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Systemic Administration (systemic + administration)
Selected AbstractsSystemic Administration of Ghrelin Induces Fos and Egr-1 Proteins in the Hypothalamic Arcuate Nucleus of Fasted and Fed RatsJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2000A. K. Hewson Abstract Ghrelin, a recently identified endogenous ligand for the growth hormone secretagogue (GHS) receptor, induces growth hormone (GH) secretion following systemic administration. We sought to determine whether systemic administration of ghrelin activates cells in the hypothalamic arcuate nucleus by examining the distribution of cells expressing Fos and Egr-1 proteins. In normally fed rats, both ghrelin and GHRP-6 (a synthetic GHS) significantly increased the number of cells expressing Fos and Egr-1 in the arcuate nucleus. The effects of ghrelin and GHRP-6 to induce Fos or Egr-1 protein expression was significantly greater in fasted than in fed rats. Thus, we show that (i) ghrelin is a centrally active peptide; (ii) it acts in a similar manner to synthetic GHS; and (iii) its central actions are increased in fasting, presumably reflecting physiological changes that accompany altered food intake and/or nutritional state. [source] Systemic Administration of Arecoline Reduces Ethanol-Induced Sleeping Through Activation of Central Muscarinic Receptor in MiceALCOHOLISM, Issue 1 2010Yan-Ping Sun Background:, Epidemiological evidence of co-use of alcohol and areca nuts suggests a potential central interaction between arecoline, a major alkaloid of areca and a muscarinic receptor agonist, and ethanol. Moreover, the central cholinergic system plays an important role in the depressant action of ethanol and barbiturates. The purpose of this study was to investigate the effects of arecoline on pentobarbital- and ethanol-induced hypnosis in mice. Methods:, Male ICR mice were tested for locomotor activity following acute systemic administration of ethanol alone, arecoline alone, or ethanol plus arecoline. For the loss of the righting reflex (LORR) induced by pentobarbital and ethanol, sleep latency and sleeping duration were evaluated in mice treated with arecoline alone or the combination of arecoline and scopolamine or methscopolamine. Results:, Ethanol (1.0 to 3.0 g/kg, i.p.) reduced locomotor activity significantly and a declining trend was observed after treatment with arecoline (0.25 to 1.0 mg/kg, i.p.), but there were no synergistic effects of ethanol and arecoline on locomotor activity. The experiments on LORR demonstrated that arecoline (0.125 to 1.0 mg/kg, s.c.) shortened the duration of sleeping induced by ethanol (4.0 g/kg, i.p.), but not pentobarbital (45 mg/kg, i.p.). In addition, alterations of sleep latency were not obvious in both pentobarbital- and ethanol-induced LORR. Statistical analyses revealed that scopolamine (centrally acting), but not methscopolamine (peripherally acting), could antagonize the effect of arecoline on the duration of ethanol-induced LORR in mice. Conclusions:, These results suggest that central muscarinic receptor is a pharmacological target for the action of arecoline to modulate ethanol-induced hypnosis. [source] Effect of Perilesional Injections of PEG-Interleukin-2 on Basal Cell CarcinomaDERMATOLOGIC SURGERY, Issue 11 2000Baruch Kaplan MD Background: Multiple modalities are available for the treatment of basal cell carcinoma (BCC). The most commonly used modalities include simple excision, Mohs micrographic surgery, curettage and electrodessication, cryosurgery, and irradiation therapy. Interleukin-2 (IL-2) is a cytokine produced chiefly by activated T lymphocytes and has effects on various components of the immune system. Until now the primary clinical use of IL-2 has been in advanced stages of metastatic melanoma and renal cell carcinoma. Systemic administration of IL-2 is known to cause significant toxicity. Objective: The objective of this study was to evaluate the therapeutic efficacy and safety of perilesional PEG-IL-2 injections in patients with BCC in an open label, uncontrolled pilot study. Methods: Patients with histologically confirmed primary BCC over 18 years of age were included in the study. Lesions were treated by injecting a total volume of 0.5 cc of IL-2 in a radial fashion in the subcutaneous tissue. Injection dosages ranged from 3000 to 1,200,000 IU in one to four weekly dosages. A total of 12 tumors were treated in eight patients. Results: Overall response rates were as follows: complete response in 8 of 12 treated tumors (66.6% cure rate), partial response in 3 of 12 injected tumors (25% partial response rate), stable disease with no improvement in 1 treatment site (8.4%). Side effects included local pain, swelling, and erythema, and in one patient flulike symptoms. There were no significant changes of blood tests as compared to baseline levels. Conclusions: The therapeutic response induced by perilesional PEG-IL-2 injections was found to be an encouraging, safe, and well-tolerated treatment of BCC. Further studies including a larger patient population and long-term follow-up are necessary in order to substantiate these findings. [source] Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Camila L. Zold Abstract There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves (,direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. ,Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism. [source] N -methyl- d -aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following strokeEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2001Andreas Arvidsson Abstract Neurogenesis in the adult rat dentate gyrus was studied following focal ischemic insults produced by middle cerebral artery occlusion (MCAO). Animals were subjected to either 30 min of MCAO, which causes damage confined to the striatum, or 2 h of MCAO, which leads to both striatal and cortical infarction. When compared to sham-operated rats, MCAO-rats showed a marked increase of the number of cells double-labelled for 5-bromo-2,-deoxyuridine-5,-monophosphate (BrdU; injected during 4,6 days postischemia) and