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1.
《Life sciences》1996,58(22):1995-2002
Nicotinamide administration can elevate plasma and brain choline levels and produce a marginal increase in striatal acetylcholine levels in the rat. We now report that subcutaneous nicotinamide produces a substantial and long-lasting rise in asternal cerebrospinal fluid (CSF) levels of choline in free-moving rats, possibly through the enzymatic formation of N1-methylnicotinamide (NMN) in brain. CSF choline levels peaked 2 hours after nicotinamide administration and were accompanied by increases in striatal, cortical, hippocampal and plasma choline levels. The enzymatic formation of [3H]NMN in rat brain was evaluated by incubating aliquots of rat brain cytosol with unlabelled nicotinamide and the methyl donor [3H]S-adenosylmethionine. High performance liquid chromatography and radiochemical detection demonstrated that [3H]NMN was specifically formed by a brain cytosolic enzyme. The production of [3H]NMN was dependent on exogenous nicotinamide and could be prevented by denaturing the cytosol. The metabolism of nicotinamide to NMN in rat brain may explain the rise in CSF choline levels since NMN, a quaternary amine, can inhibit choline transport at the choroid villus and reduce choline clearance. 相似文献
2.
Small Rises in Plasma Choline Reverse the Negative Arteriovenous Difference of Brain Choline 总被引:3,自引:3,他引:0
The concentrations of free choline in blood plasma from a peripheral artery and from the transverse sinus, in the CSF, and in total brain homogenate, have been measured in untreated rats and in rats after acute intraperitoneal administration of choline chloride. In untreated rats, the arteriovenous difference of brain choline was related to the arterial choline level. At low arterial blood levels (less than 10 microM) as observed under fasting conditions, the arteriovenous difference was negative (about -2 microM), indicating a net release of choline from the brain of about 1.6 nmol/g/min. In rats with spontaneously high arterial blood levels (greater than 15 microM), the arteriovenous difference was positive, implying a marked net uptake of choline by the brain (3.1 nmol/g/min). The CSF choline concentration, which reflects changes in the extracellular choline concentration, also increased with increasing plasma levels and closely paralleled the gradually rising net uptake. Acute administration of 6, 20, or 60 mg of choline chloride/kg caused, in a dose-dependent manner, a sharp rise of the arterial blood levels and the CSF choline, and reversed the arteriovenous difference of choline to markedly positive values. The total free choline in the brain rose only initially and to a quantitatively negligible extent. Thus, the amount of choline taken up by the brain within 30 min was stored almost completely in a metabolized form and was sufficient to sustain the release of choline from the brain as long as the plasma level remained low. We conclude that the extracellular choline concentration of the brain closely parallels fluctuations in the plasma level of choline.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
3.
Uptake and Storage of Choline by Rat Brain: Influence of Dietary Choline Supplementation 总被引:1,自引:1,他引:0
In order to elucidate the regulation of the levels of free choline in the brain, we investigated the influence of chronic and acute choline administration on choline levels in blood, CSF, and brain of the rat and on net movements of choline into and out of the brain as calculated from the arteriovenous differences of choline across the brain. Dietary choline supplementation led to an increase in plasma choline levels of 50% and to an increase in the net release of choline from the brain as compared to a matched group of animals which were kept on a standard diet and exhibited identical arterial plasma levels. Moreover, the choline concentration in the CSF and brain tissue was doubled. In the same rats, the injection of 60 mg/kg choline chloride did not lead to an additional increase of the brain choline levels, whereas in control animals choline injection caused a significant increase; however, this increase in no case surpassed the levels caused by chronic choline supplementation. The net uptake of choline after acute choline administration was strongly reduced in the high-choline group (from 418 to 158 nmol/g). Both diet groups metabolized the bulk (greater than 96%) of newly taken up choline rapidly. The results indicate that choline supplementation markedly attenuates the rise of free choline in the brain that is observed after acute choline administration. The rapid metabolic choline clearance was not reduced by dietary choline load. We conclude that the brain is protected from excess choline by rapid metabolism, as well as by adaptive, diet-induced changes of the net uptake and release of choline. 相似文献
4.
