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Various Animal Models (various + animal_models)
Selected AbstractsHelicobacter pylori vaccines,the current statusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2000Sutton In this review, we take a look at the current status in the development of a vaccine against the human pathogenic bacterium, Helicobacter pylori, a major aetiological factor in peptic ulcer disease and gastric adenocarcinoma. Various animal models are now in use from mice infected with H. pylori, through gnotobiotic pigs and primates to ferrets naturally infected with their own Helicobacter, H. mustelae. A significant problem remains the requirement for a suitable mucosal adjuvant. Detoxification or the use of low doses of adjuvants already available may provide a solution and new immune stimulating compounds have been tested with some success. New approaches include the delivery of Helicobacter antigens by DNA immunization, microparticles or live vectors such as attenuated salmonella and the examination of alternative routes of vaccine administration. The phenomenon of post-immunization gastritis and improvements in vaccine efficacy are also discussed. A major area of interest is the mechanism by which immunization actually influences Helicobacter colonization. This remains a mystery: antibodies appear to be unimportant whereas CD4+ T-cells essential. Finally, a viewpoint is given on whom should be immunized when a final vaccine becomes available. [source] Stress, the hippocampus, and epilepsyEPILEPSIA, Issue 4 2009Marian Joëls Summary Stress is among the most frequently self-reported precipitants of seizures in patients with epilepsy. This review considers how important stress mediators like corticotropin-releasing hormone, corticosteroids, and neurosteroids could contribute to this phenomenon. Cellular effects of stress mediators in the rodent hippocampus are highlighted. Overall, corticosterone,with other stress hormones,rapidly enhances CA1/CA3 hippocampal activity shortly after stress. At the same time, corticosterone starts gene-mediated events, which enhance calcium influx several hours later. This later effect serves to normalize activity but also imposes a risk for neuronal injury if and when neurons are concurrently strongly depolarized, for example, during epileptic activity. In the dentate gyrus, stress-induced elevations in corticosteroid level are less effective in changing membrane properties such as calcium influx; here, enhanced inhibitory tone mediated through neurosteroid effects on ,-aminobutyric acid (GABA) receptors might dominate. Under conditions of repetitive stress (e.g., caused from experiencing repetitive and unpredictable seizures) and/or early life stress, hormonal influences on the inhibitory tone, however, are diminished; instead, enhanced calcium influx and increased excitation become more important. In agreement, perinatal stress and elevated steroid levels accelerate epileptogenesis and lower seizure threshold in various animal models for epilepsy. It will be interesting to examine how curtailing the effects of stress in adults, for example, by brief treatment with antiglucocorticoids, may be beneficial to the treatment of epilepsy. [source] Synthesis of pathological and nonpathological human exon 1 huntingtinJOURNAL OF PEPTIDE SCIENCE, Issue 7 2010David Singer Abstract Huntington's disease (HD) is a neurodegenerative disorder that affects approximately 1 in 10 000 individuals. The underlying gene mutation was identified as a CAG-triplet repeat expansion in the gene huntingtin. The CAG sequence codes for glutamine, and in HD, an expansion of the polyglutamine (poly-Q) stretch above 35 glutamine residues results in pathogenicity. It has been demonstrated in various animal models that only the expression of exon 1 huntingtin, a 67-amino acid-long polypeptide plus a variable poly-Q stretch, is sufficient to cause full HD-like pathology. Therefore, a deeper understanding of exon 1 huntingtin, its structure, aggregation mechanism and interaction with other proteins is crucial for a better understanding of the disease. Here, we describe the synthesis of a 109-amino acid-long exon 1 huntingtin peptide including a poly-Q stretch of 42 glutamines. This microwave-assisted solid phase peptide synthesis resulted in milligram amounts of peptide with high purity. We also synthesized a nonpathogenic version of exon 1 huntingtin (90-amino acid long including a poly-Q stretch of 23 glutamine residues) using the same strategy. In circular dichroism spectroscopy, both polypeptides showed weak alpha-helical properties with the longer peptide showing a higher helical degree. These model peptides have great potential for further biomedical analyses, e.g. for large-scale pre-screenings for aggregation inhibitors, further structural analyses as well as protein,protein interaction studies. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Glial reactions in Parkinson's diseaseMOVEMENT DISORDERS, Issue 4 2008Patrick L. McGeer MD Abstract Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and ,-synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The ,-synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti-inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches. © 2007 Movement Disorder Society [source] Transforming growth factor-, and Smad signalling in kidney diseasesNEPHROLOGY, Issue 1 2005Review Article SUMMARY: Extensive studies have demonstrated that transforming growth factor-beta (TGF-,) plays an important role in the progression of renal diseases. TGF-, exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGF-,'s pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGF-, still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGF-,. They can also cause renal fibrosis via the ERK/p38 MAP kinase,Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-,, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGF-, has anti-inflammatory and immune-regulatory properties. Our most recent studies demonstrated that TGF-, transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF.,B activation via induction of I,B,, is a central mechanism by which TGF-, inhibits renal inflammation. In conclusion, TGF-, signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases. [source] Using gabapentin to treat failed back surgery syndrome caused by epidural fibrosis: A report of 2 cases. (University of Pennsylvania Health System, School of Medicine, Pennsylvania, PA).PAIN PRACTICE, Issue 4 2001Arch Phys Med Rehabil. Failed back surgery syndrome (FBSS) is a long-lasting often disabling, and relatively frequent (5% to 10%) complication of lumdosacral spine surgery. Epidural fibrosis is among the most common causes of FBSS, and it is often recalcitrant to treatment. Repeated surgery for fibrosis has only a 30% to 35% success rate, whereas 15% to 20% of patients report worsening of their symptoms. Long-term outcome studies focusing on pharmacologic management of chronic back pain secondary to epidural fibrosis are lacking in the literature. This report presented 2 cases of severe epidural fibrosis managed successfully with gabapentin monotherapy. In both cases, functional status improved markedly and pain was significantly diminished. Gabapentin has an established, favorable safety profile and has been shown to be effective in various animal models and human studies of chronic neuropathic pain. Conclude clinicians should consider gabapentin as a pharmacological treatment alternative in the management of FBSS caused by epidural fibrosis. [source] Mizoribine: Mode of action and effects in clinical usePEDIATRICS INTERNATIONAL, Issue 2 2002Shumpei Yokota Abstract Mizoribine is a new immunosuppressive drug and was authorized by the Japanese Government in 1984. The strong immunosuppressive activity of mizoribine was already demonstrated in various animal models, in renal transplantation and in steriod-resistant nephrotic syndrome. Recently, the remarkable clinical advantages of an imidazole for adults with rheumatoid arthritis, lupus nephritis and other rheumatic diseases were reported. Mizoribine is an imidazole nucleoside and the metabolites, MZ-5-P, exerts its activity through selective inhibition of inosine monophosphate synthetase and guanosine monophosphate synthetase, resulting in the complete inhibition of guanine nucleotide synthesis without incorporation into nucleotides. Thus, mizoribine is superior to azathioprine, in that it may not cause damages to normal cells and normal nucleic acid. [source] Inhibition of early and late phase allergic reactions by Euphorbia hirta L.PHYTOTHERAPY RESEARCH, Issue 4 2006G. D. Singh Abstract A 95% ethanol extract from whole aerial parts of Euphorbia hirta (EH A001) showed antihistaminic, antiinflammatory and immunosuppressive properties in various animal models. EH A001 inhibited rat peritoneal mast cell degranulation triggered by compound 48/80. It significantly inhibited dextran-induced rat paw edema. EH A001 prevented eosinophil accumulation and eosinophil peroxidase activity and reduced the protein content in bronchoalveolar lavage fluid (BALF) in a ,mild' model of asthma. Moreover, the CD4/CD8 ratio in peripheral blood was suppressed. EH A001 attenuated the release of interleukin-4 (IL-4) and augmented interferon- , (IFN- ,) in ovalbumin-sensitized mouse splenocytes. The results were compared with the effects of known compounds, ketotifen, cetirizine and cyclophosphamide. These findings demonstrated that Euphorbia hirta possessed significant activity to prevent early and late phase