neuronal-specific antigen (NeuN; a marker of postmitotic neurons) in the ipsilateral dentate granule cell layer and subgranular zone at 5 weeks following the 2 h insult. Only a modest and variable increase of BrdU-labelled cells was found after 30 min of MCAO. The enhanced neurogenesis was not dependent on cell death in the hippocampus, and its magnitude was not correlated to the degree of cortical damage. Systemic administration of the N -methyl- d -aspartate (NMDA) receptor blocker dizocilpine maleate (MK-801) completely suppressed the elevated neurogenesis following 2 h of MCAO. Our findings indicate that stroke leads to increased neurogenesis in the adult rat dentate gyrus through glutamatergic mechanisms acting on NMDA receptors. This modulatory effect may be mediated through changes in the levels of several growth factors, which occur after stroke, and could influence various regulatory steps of neurogenesis. [source] Cholinergic suppression of excitatory synaptic responses in layer II of the medial entorhinal cortexHIPPOCAMPUS, Issue 2 2007Bassam N. Hamam Abstract Theta-frequency (4,12 Hz) electroencephalographic activity is thought to play a role in mechanisms mediating sensory and mnemonic processing in the entorhinal cortex and hippocampus, but the effects of acetylcholine on excitatory synaptic inputs to the entorhinal cortex are not well understood. Field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the piriform (olfactory) cortex were recorded in the medial entorhinal cortex during behaviors associated with theta activity (active mobility) and were compared with those recorded during nontheta behaviors (awake immobility and slow wave sleep). Synaptic responses were smaller during behavioral activity than during awake immobility and sleep, and responses recorded during movement were largest during the negative phase of the theta rhythm. Systemic administration of cholinergic agonists reduced the amplitude of fEPSPs, and the muscarinic receptor blocker scopolamine strongly enhanced fEPSPs, suggesting that the theta-related suppression of fEPSPs is mediated in part by cholinergic inputs. The reduction in fEPSPs was investigated using in vitro intracellular recordings of EPSPs in Layer II neurons evoked by stimulation of Layer I afferents. Constant bath application of the muscarinic agonist carbachol depolarized membrane potential and suppressed EPSP amplitude in Layer II neurons. The suppression of EPSPs was not associated with a substantial change in input resistance, and could not be accounted for by a depolarization-induced reduction in driving force on the EPSP. The GABAA receptor-blocker bicuculline (50 ,M) did not prevent the cholinergic suppression of EPSPs, suggesting that the suppression is not dependent on inhibitory mechanisms. Paired-pulse facilitation of field and intracellular EPSPs were enhanced by carbachol, indicating that the suppression is likely due to inhibition of presynaptic glutamate release. These results indicate that, in addition to well known effects on postsynaptic conductances that increase cellular excitability, cholinergic activation in the entorhinal cortex results in a strong reduction in strength of excitatory synaptic inputs from the piriform cortex. © 2006 Wiley-Liss, Inc. [source] Selective Blockade of Voltage-Gated Potassium Channels Reduces Inflammatory Bone Resorption in Experimental Periodontal Disease,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2004Paloma Valverde Abstract The effects of the potassium channel (Kv1.3) blocker kaliotoxin on T-cell-mediated periodontal bone resorption were examined in rats. Systemic administration of kaliotoxin abrogated the bone resorption in conjunction with decreased RANKL mRNA expression by T-cells in gingival tissue. This study suggests a plausible therapeutic approach for inflammatory bone resorption by targeting Kv1.3. Introduction: Kv1.3 is a critical potassium channel to counterbalance calcium influx at T-cell receptor activation. It is not known if Kv1.3 also regulates RANKL expression by antigen-activated T-cells, and consequently affects in vivo bone resorption mediated by activated T-cells. Materials and Methods:Actinobacillus actinomycetemcomitans 29-kDa outer membrane protein-specific Th1-clone cells were used to evaluate the expression of Kv1.3 (using reverse transcriptase-polymerase chain reaction [RT-PCR] and Western blot analyses) and the effects of the potassium channel blocker kaliotoxin (0,100 nM) on T-cell activation parameters ([3H]thymidine incorporation assays and ELISA) and expression of RANKL and osteoprotegerin (OPG; flow cytometry, Western blot, and RT-PCR analyses). A rat periodontal disease model based on the adoptive transfer of activated 29-kDa outer membrane protein-specific Th1 clone cells was used to analyze the effects of kaliotoxin in T-cell-mediated alveolar bone resorption and RANKL and OPG mRNA expression by gingival T-cells. Stimulated 29-kDa outer membrane protein-specific Th1 clone cells were transferred intravenously on day 0 to all animals used in the study (n = 7 animals per group). Ten micrograms of kaliotoxin were injected subcutaneously twice per day on days 0, 1, 2, and 3, after adoptive transfer of the T-cells. The control group of rats was injected with saline as placebo on the same days as injections for the kaliotoxin-treated group. The MOCP-5 osteoclast precursor cell line was used in co-culture studies with fixed 29-kDa outer membrane protein-specific Th1-clone cells to measure T-cell-derived RANKL-mediated effects on osteoclastogenesis and resorption pit formation assays in vitro. Statistical significance was evaluated by Student's t -test. Results: Kaliotoxin decreased T-cell activation parameters of 29-kDa outer membrane protein-specific Th1 clone cells in vitro and in vivo. Most importantly, kaliotoxin administration resulted in an 84% decrease of the bone resorption induced in the saline-treated control group. T-cells recovered from the gingival tissue of kaliotoxin-treated rats displayed lower ratios of RANKL and OPG mRNA expression than those recovered from the control