Interruption of the corticostriatal pathway by undercutting the frontal cortex resulted after 2 weeks in a 40% reduction of basal acetylcholine (ACh) release in vivo, and in inhibition of the striatal sodium-dependent high-affinity uptake of choline (SDHACU) to the same extent. The lesion, too, completely prevented the rise (about 35%) in striatal ACh content induced by oxotremorine and apomorphine acting at muscarine and dopamine receptors, respectively. Acute intraperitoneal injections of 100 mg/kg of either oxiracetam or choline chloride resulted in time-dependent recovery of ACh output from the striata of decorticated rats to control levels. Oxiracetam also normalized the ex vivo striatal SDHACU activity of decorticated rats 2 h after administration without any effect in sham-operated rats. Oxiracetam or choline chloride administered before oxotremorine (0.8 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.) reinstated the ACh-increasing effect of these agonists. It is suggested that choline chloride acts directly simply by being the precursor for ACh, whereas oxiracetam may act indirectly, possibly by increasing the availability of choline chloride for ACh synthesis. Furthermore, the frontally decorticated rat could constitute a useful model for studying means to restore the deficit in striatal cholinergic neurotransmission. 相似文献
5.
Regional CNS Levels of Acetylcholine and Choline During Hypoglycemic Stupor and Recovery 总被引:1,自引:1,他引:0
Jay M. Gorell Carolyn P. Navarro Susan P. W. Schwendner 《Journal of neurochemistry》1981,36(1):321-324
During insulin stupor in mice, acetylcholine levels in cerebral cortex, cerebellum. brainstem, striatum, and hippocampus were unchanged from control values despite brain glucose concentrations 3-10% of normal, whereas choline levels rose 2.4-3.6-fold in all five CNS regions. Brain acetylcholine and choline levels did not change during recovery following glucose injection. The data suggest that. in hypoglycemic stupor, (1) overall rates of acetylcholine synthesis and degradation remain balanced within each of the CNS regions studied: (2) the biochemical mechanism that elevates brain choline levels is unlikely to be related only to cholinergic synaptic processes: and (3) brain choline levels need not rise for stupor to occur. 相似文献
6.
Agar cultures of C57 BL bone marrow cells were used to determine colony stimulating factor (CSF) and serum CSF-inhibitor levels in C57 BL and BALB/c mice following irradiation. Whole-body irradiation caused an acute, dose-dependent, rise in serum CSF levels and fall in CSF-inhibitor levels. The regeneration of granulocytic and macrophage progenitor cells ( in vitro CFCs) in the femur after 250 rads whole-body irradiation was preceded or paralleled by a fall in serum CSF-inhibitors and a dramatic rise in the capacity of bone-adherent cells in the marrow ('stromal cells') to produce material with colony-stimulating activity. No comparable changes were observed in the activity of marrow haemopoietic cells during regeneration or in the lungs or spleen. A similar rise in the activity of bone-adherent cells was observed in shielded femurs during regeneration of in vitro CFCs.
Regeneration of granulocytic and macrophage progenitor cells following irradiation may be regulated by fluctuations in circulating CSF-inhibitor levels and local production of CSF within the marrow cavity. 相似文献
Regeneration of granulocytic and macrophage progenitor cells following irradiation may be regulated by fluctuations in circulating CSF-inhibitor levels and local production of CSF within the marrow cavity. 相似文献
7.
