Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy

BACKGROUND: The cerebellum of the neonatal rat is highly susceptible to ethanol, with profound loss of Purkinje cells resulting from even brief exposure during the first postnatal week. Developmental ethanol exposure previously has been shown to induce free radicals/oxidative stress processes and/or down-regulate protective antioxidants. In an earlier study, we found antioxidants protected against ethanol neurotoxicity in a tissue culture environment. The present study was designed to determine whether similar protection could be manifested in the intact animal. METHODS: Neonatal rats were administered a liquid diet via intragastric intubation on postnatal days 4 and 5 (P4-P5), the peak period of ethanol sensitivity in the developing cerebellum. The diet consisted of milk formula with 12% ethanol, the isocaloric substitution of maltose-dextrin for ethanol, or ethanol plus the antioxidant vitamin E. Unbiased three-dimensional counting was utilized to analyze Purkinje cell numbers and density within defined volumes from these animals on P5. RESULTS: These determinations revealed a substantial loss of Purkinje cells in the ethanol-treated animals compared to controls (approximately 30-44%), but this loss was prevented by the inclusion of vitamin E (601U/100 ml) in the diet. A lower concentration of the antioxidant (301U/100 ml) was not effective in this regard, however. CONCLUSIONS: These results suggest that ethanol-related cerebellar damage during this early postnatal period may be related to oxidative stress processes or the insufficiency of protective antioxidants. Thus, antioxidant treatment may represent a possible therapy for preventing or ameliorating the central nervous system (CNS) damage seen in the fetal alcohol syndrome.     

Genetic influence on dysmorphogenesis in embryos from different rat strains exposed to ethanol in vivo and in vitro

Background: The aim was to investigate the susceptibility of embryos from 2 rat strains (U and H) to a 48 hours ethanol exposure in early pregnancy, both in vivo and in vitro. Methods: The embryos were studied on gestational days 9 to 11. We used 1 ethanol dose in vivo (6 g/kg × 2), 3 different ethanol concentrations in vitro (88 mM, 132 mM, 176 mM) and also attempted to diminish the teratogenic effect in vitro by supplying the antioxidant N–acetylcysteine (NAC, 0.5 mM) to the culture medium. Results: The U embryos were more damaged by ethanol than the H embryos, both in vivo and in vitro. NAC addition diminished, but failed to completely normalize, the embryonic maldevelopment. Ethanol increased the Bax/Bcl‐2 ratio in the U embryos both in vivo and in vitro, but not in the H embryos. Furthermore, ethanol caused increased Caspase‐3 immunostaining in U embryos, but not in H embryos. Ethanol exposure in vivo did not alter CuZnSOD and MnSOD mRNA levels in U and H embryos. In vitro, however, the ethanol‐exposed U embryos increased their CuZnSOD and MnSOD mRNA levels, whereas the CuZnSOD mRNA was unchanged and MnSOD mRNA decreased in the H embryos, in neither strain did NAC exert any effect. The U embryos increased catalase gene expression in response to ethanol in vivo, but decreased catalase mRNA levels in vitro, changes normalized by NAC. The H embryos did not alter catalase mRNA levels in vivo, but increased gene expression in vitro, with no NAC effect. Ethanol affected the gene expression of the other ROS scavenging enzymes and the developmental genes studied – Bmp‐4, Ret, Shh, Pax‐6 – similarly in the 2 strains. Conclusions: The findings support a role for genetic predisposition, oxidative stress, and apoptosis in ethanol teratogenicity, and suggest that the teratogenic predisposition of the more susceptible U rats may reside, at least in part, in the regulation of the ROS scavenging enzymes in the U embryos.     

