PubMed · 9046878
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J G Hunter. 1997. Advanced laparoscopic surgery.. https://doi.org/10.1016/s0002-9610(96)00376-5
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The influence of endogenous glucocorticoids (GC) on glomerular injury was studied in a rat model of heterologous anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (ADX) or sham-operation 3 days prior to i.v. administration of both nephritogenic (100 microgram/g) and subnephritogenic (50 microgram/g) doses of sheep anti-rat GBM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulted in exacerbation of GN compared with sham-operated animals (24 h protein excretion: 190.8 +/- 32.8 versus 42.5 +/- 2.6 mg/24 h; P < 0.005). In ADX animals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 +/- 5.8 mg/24 h), accumulation of neutrophils which peaked at 6 h (7.2 +/- 1.37 neutrophils per glomerular cross-section (neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 +/- 1.2 macrophages/gcs). Sham-adrenalectomized animals given the same dose of anti-GBM globulin developed minimal or no glomerular injury: urinary protein excretion (8.7 +/- 1.5 mg/24 h, P < 0.001); neutrophils (0.2 +/- 0.04 neutrophils/gcs, P < 0.001); macrophages (1.2 +/- 0.5 macrophages/gcs, P < 0.001). The increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selectin expression was not detected in sham-operated rats after anti-GBM injection. Complement deposition in glomeruli was minimal in both groups. Physiologic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reversed the observed susceptibility to GN development, with urinary protein excretion (7.8 +/- 1.12, P < 0.005) and no detectable P-selectin expression or leucocyte accumulation in glomeruli. These results suggest that endogenous GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.
The nuclear binding of the activated glucocorticoid-receptor (GR) is inhibited by endogenous macromolecules in vitro. Previously, we have separated the inhibitors into three species (MTI-I, MTI-II and MTI-III). In this study, we purified the most potent of the three species (MTI-II) from the livers of adrenalectomized rats to apparent homogeneity as judged by two-dimensional PAGE. Purified MTI-II inhibits GR binding to DNA containing glucocorticoid-response elements. To obtain the amino acid sequence of MTI-II, we digested the MTI-II with endopeptidases. The N-terminal amino acid sequences of the four digested fragments indicated that MTI-II is an 11.5-kDa Zn2+-binding protein (ZnBP, also known as parathymosin). Furthermore, we purified ZnBP to apparent homogeneity and found that it also inhibits GR binding to nuclei. ZnBP is known to be an abundant acidic protein involved in cell proliferation, and interacts with histone H1 or key enzymes of carbohydrate metabolism via its acidic domain. We also showed that the inhibition of GR binding to nuclei is mediated by the acidic domain of MTI-II (ZnBP, parathymosin) and that GR binds to the MTI-II affinity matrix. Our findings add a new biological function, i.e. the inhibition of GR binding to nuclei and DNA, to this ZnBP. Moreover, our findings suggest that the abundant acidic protein is involved in glucocorticoid action.
Polygodial, a sesquiterpene isolated from the bark of Drymis winteri given systemically, intraplantarly, or by spinal or supraspinal sites, produced antinociception when assessed in both phases of the formalin test and against capsaicin-induced pain. Polygodial, even at high doses, had no antinociceptive or antihyperalgesic effect when assessed in hot-plate assay or in glutamate-induced hyperalgesia, nor did it significantly interfere with the motor coordination of animals when tested in the rota-rod test. The polygodial antinociception assessed in the formalin test was not affected by i.p. treatment of animals with cyprodime, yohimbine, phaclofen, bicuculine, or nitric oxide precursor or by intrathecal administration of potassium channel blockers such as apamin, charybdotoxin, glibenclamide, or tetraethylammonium. In contrast, polygodial antinociception was significantly attenuated by i.p. treatment of animals with naloxone, naltrindole, 2-(3, 4-dichlorophenyl)-n-methyl-n-[(1S)-1-(3-isothiocynatophenyl)-2-(1- pry rolidinyl)ethyl]acetamide, p-chlorophenylalanine, prazosin, or by i. c.v. treatment with pertussis toxin. In addition, polygodial antinociception was not cross-tolerant to morphine, nor was its effect affected by the adrenalectomy of animals. Together, these results show that polygodial produces pronounced systemic, spinal, and supraspinal antinociception in mice, mainly preventing the neurogenic pain produced by formalin and capsaicin. The mechanism by which polygodial produces antinociception seems likely to involve an interaction with the opioid system, mainly kappa and delta subtypes, depend on the activation of G(i/o) protein sensitive to pertussis toxin, alpha(1)-adrenoceptors, and the serotoninergic system. Collectively, these results suggest that polygodial itself or its derivatives may have potential therapeutic value for the development of new analgesic drugs.