Intraperitoneal injection of choline (40, 80 or 120 mg/kg) produced a dose-dependent increase in serum glucose and choline levels in rats. The increases in serum glucose and choline were associated with an increase of serum insulin as well as plasma levels of epinephrine and norepinephrine. The increases in serum glucose and plasma catecholamine concentrations induced by choline (120 mg/kg) were blocked by pretreatment with the ganglionic nicotinic receptor antagonist hexamethonium (15 mg/kg), but were not affected by pretreatment with atropine (5 mg/kg). The choline-induced rise in serum insulin was blocked by pretreatment with atropine and with hexamethonium each. The increase in serum glucose evoked by choline (120 mg/kg) was blocked by alpha-adrenoceptor blockade and bilateral adrenalectomy each. Blockade of beta-adrenoceptor by propranolol or chemical sympathectomy by 6-hydroxydopamine failed to alter the hyperglycemic response to choline. These results show that choline, a precursor of the neurotransmitter acetylcholine, increases serum glucose and insulin levels. The effect of choline on serum insulin is mediated by both muscarinic and nicotinic acetylcholine receptors, whereas the effect of choline on serum glucose is mediated solely by nicotinic receptors. The stimulation of adrenal medullary catecholamine release and subsequent activation of alpha-adrenoceptors apparently mediates the hyperglycemic effect of choline. 相似文献
8.
Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. 总被引:5,自引:0,他引:5
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K. Gijbels S. Brocke J. S. Abrams L. Steinman 《Molecular medicine (Cambridge, Mass.)》1995,1(7):795-805
BACKGROUND: We previously demonstrated the local production of the pleiotropic cytokine interleukin-6 (IL-6) in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. MATERIALS AND METHODS: To assess the role of IL-6 in autoimmune CNS inflammation, we administered neutralizing antibodies to IL-6 in the EAE model. Their effect was examined at the clinical and histopathological level. Levels of administered antibody and IL-6 bioactivity were followed in serum and cerebrospinal fluid (CSF). RESULTS: Systemically administered antibodies penetrated into the fluid CSF in animals in which EAE was induced. Administration of anti-IL-6 reduced the development of actively induced as well as adoptively transferred EAE and was associated with increased levels of IL-6 activity in the CSF and to a lesser extent in the serum. Anti-IL-6 was still effective when given 1 day before the onset of disease signs in adoptively transferred EAE. The disease-reducing effect of anti-IL-6 was also reflected at the pathological level by the absence of inflammatory infiltrates in the CNS. CONCLUSIONS: Our study indicates that IL-6 plays an important role in autoimmune CNS inflammation. However, due to the complex nature of the in vivo interactions of administered antibodies, the disease-reducing effect of the anti-IL-6 antibodies could be caused by neutralization of IL-6 activity or by enhancement of IL-6 activity via induction of higher IL-6 levels in the CNS. 相似文献
9.
Age-related increase of kynurenic acid in human cerebrospinal fluid - IgG and beta2-microglobulin changes 总被引:2,自引:0,他引:2
Kynurenic acid (KYNA) is an endogenous metabolite in the kynurenine pathway of tryptophan degradation and is an antagonist at the glycine site of the N-methyl-D-aspartate as well as at the alpha 7 nicotinic cholinergic receptors. In the brain tissue KYNA is synthesised from L-kynurenine by kynurenine aminotransferases (KAT) I and II. A host of immune mediators influence tryptophan degradation. In the present study, the levels of KYNA in cerebrospinal fluid (CSF) and serum in a group of human subjects aged between 25 and 74 years were determined by using a high performance liquid chromatography method. In CSF and serum KAT I and II activities were investigated by radioenzymatic assay, and the levels of beta(2)-microglobulin, a marker for cellular immune activation, were determined by ELISA. The correlations between neurochemical and biological parameters were evaluated. Two subject groups with significantly different ages, i.e. <50 years and >50 years, p < 0.001, showed statistically significantly different CSF KYNA levels, i.e. 2.84 +/- 0.16 fmol/microl vs. 4.09 +/- 0.14 fmol/microl, p < 0.001, respectively; but this difference was not seen in serum samples. Interestingly, KYNA is synthesised in CSF principally by KAT I and not KAT II, however no relationship was found between enzyme activity and ageing. A positive relationship between CSF KYNA levels and age of subjects indicates a 95% probability of elevated CSF KYNA with ageing (R = 0.6639, p = 0.0001). KYNA levels significantly correlated with IgG and beta(2)-microglobulin levels (R = 0.5244, p = 0.0049; R = 0.4253, p = 0.043, respectively). No correlation was found between other biological parameters in CSF or serum. In summary, a positive relationship between the CSF KYNA level and ageing was found, and the data would suggest age-dependent increase of kynurenine metabolism in the CNS. An enhancement of CSF IgG and beta(2)-microglobulin levels would suggest an activation of the immune system during ageing. Increased KYNA metabolism may be involved in the hypofunction of the glutamatergic and/or nicotinic cholinergic neurotransmission in the ageing CNS. 相似文献
10.