allergic reactions. Copyright © 2006 John Wiley & Sons, Ltd. [source] Evaluation of Liver Support Systems for Preclinical Testing by Animal TrialsARTIFICIAL ORGANS, Issue 10 2006Oleksandr Seleverstov Abstract:, In the present review, various animal models of acute liver failure are reviewed with respect to their suitability for evaluating liver support systems (LSS) according to envisaged modes of therapy. In order to increase the value of the preclinical testing of LSS, it would be advantageous to include more than one animal model in the evaluation program. It is possible to identify appropriate sets of models, which make a suitable test system for particular clinical applications. A standardization of evaluation methods between testing groups would also be beneficial to the field of liver support. [source] RESEARCH PAPER: The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of actionBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2010A Micov BACKGROUND AND PURPOSE Levetiracetam, a novel antiepileptic drug, has recently been shown to have antinociceptive effects in various animal models of pain. The purpose of this study was to investigate the antihyperalgesic effect of levetiracetam and its mechanism of action, by examining the involvement of GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic) and adrenergic systems in its effect, in a rat model of inflammatory pain. EXPERIMENTAL APPROACH Rats were intraplantarly injected with the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of levetiracetam on carrageenan-induced hyperalgesia; and (ii) the effects of bicuculline (selective GABAA receptor antagonist), naloxone (non-selective opioid receptor antagonist), methysergide (non-selective 5-HT receptor antagonist) and yohimbine (selective ,2 -adrenoceptor antagonist) on the antihyperalgesic action of levetiracetam. RESULTS Levetiracetam (10,200 mg·kg,1; p.o.) significantly reduced, in a dose-dependent manner, the inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of levetiracetam was significantly decreased after administration of bicuculline (0.5,2 mg·kg,1; i.p.), naloxone (1,3 mg·kg,1; i.p.), methysergide (0.25,1 mg·kg,1; i.p.) and yohimbine (1,3 mg·kg,1; i.p.). CONCLUSIONS AND IMPLICATIONS These results show that levetiracetam produced antihyperalgesia which is at least in part mediated by GABAA, opioid, 5-HT and ,2 -adrenergic receptors, in an inflammatory model of pain. The efficacy of levetiracetam in this animal model of inflammatory pain suggests that it could be a potentially important agent for treating inflammatory pain conditions in humans. [source] 3122: Regulation of retinal tissue oxygenationACTA OPHTHALMOLOGICA, Issue 2010CJ POURNARAS Purpose To evaluate the changes in the retinal oxygen partial pressure (PO2) following physiological stimuli. Methods Evaluation of either the preretinal and intraretina partial pressure of oxygen (PO2) distribution, using oxygen sensitive microelectrodes, in various animal models. Measurements were obtained during changes of the perfusion pressure, systemic hyperoxia, hypoxia, hypercapnia, carbogen breathing and following carbonic anydrase inhibitors use. Results The oxygen tension (PO2) in the inner half of the retina remains largely unaffected by moderate changes in perfusion pressure. The increase of the systemic PaO2 through breathing of 100% O2 (hyperoxia) induces endothelin (ET) mediated marked vasoconstriction of the inner retinal arterioles in both anesthetized animals and normal human subjects. The regulatory vasoconstriction maintains the PO2 in retinal tissue constant. A decrease in PaO2 (hypoxia) induces a vasodilation of the retinal arterioles through endothelium-derived NO release. As a result, trans-retinal PO2 profiles made during steps of systemic hypoxia have shown that the values measured in the inner retina up to half of its thickness, remain rather stable. By contrast, the PO2 values, measured close to the choroid and in the outer retina, decrease in a linear manner with the decrease of the PaO2. An increase in the PaCO2 (hypercapnia) of arteriolar blood, produces an increase in retinal blood flow and retinal tissue PO2. Intravenous injection of acetazolamide (carbonic anhydrase inhibitor) produces an increase in preretinal PO2 due to dilation of the retinal vessels Conclusion Thanks to the autoregulatory capability of the retinal circulation, the oxygen tension (PO2) in the inner half of the retina, remains largely unaffected during physiological stimuli. [source] Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupusCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2010P. Lenert Summary Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-,B activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis. [source] | |||||||||||||||||||