivnú P Palicka V 《Neuroscience letters》2003,339(3):251-253
Cyclosporine A (CsA) is the major immunosuppressive drug used for organ and neural transplantation and the therapy of selected autoimmune diseases. We investigated the effect of CsA on the activity of acetylcholinesterase (AChE) in the frontal cortex, hippocampus, septum, and basal ganglia. AChE was determined spectrophotometrically with acetylthiocholine as substrate and 5,5-bis-2-nitrobenzoic acid as chromogen. CsA was administered in single doses of 20 or 45 mg/kg perorally; in the case of the higher dose we also performed a repeated administration of CsA in three consecutive doses separated by 24 h intervals. Both lower and higher doses of CsA decreased AChE activity in the frontal cortex and hippocampus to practically the same extent. On the contrary, AChE activity was more diminished in the case of the higher dose of CsA used in the septum and basal ganglia. Repeated administration of the higher dose of CsA did not lead, with the exception of the hippocampus, to a further decrease in AChE activity in the brain structures observed. These findings contribute to rare evidence concerning the interaction of CsA and the cholinergic system in the brain. 相似文献
20.
目的:探讨IL-1β对大鼠胆碱能神经元的影响及机理。方法:检测不同时相、不同脑区的培养神经细胞AChE、BuchE及ChAT的活性和前脑基底、皮层中胆碱酯酶阳性细胞数目。 结果:IL-1β对AChE活性的最大促进作用时相为24 h,皮层、前脑基底和海马部位的AChE活性明显高于对照组(P<0.01),且能够完全被IL-1ra所阻断; 而小脑、脊髓、基底神经节部位的AChE活性则未见明显变化,同时各组BuchE、ChAT的活性均无明显变化,前脑基底、皮层中胆碱酯酶阳性细胞数目亦未见明显变化。结论: IL-1β能够明显升高特定脑区AChE活性,使乙酰胆碱的生成减少;而AChE活性的增高可能与其基因的转录和翻译增加有关。 相似文献