Kern MA Bamborschke S Nekic M Schubert D Rydin C Lindholm D Schirmacher P 《Cytokine》2001,14(3):170-176
Hepatocyte growth factor (HGF) and its specific receptor, MET, are expressed in the developing and adult mammalian brain. Recent studies have shown a neurotrophic activity of HGF in the nervous system. The present study focused on HGF concentrations in the cerebrospinal fluid (CSF) and serum in normal persons and in different central nervous system (CNS) diseases considering blood-CSF barrier (BCB) function. Concentrations of HGF were analyzed using an enzyme-linked immunosorbent assay (ELISA). HGF was present in normal human CSF (346+/-126 pg/ml) representing approximately half of the HGF serum concentrations. The CSF HGF levels were not significantly changed in chronic CNS disease and in aseptic meningitis (419+/-71 pg/ml), but significantly increased in patients with bacterial meningitis (6101+/- 5200 pg/ml). The HGF levels in CSF were not influenced by increased serum concentrations in patients with normal or mildly affected BCB function. The results show that HGF is present in normal CSF and does not appear to cross the CSF barrier significantly unless it is severely disrupted. So far, strong increases of HGF concentration in CSF are only present in acute bacterial meningitis. 相似文献
11.
A sensitive chemiluminescence method for assay of choline which has been developed for analysis of erythrocyte and plasma levels of choline is reported here. This method includes a charcoal purification step which yields consistent results with plasma and erythrocyte extracts. Further, choline derived from membrane phosphatidylcholine may also be measured by an extension of this method following digestion with phospholipase D. This method has been used to study abnormal levels of erythrocyte choline that occur in cluster headache patients compared to control subjects and migraine patients. In addition, the time course of changes in plasma and erythrocyte choline following a fatty meal have been monitored. Plasma choline levels rise to a maximum between 1 and 3 h after the meal and this is followed by a rise in erythrocyte choline levels which are maximal 3 h after the meal. 相似文献
12.
Baraczka K Pozsonyi T Szüts I Ormos G Nékám K 《Acta microbiologica et immunologica Hungarica》2003,50(4):339-348
The aim of the present study was to investigate the serum and cerebrospinal fluid (CSF) concentrations of tumor necrosis factor alpha (TNF-alpha) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with primary progressive form of multiple sclerosis (MS) and in patients with connective tissue diseases (CTDs) complicated with central nervous system (CNS) involvement. Stimulation of sVCAM-1 release by TNF-alpha was demonstrated on endothelial cells of brain vessels. We intended to present the TNF-alpha stimulated elevation of sVCAM-1 in the serum and CSF in any cases of CNS lesion. Fifty patients with several CTDs complicated with neuropsychiatric symptoms and 25 MS patients with primary chronic progressive form of the disease were selected. Determinations of TNF-alpha and sVCAM-1 were performed using ELISA methods. TNF-alpha and sVCAM-1 concentrations were elevated in the CSF of all patients, intrathecal synthesis of sVCAM-1 was demonstrated in MS patients. The changes in the TNF-alpha and sVCAM-1 concentrations were independent from the clinical manifestations, immunoserological changes and quality of neuropsychiatric symptoms of the CTDs. The stimulatory effect of TNF-alpha was more pronounced in the CSF of MS patients. 相似文献
13.
João Casaca-Carreira Yasin Temel Sarah-Anna Hescham Ali Jahanshahi 《Molecular neurobiology》2018,55(4):2780-2788
Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases. 相似文献
14.