group. The ratio of RANKL and osteoprotegerin protein expression and induction of RANKL-dependent osteoclastogenesis by the activated T-cells were also markedly decreased after kaliotoxin treatments in vitro. Conclusion: The use of kaliotoxin or other means to block Kv1.3 may constitute a potential intervention therapy to prevent alveolar bone loss in periodontal disease. [source] Effect of systemic parathyroid hormone (1,34) and a , -tricalcium phosphate biomaterial on local bone formation in a critical-size rat calvarial defect modelJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 5 2010Jonathan I. Yun Yun JI, Wikesjö UME, Borke JL, Bisch FC, Lewis JE, Herold RW, Swiec GD, Wood JC, McPherson III JC. Effect of systemic parathyroid hormone (1,34) and a ,-tricalcium phosphate biomaterial on local bone formation in a critical-size rat calvarial defect model. J Clin Periodontol 2010; 37: 419,426 doi: 10.1111/j.1600-051X.2010.01547.x Abstract Objective: The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1,34) (PTH), a surgically implanted synthetic , -tricalcium phosphate (, -TCP) bone biomaterial serving as a matrix to support new bone formation. Materials and Methods: Critical-size, 8 mm, calvarial through-and-through osteotomy defects were surgically created in 100 adult male Sprague,Dawley rats. The animals were randomized into five groups of 20 animals each to receive one of the following treatments: PTH (15 ,g PTH/kg/day; subcutaneously), PTH/, -TCP, , -TCP, or particulate human demineralized freeze-dried bone (DFDB), and sham-surgery controls. Ten animals/group were euthanized at 4 and 8 weeks post-surgery for radiographic and histometric analysis. Results: The histometric analysis showed that systemic PTH significantly enhanced local bone formation, bone fill averaging (±SE) 32.2±4.0% compared with PTH/, -TCP (15.7±2.4%), , -TCP (12.5±2.3%), DFDB (14.5±2.3%), and sham-surgery control (10.0±1.5%) at 4 weeks (p<0.014). Systemic PTH showed significantly enhanced bone formation (41.5±4.0%) compared with PTH/, -TCP (22.4±3.0%), , -TCP (21.3±4.4%), and with the sham-surgery control (23.8±4.2%) at 8 weeks (p<0.025). The DFDB group showed significantly increased bone formation from 4 (14.5±2.3%) to 8 weeks (32.0±3.2%) (p<0.006). The PTH/, -TCP and , -TCP groups both showed limited biomaterials resorption. The radiographic analysis was not diagnostic to distinguish local bone formation from the radiopaque , -TCP biomaterial. Conclusions: Systemic administration of PTH significantly stimulates local bone formation. Bone formation was significantly limited by the , -TCP biomaterial. [source] Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 4 2006Christiana Xajigeorgiou Abstract Aim: To evaluate and compare the effects of adjunctive metronidazole plus amoxicillin, doxycycline and metronidazole on clinical and microbiological parameters in patients with generalized aggressive periodontitis. Material and Methods: Forty-three patients participated in this randomized clinical trial divided into four groups. Six weeks after scaling and root planning (SRP), groups 1,3 received adjunctive metronidazole, plus amoxicillin, doxycycline and metronidazole respectively, and group 4 acted as controls. Clinical recordings concerning probing depth, probing attachment level and bleeding on probing were performed at baseline, 6 weeks after SRP and 6 months from baseline. Subgingival samples were analysed using the ,checkerboard' DNA,DNA hybridization for Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Tannerella forsythia and Treponema denticola. Results: All treatments resulted in improvement of clinical parameters (ANOVA p>0.05). Systemic administration of metronidazole plus amoxicillin or metronidazole resulted in statistically significant greater reduction of the proportion of sites > 6mm than SRP (z -test, p<0.05). These antimicrobials yielded a significant effect on levels of important periodontal pathogens for 6 months. Conclusion: Adjunctive metronidazole plus amoxicillin or metronidazole alone (when A.actinomycetemcomitans is not involved) is effective in deep pockets of aggressive periodontitis patients. [source] Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat modelsAGING CELL, Issue 2 2010Li-Fang Hu Summary Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H2S, a novel biological gas) on PD. The endogenous H2S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H2S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H2S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-, and nitric oxide) in the striatum via NF-,B pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD. [source] In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chlorideJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 4 2005Yu-Ting Kuo MD Abstract Purpose To measure regional T1 and T2 values for normal C57Bl/6 mouse brain and changes in T1 after systemic administration of manganese chloride (MnCl2) at 9.4 T. Materials and Methods C57Bl/6 mice were anesthetized and baseline T1 and T2 measurements obtained prior to measurement of T1 after administration of MnCl2 at 9.4 T. MnCl2 was administered systemically either by the intravenous (IV), intraperitoneal (IP), or subcutaneous (SC) routes. T1 and T2 maps for each MRI transverse slice were generated using commercial software, and T1 and T2 values of white matter (WM), gray matter (GM), pituitary gland, and lateral ventricle were obtained. Results When compared with baseline values at low-field, significant lengthening of the T1 values was shown at 9.4 T, while no significant change was seen for T2 values. Significant T1 shortening of the normal mouse brain was observed following IV, IP, and SC administration of MnCl2, with IV and IP showing similar acute effects. Significant decreases in T1 values were seen for the pituitary gland and the ventricles 15 minutes after either IV or IP injection. GM showed greater uptake of the contrast agent than WM at 15 and 45 minutes after either IV or IP injections. Although both structures are within the blood-brain barrier (BBB), GM and WM revealed a steady decrease