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1.
In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response
to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in
different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders.
We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with
carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory
illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug
responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug
efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced
endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced
adaptations dissipate (the “time-off seizure” effect), leading to the re-emergence of seizures, a re-induction of a new, but
diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats,
an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance.
We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous
adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression
and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can
be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive
(decreasing the stimulation current.), increasing drug dosage, switching to a new drug that does not show crosstolerance to
the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal.
Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression
of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined
that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity
can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted
by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the
neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the
biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent
illness emergence and progression and its associated accumulating neurobiological, vulnerability factors. 相似文献
2.
Learning-Induced Expression of Meningeal Ependymin mRNA and Demonstration of Ependymin in Neurons and Glial Cells 总被引:1,自引:0,他引:1
Stefan Rother Rupert Schmidt Wolfgang Brysch †Karl-Hermann Schlingensiepen 《Journal of neurochemistry》1995,65(4):1456-1464
Abstract: The turnover of a CNS-specific cell adhesion glycoprotein, ependymin, has earlier been found to increase during periods of neuronal plasticity. Here, ependymin mRNA expression was analyzed by semiquantitative in situ hybridization in goldfish. Learning of an active avoidance response resulted in a significant increase in ependymin mRNA expression 20 min to 4 h after acquisition of the task. In contrast, yoked control animals that were exposed to the same numbers of conditioned and unconditioned stimuli in a random, unpaired manner exhibited a strong down-regulation of ependymin mRNA. Hybridization signals were also increased by injection of anti-ependymin antiserum into brain ventricles. Ependymin mRNA was exclusively localized to reticular-shaped fibroblasts of the inner endomeningeal cell layer. Immunoelectron microscopic investigation, however, revealed ependymin also in distinct neuronal and glial cell populations in which no ependymin mRNA had been detected. Uptake of meningeal protein factors into glial and neuronal cells may therefore be of functional importance for plastic adaptations of the CNS. 相似文献
3.
Most Serratia marcescens strains produce a new type of cytolysin (hemolysin) which is also found in other Serratia species. The hemolytic polypeptide ShlA (M(r) 162 101) is secreted across the outer membrane through the help of the ShlB protein which also involves conversion of an inactive precursor in an hemolytically active form. Both proteins are synthesized with signal sequences which are released during export across the cytoplasmic membrane. Mutants expressing inactive ShlB derivatives are impaired in activation and secretion suggesting a tight coupling between both processes. The region of ShlA for activation and secretion is confined to the N-terminal 16% of the polypeptide which contains the sequence NPNG which is also found in the Proteus hemolysin, the Bordetella pertussis filamentous hemagglutinin and two highly expressed outer membrane proteins of Haemophilus influenzae. Substitution of the first asparagine (N) residue by isoleucine converts the Serratia hemolysin into an inactive secretion incompetent form. It is concluded that this region is recognized by ShlB for activation and secretion of ShlA. The Serratia hemolysin forms defined pores in erythrocyte membranes. 相似文献
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Streptococcus pyogenes is commonly found on pharynx, mouth and rarely on skin, lower gastrointestinal tract. It is a potential pathogen causing tonsillitis, pneumonia, endocarditis. The present study was undertaken to study the effects of low shear modeled microgravity on growth, morphology, antibiotic resistance, cross-stress resistance to various stresses and alteration in gene expression of S. pyogenes. The growth analysis performed using UV–Visible spectroscopy indicated decrease in growth of S. pyogenes under low shear modeled microgravity. Morphological analysis by Bio-transmission electron microscopy (TEM), Bio-scanning electron microscopy (SEM) did not reveal much difference between normal and low shear modeled microgravity grown S. pyogenes. The sensitivity of S. pyogenes to antibiotics ampicillin, penicillin, streptomycin, kanamycin, hygromycin, rifampicin indicates that the bacterium is resistant to hygromycin. Further S. pyogenes cultured under low shear modeled microgravity was found to be more sensitive to ampicillin and rifampicin as compared with normal gravity grown S. pyogenes. The bacteria were tested for the acid, osmotic, temperature and oxidative cross stress resistances. The gene expression of S. pyogenes under low shear modeled microgravity analyzed by microarray revealed upregulation of 26 genes and down regulation of 22 genes by a fold change of 1.5. 相似文献
7.
Sally A. Amundson Michael Bittner Paul Meltzer Jeffrey Trent Albert J. Fornace Jr. 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2001,129(4)
The responses to ionizing radiation and other genotoxic environmental stresses are complex and are regulated by a number of overlapping molecular pathways. One such stress signaling pathway involves p53, which regulates the expression of over 100 genes already identified. It is also becoming increasingly apparent that the pattern of stress gene expression has some cell type specificity. It may be possible to exploit these differences in stress gene responsiveness as molecular markers through the use of a combined informatics and functional genomics approach. The techniques of microarray analysis potentially offer the opportunity to monitor changes in gene expression across the entire set of expressed genes in a cell or organism. As an initial step in the development of a functional genomics approach to stress gene analysis, we have recently demonstrated the utility of cDNA microarray hybridization to measure radiation-stress gene responses and identified a number of previously unknown radiation-regulated genes. The responses of some of these genes to DNA-damaging agents vary widely in cell lines from different tissues of origin and different genetic backgrounds. While this again highlights the importance of a cellular context to genotoxic stress responses, it also raises the prospect of expression-profiling of cell lines, tissues, and tumors. Such profiles may have a predictive value if they can define regions of ‘expression space’ that correlate with important endpoints, such as response to cancer therapy regimens, or identification of exposures to environmental toxins. 相似文献
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10.
Kaori Matsumoto Yuji Nakai Masaru Hoshino Koki Yamazaki Yoshiaki Takioto Satoru Takadera 《Bioscience, biotechnology, and biochemistry》2017,81(10):1926-1936
Tenascin-C (TNC), an extracellular matrix glycoprotein, plays a pivotal role in tumor growth. However, the mechanism whereby TNC affects tumor biology remains unclear. To investigate the exact role of TNC in primary tumor growth, a mouse mammary tumor cell line, GLMT1, was first developed. Subsequently, global gene expression in GLMT1-derived tumors was compared between wild-type (WT) and TNC-knockout (TNKO) mice. Tumors in WT mice were significantly larger than those in TNKO mice. DNA microarray analysis revealed 447 up and 667 downregulated in the tumors inoculated into TNKO mice as compared to tumors in WT mice. Validation by quantitative gene expression analysis showed that Tnc, Cxcl1, Cxcl2, and Cxcr2 were significantly upregulated in WT mice. We hypothesize that TNC stimulates the CXCL1/2-CXCR2 pathway involved in cancer cell proliferation. 相似文献