Felicita Pedata Lisa Giovannelli Patrizia De Sarno Giancarlo Pepeu 《Journal of neurochemistry》1986,46(5):1593-1598
Synaptosomes, prepared from rat cerebral cortex and hippocampus, were preincubated with [methyl-3H]choline. The effect of adenosine, cyclohexyladenosine, N-ethylcarboxamide adenosine, 2'-deoxyadenosine, and oxotremorine on K+-evoked 3H efflux was investigated. High-voltage electrophoretic separation showed that in the presence of physostigmine, the K+-evoked 3H efflux from hippocampal synaptosomes was 90% [3H]acetylcholine and 10% [3H]choline. Adenosine (30 microM) and oxotremorine (100 microM) both decreased [3H]acetylcholine release from hippocampal synaptosomes. The effect was inversely proportional to the KCl concentration and disappeared at a KCl concentration of 50 mM. Cyclohexyladenosine was approximately 3,000 times more active than adenosine, whereas N-ethylcarboxamide adenosine and 2'-deoxyadenosine were inactive. This indicates that A1 adenosine receptors were involved in the inhibitory effect. Caffeine antagonized the adenosine effect, and at a concentration of 100 microM, it stimulated [3H]acetylcholine efflux. The inhibitory effect of oxotremorine was as great in cortical as in hippocampal synaptosomes. In contrast, adenosine was much less active in cortical than in hippocampal synaptosomes. When inhibitory concentrations of adenosine and oxotremorine were added together into the incubation medium, the effect of adenosine on [3H]acetylcholine release was consistently reduced. An interaction between muscarinic and A1 adenosine presynaptic receptors at a common site modulating acetylcholine release can be assumed. 相似文献
15.
Michel U Gerber J E O'Connor A Bunkowski S Brück W Nau R Phillips DJ 《Journal of neurochemistry》2003,86(1):238-245
Activin, a member of the transforming growth factor superfamily, is upregulated in a number of inflammatory episodes such as septicemia and rheumatoid arthritis. In the CNS, activin has been predominantly assessed in terms of a neuroprotective role. In this report we characterized the activin response in the CNS in a rabbit model of meningitis. In normal animals, cerebrospinal fluid (CSF) activin levels were higher than those in serum, indicating an intracranial secretion of this cytokine. Following intracisternal inoculation with Streptococcus pneumoniae, activin in CSF was unchanged for the first 12 h and then rose progressively; levels were increased approximately 15-fold within 24 h. Activin levels were correlated positively with CSF protein content and with the number of apoptotic neurons in the dentate gyrus. No apparent correlation was observed between CSF activin concentrations and bacterial titer, lactate concentrations or leukocyte density. Using immunohistochemistry, activin staining was localized to epithelial cells of the choroid plexus, cortical neurons and the CA3 region of the hippocampus, with similar staining intensities in both normal and meningitic brains. However, in meningitic brains there was also strong staining in activated microglia and infiltrating macrophages. Taken together, these results demonstrate that activin forms part of the CNS response to immune challenge and may be an important mediator to modulate inflammatory processes in the brain. 相似文献
16.
Tina Sartorius Andreas Peter Martin Heni Walter Maetzler Andreas Fritsche Hans-Ulrich H?ring Anita M. Hennige 《PloS one》2015,10(5)
ObjectivesIt is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.MethodsInsulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.ResultsIn humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.ConclusionsThis study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system. 相似文献
17.
Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels. 相似文献
18.
N M van Gelder 《Journal of neurochemistry》1969,16(9):1355-1360
Abstract— The action of hydrazinopropionic acid in vivo on the metabolism of amino acids in the CNS of mice was studied over a period of 24 hr. At 82 μmoles/kg, a transient fourfold rise in the levels of tyrosine occurred followed by a more moderate and prolonged increase in the levels of GABA. When the dose of hydrazinopropionate was raised to 123 μmoles/kg, the changes in the levels of tyrosine were identical with those at the lower dose, while levels of GABA rose further before reaching a steady state. Levels of glutamate decreased concomitantly. In addition, the concentrations of alanine, β-aminoisobutyric acid and an unknown compound tended to rise. A doubling of the dose to 246 μmoles/kg enhanced the effects obtained with the lower doses but did not produce any new changes in the patterns of amino acids of the CNS. The elevation in the concentrations of alanine paralleled changes in the levels of tyrosine. The changes in the concentrations of the unknown compound, tentatively identified as α-aminoadipate, and of β-aminoisobutyric acid resembled those of GABA. The results are interpreted to indicate an inhibition by hydrazinopropionic acid of tyrosine aminotransferase and aminobutyrate aminotransferase. 相似文献
19.