in T1 values at 24 and 72 hours after MnCl2 injection regardless of the route of administration. Conclusion Systemic administration of MnCl2 by IV and IP routes induced similar time-course of T1 changes in different regions of the mouse brain. Acute effects of MnCl2 administration were mainly influenced by either the presence or absence of BBB. SC injection also provided significant T1 change at subacute stage after MnCl2 administration. J. Magn. Reson. Imaging 2005;21:334,339. © 2005 Wiley-Liss, Inc. [source] Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal NOS-dependent mechanismJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Stephen Sammut Abstract Striatal nitric oxide (NO) signaling plays a critical role in modulating neural processing and motor behavior. Nitrergic interneurons receive synaptic inputs from corticostriatal neurons and are activated via ionotropic glutamate receptor stimulation. However, the afferent regulation of NO signaling is poorly characterized. The role of frontal cortical afferents in regulating NO transmission was assessed in anesthetized rats using amperometric microsensor measurements of NO efflux and local field potential recordings. Low frequency (3 Hz) electrical stimulation of the ipsilateral cortex did not consistently evoke detectable changes in striatal NO efflux. In contrast, train stimulation (30 Hz) of frontal cortical afferents facilitated NO efflux in a stimulus intensity-dependent manner. Nitric oxide efflux evoked by train stimulation was transient, reproducible over time, and attenuated by systemic administration of either the NMDA receptor antagonist MK-801 or the neuronal NO synthase inhibitors 7-nitroindazole and NG -propyl- l -arginine. The interaction between NO efflux evoked via train stimulation and local striatal neuron activity was assessed using dual microsensor and local field potential recordings carried out concurrently in the contralateral and ipsilateral striatum, respectively. Systemic administration of the non-specific NO synthase inhibitor methylene blue attenuated both evoked NO efflux and the peak oscillation frequency (within the delta band) of local field potentials recorded immediately after train stimulation. Taken together, these observations indicate that feed-forward activation of neuronal NO signaling by phasic activation of frontal cortical afferents facilitates the synchronization of glutamate driven oscillations in striatal neurons. Thus, NO signaling may act to amplify coherent corticostriatal transmission and synchronize striatal output. [source] Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout miceJOURNAL OF NEUROCHEMISTRY, Issue 1 2003A. M. Gardier Abstract The role of serotonin (5-HT)1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT1B receptor knockout (KO 5-HT1B) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal [5-HT]ext values in the medial prefrontal cortex and ventral hippocampus, ,,20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in saline-pretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT1A autoreceptors, 1 µm paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wild-type mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in the medial prefrontal cortex and ventral hippocampus of wild-type and KO 5-HT1B mice, we found that basal [5-HT]ext and the extraction fraction of 5-HT were similar in the medial prefrontal cortex and ventral hippocampus of both genotypes, suggesting that no compensatory response to the constitutive deletion of the 5-HT1B receptor involving changes in 5-HT uptake capacity occurred in vivo. As steady-state brain concentrations of paroxetine at day 14 were similar in both genotypes, it is unlikely that differences in the effects of a paroxetine challenge on hippocampal [5-HT]ext are due to alterations of the drug's pharmacokinetic properties in mutants. These data suggest that there are differences between the ventral hippocampus and medial prefrontal cortex in activation of terminal 5-HT1B autoreceptors and their role in regulating dialysate 5-HT levels. These presynaptic receptors retain their capacity to limit 5-HT release mainly in the ventral hippocampus following chronic paroxetine treatment in mice. [source] Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Sergio Veiga Abstract The peripheral-type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5-4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5-4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions. © 2005 Wiley-Liss, Inc. [source] Region-Specific Induction of FosB/,FosB by Voluntary Alcohol Intake: Effects of NaltrexoneALCOHOLISM, Issue 10 2010Jing Li Background:, ,FosB is the best characterized transcription factor induced by chronic stimulation. Although previous studies have demonstrated that chronic passive ethanol exposure alters ,FosB immunoreactivity (IR), the effect of chronic voluntary ethanol consumption on ,FosB remains unknown. Furthermore, although previous studies have demonstrated that the opioid antagonist naltrexone reduces alcohol consumption in clinical and preclinical settings, the effect of naltrexone on FosB/,FosB has not been explored. Here, we examined the effects of chronic voluntary ethanol intake and naltrexone on FosB/,FosB IR in striatal region and prefrontal cortex, and the effect of naltrexone on voluntary ethanol intake. Methods:, We utilized immunohistochemistry to define the changes in FosB/,FosB IR induced by chronic voluntary ethanol intake under a two-bottle intermittent access of 20% ethanol model and by systematic administration (intraperitoneal injection) of naltrexone in Sprague-Dawley rats. Results:, Chronic (15 drinking sessions in 35 days) voluntary ethanol intake robustly induces FosB/,FosB IR in nucleus accumbens core, dorsolateral striatum, and orbitofrontal cortex, but not in nucleus accumbens shell, dorsomedial striatum, and medial prefrontal cortex. Systemic administration of naltrexone for 6 days significantly reduced voluntary ethanol consumption and FosB/,FosB IR induced by chronic voluntary ethanol intake. Conclusion:, Our results suggest that chronic voluntary ethanol intake induces FosB/,FosB IR in a subregion-specific manner which involves the activation of endogenous opioid system. [source] Suppression of melatonin biosynthesis in the chicken pineal gland by retinally perceived light , involvement of D1-dopamine receptorsJOURNAL OF PINEAL RESEARCH, Issue 2 2004Jolanta B. Zawilska Abstract:, In this study the role of retinal dopamine (DA) receptors in the light-induced suppression of melatonin biosynthesis in the chicken pineal gland was examined. Exposure of dark-adapted chickens to low intensity light (4 lux) at night significantly decreased the activity of serotonin N-acetyltransferase (AA-NAT; the penultimate and key regulatory enzyme in melatonin production) and melatonin content in the pineal gland. This suppressive action of light was blocked by intraocular (i.oc.) administration of SCH 23390 (a selective antagonist of D1-DA receptors), but was not affected by sulpiride (a selective antagonist of D2-DA receptors). Injection of DA (i.oc.) to dark-adapted chickens significantly decreased pineal AA-NAT activity and melatonin content in a dose- and time-dependent manner. The action of DA was mimicked by selective agonists of D1-DA receptors, SKF 38393 and SKF 81297, and non-hydrolyzable analogs of cyclic AMP (cAMP), dibutyryl-cAMP and 8-bromo-cAMP. However, i.oc. administration of quinpirole, a selective agonist of D2-DA receptors, did not modify pineal AA-NAT activity. In contrast, quinpirole potently decreased nocturnal AA-NAT activity in the retina. Systemic administration of SCH 23390 to chickens blocked the i.oc. DA-evoked decline in nighttime pineal AA-NAT activity, whereas sulpiride was ineffective. These findings indicate that light activation of retinal dopaminergic neurotransmission, with concomitant stimulation of D1-DA receptors positively coupled to the cAMP generating system, plays an important role in a cascade of events regulating pineal activity. [source] Physiology and Treatment of Retained Fetal Membranes in CattleJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2010J.C. Beagley Retained fetal membranes (RFM) in cattle have adverse effects on fertility and production. Understanding the pathophysiology and causes of RFM is important for managing this disease. The hormonal processes that lead to normal placental separation are multifactorial and begin before parturition. A variety of risk factors, including early or induced parturition, dystocia, hormonal imbalances, and immunosuppression, can interrupt these normal processes and result in retention of the placenta. Current research does not support the efficacy of many commonly practiced treatments for RFM. Systemic administration of antibiotics can be beneficial for treating metritis after RFM, but antibiotic administration has not been shown to significantly improve future reproduction in cows with RFM. Collagenase injected into the umbilical arteries of retained placentas specifically targets the lack of placentome proteolysis and might enhance placental release. However, such therapy is costly and its benefits in terms of improving subsequent reproductive function have not been evaluated. [source] Administration of dendritic cells modified by RNA interference prolongs cardiac allograft survivalMICROSURGERY, Issue 4 2007Jianbin Xiang M.D. Systemic administration of immature donor-dendritic cells (DC) that are deficient in co-stimulatory molecules delays the onset of allograft rejection. However, it is not easy to control culture condition and guarantee that the administered DC are in the immature stages, which obviously affects their therapeutic effect. In this study, we attempted to inhibit expression of CD86 on DC using an RNA interference technology. The function of CD86low DC was determined by the influence on their capacity to stimulate T cell proliferation and by the effect of DC systemic administration on survival of cardiac allografts. CD86low DC stimulated low T cell proliferative responses in vitro and administration of CD86low DC prolonged survival of heart allografts in vivo. These results suggest that RNA interference is a useful approach to modify DC function, which has potentials for clinical application. © 2007 Wiley-Liss, Inc. Microsurgery 2007. [source] A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease,MOVEMENT DISORDERS, Issue S1 2010C. Savio Chan PhD Abstract Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca2+ channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca2+ channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD. © 2010 Movement Disorder Society [source] Oxytocin receptor expressed on the smooth muscle mediates the excitatory effect of oxytocin on gastric motility in ratsNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2009J. Qin Abstract, The aim of this study was to localize oxytocin receptor (OTR) in the stomach and to investigate the effect of OT on gastric motility in rats. Western blot and immunohistochemistry methods were used to localize OTR in stomach. The motility of stomach was recorded in vivo (recording of the intragastric pressure), in vitro (recording of the contraction of muscle strips) and on isolated smooth muscle cells. OTR was expressed on cells of both circular and longitudinal muscle of stomach. Systemic administration of OT induced an early transient decrease and a subsequent increase on intragastric pressure. Devazepide (1 mg kg,1, i.v.), a cholecystokinin-1 (CCK1) receptor antagonist, completely abolished the transient response but did not influence the subsequent one. OT (10,9,10,6 mol L,1) dose-dependently increased the contraction of the muscle strips of gastric body, antrum, and pyloric sphincter, and decreased the average cell length of isolated smooth muscle cells. Tetrodotoxin and atropine did not influence the effect of OT on muscle strips. Pretreatment with atosiban, an OTR antagonist, inhibited the spontaneous contraction of muscle strips and abolished the excitatory effect of OT on the muscle strips and the isolated cells. These results suggest that the OTR is expressed on the smooth muscle of the stomach