Th1/Th2 cytokine balance and nitric oxide in cerebrospinal fluid and serum from patients with multiple sclerosis 总被引:3,自引:0,他引:3
Rodríguez-Sáinz Mdel C Sánchez-Ramón S de Andrés C Rodríguez-Mahou M Muñoz-Fernández MA 《European cytokine network》2002,13(1):110-114
Tumor necrosis factor (TNF-alpha) and IL-10 are key regulators of the T helper (Th)1/Th2 balance, which is critically skewed in many pathological conditions including immune-mediated inflammatory diseases of central nervous system (CNS) such as multiple sclerosis (MS). Nitric oxide (NO) has been reported to have dual effects on CNS pathology, and to play an important role in MS. We performed a cross-sectional study in 17 randomly selected patients during MS flare-up, and compared levels of TNF-alpha, IL-10 and NO in serum and cerebrospinal fluid (CSF) with the serum values of these mediators in two different control groups, healthy subjects and HIV-infected untreated patients. Serum and CSF values of TNF-alpha, IL-10 and NO were higher in MS patients than in the serum of healthy controls. Two MS patients showed increased levels of NO in CSF, with inversion of the NO(SERUM)/NO(CSF) quotient, which is clearly indicative of an intrathecal production of NO. No correlation among the values of both cytokines and NO, and the laboratory parameters analysed in MS patients (IgG index, presence of IgG oligoclonal bands and albumin quotient) was found. The high levels of TNF-alpha and IL-10 (both in serum and CSF) accompanying an MS attack suggest a simultaneous expression of Th1 and Th2 cytokines as opposed to sequential expression of Th1 followed by Th2 as described in the models of experimental autoimmune encephalomyelitis (EAE). Globally, our results support the inherent heterogeneity of the disease. 相似文献
20.
Banks WA Jaeger LB Urayama A Kumar VB Hileman SM Gaskin FS Llanza NV Farr SA Morley JE 《Peptides》2006,27(4):784-796
Antisense potentially can manipulate target gene expression in the brain if it can cross the blood-brain barrier (BBB). We designed three (10mer, 17mer, and 19mer) phosphorothioated antisenses (PS-ODNs) directed against the precursor molecule of methionine enkephalin (Met-Enk), an opiate peptide which suppresses voluntary ethanol drinking. We measured the ability of the antisenses to cross the BBB, accumulate in the brain and CSF, decrease levels of Met-Enk in brain and blood, and affect voluntary ethanol drinking. Each antisense readily crossed the BBB, with 0.07-0.16% of the i.v. dose accumulating per gram of brain. Capillary depletion and CSF sampling each confirmed that the antisenses entered the CNS. Gel electrophoresis of radioactivity recovered from brain and serum showed intact antisense and a higher molecular weight form likely representing antisense bound to protein, but no degradation products. Each antisense molecule and a cocktail of all three reduced Met-Enk levels in brain and serum. Met-Enk levels in the brain were reduced more rapidly and for a longer duration than Met-Enk levels in the serum, indicating a degree of selective targeting to the CNS. Additionally, administration of the cocktail was more effective in reducing Met-Enk levels than any of the individual antisenses. Each antisense increased voluntary ethanol drinking by about 20% and the cocktail increased it by about 80%. Taken together, these results used pharmacokinetic, immunochemical, and behavioral methods to show that PS-ODN antisenses that readily cross the BBB can decrease brain levels of Met-Enk and increase voluntary ethanol drinking. 相似文献