and mediates excitatory effect of OT on gastric motility. [source] Effect of nebulized albuterol on blood glucose in patients with diabetes mellitus with and without cystic fibrosisPEDIATRIC PULMONOLOGY, Issue 2 2005P. König MD Abstract Over 90% of cystic fibrosis (CF) patients are treated with bronchodilators, and 6% have diabetes. Some with asthma also have diabetes, and most are treated with bronchodilators. Systemic administration of adrenergic agents can cause increases in blood glucose, but the effect of inhaled agents is unclear. A double-blind study was performed on 10 patients with type 1 diabetes mellitus (DM) without CF (3 male, 7 female, mean age 25.5 years) and 9 patients with insulin-dependent CF-related diabetes (CFRD) (8 male, 1 female, mean age 21.9 years). On 2 separate days before 9 AM fasting and the morning dose of insulin, 2.5 mg of albuterol or nebulized placebo were given. Blood glucose was measured by finger stick with a glucose reflectance meter before and 15, 30, 45, and 60 min after treatment. No significant changes from baseline or differences between placebo and albuterol occurred in either group. The mean maximum increase from baseline in DM was 20 mg/dl on placebo, and 38 mg/dl on albuterol; in the CFRD, the respective changes were 7 and 7 mg/dl. Two DM patients had a >,50 mg/dl increase on albuterol vs. placebo; no CFRD patients had differences of such magnitude. DM patients had greater increases from baseline than CFRD patients on placebo and albuterol. Differences reached statistical significance at 30 and 45 min on placebo, and 45 min on albuterol. Albuterol 2.5 mg by nebulizer causes no clinically significant increases in blood glucose in DM or CFRD patients. Diabetes patients without CF have a significantly greater increase of glucose with time (placebo or albuterol) than CFRD patients. Pediatr Pulmonol. 2005; 40:105,108. © 2005 Wiley-Liss, Inc. [source] Dynamics of circulating concentrations of gonadotropins and ovarian hormones throughout the menstrual cycle in the bonnet monkey: role of inhibin A in the regulation of follicle-stimulating hormone secretionAMERICAN JOURNAL OF PRIMATOLOGY, Issue 10 2009P.S. Suresh Abstract In higher primates, increased circulating follicle-stimulating hormone (FSH) levels seen during late menstrual cycle and during menstruation has been suggested to be necessary for initiation of follicular growth, recruitment of follicles and eventually culminating in ovulation of a single follicle. With a view to establish the dynamics of circulating FSH secretion with that of inhibin A (INH A) and progesterone (P4) secretions during the menstrual cycle, blood was collected daily from bonnet monkeys beginning day 1 of the menstrual cycle up to 35 days. Serum INH A levels were low during early follicular phase, increased significantly coinciding with the mid cycle luteinizing hormone (LH) surge to reach maximal levels during the mid luteal phase before declining at the late luteal phase, essentially paralleling the pattern of P4 secretion seen throughout the luteal phase. Circulating FSH levels were low during early and mid luteal phases, but progressively increased during the late luteal phase and remained high for few days after the onset of menses. In another experiment, lutectomy performed during the mid luteal phase resulted in significant decrease in INH A concentration within 2,hr (58.3±2 vs. 27.3±3,pg/mL), and a 2- to 3-fold rise in circulating FSH levels by 24,hr (0.20±0.02 vs. 0.53±0.14,ng/mL) that remained high until 48,hr postlutectomy. Systemic administration of Cetrorelix (150,µg/kg body weight), a gonadotropin releasing hormone receptor antagonist, at mid luteal phase in monkeys led to suppression of serum INH A and P4 concentrations 24,hr post treatment, but circulating FSH levels did not change. Administration of exogenous LH, but not FSH, significantly increased INH A concentration. The results taken together suggest a tight coupling between LH and INH A secretion and that INH A is largely responsible for maintenance of low FSH concentration seen during the luteal phase. Am. J. Primatol. 71:817,824, 2009. © 2009 Wiley-Liss, Inc. [source] Development and characterization of a synthetic promoter for selective expression in proliferating endothelial cellsTHE JOURNAL OF GENE MEDICINE, Issue 4 2006P. Szymanski Abstract Background Systemic administration of non-viral gene therapy provides better access to tumors than local administration. Development of a promoter that restricts expression of cytotoxic proteins to the tumor vasculature will increase the safety of the system by minimizing expression in the non-dividing endothelial cells of the vasculature of non-target tissues. Methods Cell cycle promoters were tested for selective expression in dividing cells vs. non-dividing cells in vitro and promoter strength was compared to the cytomegalovirus (CMV) promoter. Successful promoter candidates were tested in vivo using two proliferating endothelium mouse models. Ovarectomized mice were injected with estradiol prior to lipoplex administration and expression levels were measured in the lungs and uterus 4 days after administration. The second model was a subcutaneous tumor model and expression levels were measured in the lungs and tumors. For both animal models, expression levels from the proliferating endothelium promoter were compared to that obtained from a CMV promoter. Results The results showed that the Cdc6 promoter yielded higher expression in proliferating vs. non-proliferating cells. Secondly, promoter strength could be selectively increased in endothelial cells by the addition of a multimerized endothelin enhancer (ET) to the Cdc6 promoter. Thirdly, comparison of expression levels in the lungs vs. uterus in the ovarectomized mouse model and lungs vs. tumor in the mouse tumor model showed expression was much higher in the uterus and the tumor than in the lungs for the ET/Cdc6 promoter, and expression levels were comparable to that of the CMV promoter in the hypervascularized tissues. Conclusions These results demonstrate that the combination of the endothelin enhancer with the Cdc6 promoter yields selective expression in proliferating endothelium and can be used to express cytotoxic proteins to treat vascularized tumors. Copyright © 2006 John Wiley & Sons, Ltd. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Acute and Repeated Flibanserin Administration in Female Rats Modulates Monoamines Differentially Across Brain Areas: A Microdialysis StudyTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2010Kelly A. Allers PhD ABSTRACT Introduction., Hypoactive sexual desire disorder (HSDD) is defined as persistent lack of sexual fantasies or desire marked by distress. With a prevalence of 10% it is the most common form of female sexual dysfunction. Recently, the serotonin-1A (5-HT1A) receptor agonist and the serotonin-2A (5-HT2A) receptor antagonist flibanserin were shown to be safe and efficacious in premenopausal women suffering from HSDD in phase III clinical trials. Aim., The current study aims to assess the effect of flibanserin on neurotransmitters serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and ,-aminobutyric acid (GABA) in brain areas associated with sexual behavior. Methods., Flibanserin was administered to female Wistar rats (280,350 g). Microdialysis probes were stereotactically inserted into the mPFC, NAC, or MPOA, under isoflurane anesthesia. The extracellular levels of neurotransmitters were assessed in freely moving animals, 24 hours after the surgery. Main Outcome Measures., Dialysate levels of DA, NE, and serotonin from medial prefrontal cortex (mPFC), nucleus accumbens (NAC), and hypothalamic medial preoptic area (MPOA) from female rats. Results., Acute flibanserin administration decreased 5-HT and increased NE levels in all tested areas. DA was increased in mPFC and MPOA, but not in the NAC. Basal levels of NE in mPFC and NAC and of DA in mPFC were increased upon repeated flibanserin administration, when compared to vehicle-treated animals. The basal levels of 5-HT were not altered by repeated flibanserin administration, but basal DA and NE levels were increased in the mPFC. Glutamate and GABA levels remained unchanged following either repeated or acute flibanserin treatment. Conclusions., Systemic administration of flibanserin to female rats differentially affects the monoamine systems of the brain. This may be the mechanistic underpinning of flibanserin's therapeutic efficacy in HSDD, as sexual behavior is controlled by an intricate interplay between stimulatory (catecholaminergic) and inhibitory (serotonergic) systems. Allers KA, Dremencov E, Ceci A, Flik G, Ferger B, Cremers TIFH, Ittrich C, and Sommer B. Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: A microdialysis study. J Sex Med 2010;7:1757,1767. [source] Silencing Nogo-A promotes functional recovery in demyelinating diseaseANNALS OF NEUROLOGY, Issue 4 2010Yuhong Yang MD Objective To determine if suppressing Nogo-A, an axonal inhibitory protein, will promote functional recovery in a murine model of multiple sclerosis (MS). Methods A small interfering RNA was developed to specifically suppress Nogo-A (siRNA-NogoA). The siRNA-NogoA silencing effect was evaluated in vitro and in vivo via immunohistochemistry. The siRNA was administered intravenously in 2 models of experimental autoimmune encephalomyelitis (EAE). Axonal repair was measured by upregulation of GAP43. Enzyme-linked immunosorbent assay, flow cytometry, and 3H-thymidine incorporation were used to determine immunological changes in myelin-specific T cells in mice with EAE. Results The siRNA-NogoA suppressed Nogo-A expression in vitro and in vivo. Systemic administration of siRNA-NogoA ameliorated EAE and promoted axonal repair, as demonstrated by enhanced GAP43+ axons in the lesions. Myelin-specific T-cell proliferation and cytokine production were unchanged in the siRNA-NogoA,treated mice. Interpretation Silencing Nogo-A in EAE promotes functional recovery. The therapeutic benefit appears to be mediated by axonal growth and repair, and is not attributable to changes in the encephalitogenic capacity of the myelin-specific T cells. Silencing Nogo-A may be a therapeutic option for MS patients to prevent permanent functional deficits caused by immune-mediated axonal damage. ANN NEUROL 2010;67:498,507 [source] Lack of nigrostriatal pathology in a rat model of proteasome inhibitionANNALS OF NEUROLOGY, Issue 2 2006Amy B. Manning-Bo Systemic administration of ubiquitin-proteasome system inhibitors to rodents has been reported to induce certain behavioral and neuropathological features of Parkinson's disease. The goal of this study was to replicate these observations by administering a proteasome inhibitor (PSI) to rats using McNaught and colleagues' protocol. No alterations in locomotor activity or striatal dopamine and its metabolites were observed. Differences in nigral dopaminergic cell number between proteasome inhibitor, and vehicle-treated rats and inclusion bodies were not found. Extending the time of survival after administration and using different solvents failed to alter results, indicating this proteasome inhibitor does not consistently produce the selective toxicity and pathological hallmarks characterizing Parkinson's disease. Ann Neurol 2006;60:256,260 [source] Regulation of pulmonary inflammation and fibrosis through expression of integrins ,V,3 and ,V,5 on pulmonary T lymphocytesARTHRITIS & RHEUMATISM, Issue 5 2009Irina G. Luzina Objective Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several ,V-containing integrins, including ,V,3 and ,V,5, have been shown to directly activate transforming growth factor , (TGF,) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation. Methods Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism. Results Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins ,V,3 and ,V,5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti,integrin ,V antibody or a genetic deficiency of integrin ,3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin ,V,3 or integrin ,V,5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGF, antibody attenuated the profibrotic effect of integrin-expressing T cells. Conclusion Pulmonary infiltrating T lymphocytes may express integrins ,V,3 and ,V,5 that are necessary for lymphocytic infiltration and T cell,associated TGF, activation and collagen accumulation. [source] Region-specific effects of N,N,-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivoBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2008S Rahman Background and purpose: Systemic administration of N,N,-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). Experimental approach: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. Key results: Nicotine (0.4 mg kg,1, s.c.) increased extracellular dopamine in NAcc, which was attenuated by intra-VTA perfusion of mecamylamine (100 ,M). Intra-VTA perfusion of bPiDDB (1 and 10 ,M) reduced nicotine-induced increases in extracellular dopamine in NAcc. In contrast, intra-NAcc perfusion of bPiDDB (1 or 10 ,M) failed to alter the nicotine-induced increase in dopamine in NAcc. Intra-VTA perfusion of bPiDDB alone did not alter basal dopamine levels, compared to control, nor the increased dopamine in NAcc following amphetamine (0.5 mg kg,1, s.c.). Using Xenopus oocytes, bPiDDB (0.01,100 ,M) inhibited the response to ACh on specific combinations of rat neuronal nAChR subunits, with highest potency at ,3,4,3 and lowest potency at ,6/3,2,3. Conclusions and implications: bPiDDB-Sensitive nAChRs involved in regulating nicotine-induced dopamine release are located in the VTA, rather than in the NAcc. As bPiDDB has properties different from the prototypical nAChR antagonist mecamylamine, further development may lead to novel nAChR antagonists for the treatment of tobacco dependence. British Journal of Pharmacology (2008) 153, 792,804; doi:10.1038/sj.bjp.0707612; published online 3 December 2007 [source] Cross-reactivity between nickel and palladium demonstrated by systemic administration of nickelCONTACT DERMATITIS, Issue 1 2005M. Hindsén Concomitant patch test reactions to nickel and palladium have frequently been reported in patients undergoing investigation because of suspected allergic contact dermatitis. Theoretically, these reactions can be explained by multiple, concomitant, simultaneous sensitization as well as cross-sensitization. We studied whether concomitant reactions to nickel and palladium could represent cross-sensitization in females hypersensitive to combinations of nickel, palladium and cobalt. Females were patch tested with serial dilutions of nickel sulfate, cobalt chloride and palladium chloride on the upper back. 1 month later, when the patch test reactions were gone, the patients were randomized into 2 groups that were challenged orally with either nickel or placebo. 1 day later, the areas of previous positive patch test reactions were read in a blind way looking for flare-up reactions. Nickel provocation but not placebo yielded flare-up reactions on sites previously tested with nickel (P = 0.012) and palladium (P = 0.006), but were also observed on sites previously tested with cobalt, even though this was not statistically significant. Flare-up reactions of previous patch test reactions to nickel and palladium after oral challenge with nickel speak in favour of a cross-reactivity mechanism. [source] Upregulation of Brain Expression of P-Glycoprotein in MRP2-deficient TR - Rats Resembles Seizure-induced Up-regulation of This Drug Efflux Transporter in Normal RatsEPILEPSIA, Issue 4 2007Katrin Hoffmann Summary:,Purpose: The multidrug resistance protein 2 (MRP2) is a drug efflux transporter that is expressed predominantly at the apical domain of hepatocytes but seems also to be expressed at the apical membrane of brain capillary endothelial cells that form the blood,brain barrier (BBB). MRP2 is absent in the transport-deficient (TR,) Wistar rat mutant, so that this rat strain was very helpful in defining substrates of MRP2 by comparing tissue concentrations or functional activities of compounds in MRP2-deficient rats with those in transport-competent Wistar rats. By using this strategy to study the involvement of MRP2 in brain access of antiepileptic drugs (AEDs), we recently reported that phenytoin is a substrate for MRP2 in the BBB. However, one drawback of such studies in genetically deficient rats is the fact that compensatory changes with upregulation of other transporters can occur. This prompted us to study the brain expression of P-glycoprotein (Pgp), a major drug efflux transporter in many tissues, including the BBB, in TR, rats compared with nonmutant (wild-type) Wistar rats. Methods: The expression of MRP2 and Pgp in brain and liver sections of TR, rats and normal Wistar rats was determined with immunohistochemistry, by using a novel, highly selective monoclonal MRP2 antibody and the monoclonal Pgp antibody C219, respectively. Results: Immunofluorescence staining with the MRP2 antibody was found to label a high number of microvessels throughout the brain in normal Wistar rats, whereas such labeling was absent in TR, rats. TR, rats exhibited a significant up-regulation of Pgp in brain capillary endothelial cells compared with wild-type controls. No such obvious upregulation of Pgp was observed in liver sections. A comparable overexpression of Pgp in the BBB was obtained after pilocarpine-induced seizures in wild-type Wistar rats. Experiments with systemic administration of the Pgp substrate phenobarbital and the selective Pgp inhibitor tariquidar in TR, rats substantiated that Pgp is functional and compensates for the lack of MRP2 in the BBB. Conclusions: The data on TR, rats indicate that Pgp plays an important role in the compensation of MRP2 deficiency in the BBB. Because such a compensatory mechanism most likely occurs to reduce injury to the brain from cytotoxic compounds, the present data substantiate the concept that MRP2 performs a protective role in the BBB. Furthermore, our data suggest that TR, rats are an interesting tool to study consequences of overexpression of Pgp in the BBB on access of drugs in the brain, without the need of inducing seizures or other Pgp-enhancing events for this purpose. 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