Microsomal Acetaldehyde Oxidation is Negligible in the Presence of Ethanol

The microsomal ethanol oxidizing system (MEOS), inducible by ethanol and acetone, oxidizes ethanol to acetaldehyde, which causes many toxic effects associated with excess ethanol. Recent studies reported that rat liver microsomes also oxidize acetaldehyde, thereby challenging the validity of the assessment of MEOS activity by measuring acetaldehyde production and suggesting that MEOS activity results in the accumulation not of acetaldehyde but, rather, of its less toxic metabolite, acetate. To address these issues, we compared both metabolic rates of ethanol and acetaldehyde and the effect of ethanol on the acetaldehyde metabolism. Liver microsomes were prepared from Sprague-Dawley rats induced either with acetone for 3 days or ethanol for 3 weeks. NADPH-dependent acetaldehyde (300 /μM) metabolism was measured in two ways: (1) by detection of acetaldehyde disappearance by headspace gas chromatography, and (2) by assessment of acetaldehyde oxidation by liquid scintillation counting of acetate formed from [1,2-¹⁴C]acetaldehyde. Ethanol (50 mM) oxidation was measured by gas chromatography. In acetone- and ethanol-induced rat liver microsomes, the acetaldehyde disappearance (p < 0.0001) and oxidation (p < 0.0001) rates were both significantly increased. The rates of acetaldehyde oxidation paralleled those of p-nitrophenol hydroxylation (r= 0.974, p < 0.0001), with a K_m of 82 ± 14 μM and a V_max of 4.8 ± 0.5 nmol/min/mg protein in acetone-induced microsomes. Acetaldehyde disappearance in acetone-induced microsomes and acetaldehyde oxidation in acetone-induced and ethanol-induced microsomes were significantly lower than the corresponding ethanol oxidation, with rates (nmol/min/mg protein) of 4.6 ± 0.6 versus 9.0 ± 0.8 (p < 0.005), 4.4 ± 0.3 versus 9.1 ± 0.5 (p < 0.0005), and 14.0 ± 0.9 versus 19.5 ± 1.8 (p < 0.05), respectively. The presence of 50 mM ethanol decreased this metabolism to 0.9 ± 0.3 (p < 0.005), 0.5 ± 0.1 (p < 0.001), and 1.8 ± 0.3 (p < 0.001), resulting in rates of acetaldehyde metabolism of only 9.8 ± 3.2%, 6.0 ± 0.5%, and 9.5 ± 1.2% (respectively) of those of ethanol oxidation. In conclusion, rat liver microsomes oxidize acetaldehyde at much lower rates than ethanol, and this acetaldehyde metabolism is strikingly inhibited by ethanol. Accordingly, acetaldehyde formation provides an accurate assessment of MEOS activity. Furthermore, because acetaldehyde production vastly exceeds its oxidation, the net result of MEOS activity is the accumulation of this toxic metabolite.     

低硒低维生素E诱导肝细胞凋亡及cAMP和细胞内Ca2+的作用

目的 研究低硒（Ｓｅ）低维生素Ｅ（ＶＥ）能否诱导大鼠肝细胞凋亡及ｃＡＭＰ和细胞内Ｃａ＾２＋所起的作用。方法 以天然的和人工半合成的低Ｓｅ低ＶＥ饲料喂养大鼠１７周,采用流式细胞术检测肝细胞凋亡,采用放免法检测ｃＡＭＰ含量,Ｆｕｒａ－２负载荧光分光光度法测定细胞内Ｃａ＾２＋含量。结果 与补Ｓｅ和ＶＥ组大鼠相比,低Ｓｅ低ＶＥ组大鼠肝细胞凋亡显著增加;ｃＡＭＰ含量明显升高;细胞内Ｃａ＾２＋含量明显升高。结     

Ethanol dependence has limited effects on GABA or glutamate transporters in rat brain

BACKGROUND: Neuroadaptations of GABAergic and glutamatergic systems appear to play an important role in both the acute as well as chronic effects of ethanol. Chronic ethanol intake leads to the development of ethanol tolerance and dependence that is associated with a decrease in GABAergic and an increase in glutamatergic function. The present report assessed the involvement of GABA and glutamate transporters in the chronic ethanol-induced adaptations of these two neuronal systems. METHODS: Male and female rats were made ethanol dependent by 2-week administration of ethanol in a liquid diet. Levels of GABA (GAT-1, GAT-3) and glutamate (GLT-1, EAAC-1) transporters were assayed by immunoblotting. Transporter function was assessed by [3H]GABA and [3H]glutamate uptake assays. RESULTS: Ethanol dependence did not alter levels of GABA or glutamate transporters in cerebral cortex compared with pair-fed control values. There were increases in some, but not all, transporter levels in hippocampus and hypothalamus with the development of ethanol dependence. A decreased rate of uptake was observed for GABA in cerebral cortex. There was no change in maximal GABA uptake or in glutamate uptake (Vmax). CONCLUSIONS: These results suggest that alterations in GABA and glutamate transporters have only a limited role in neuroadaptations to chronic ethanol intake in rats. However, the observed alterations were region-specific, supporting the complex responses to chronic ethanol exposure and suggesting that neuroadaptations of GABAergic and glutamatergic systems vary across the brain.     

维生素E对大鼠肝星状细胞增殖及细胞外基质的影响

目的 观察维生素E（VE）对大鼠肝星状细胞（HSC）过氧化脂质和细胞外基质（ECM）产生的影响。方法 采用原位灌注方法分离大鼠HSC。结果 新分离的大鼠HC培养1w时具有增殖和ECM分泌的活性。VE可有效抑制大鼠HSC^3H-胸腺嗜啶（^3H-TdR）、^3H-脯氨酸（^3H-Pro）的掺入和Ⅲ型前胶原（PCⅢ）及透明质酸（HA）的分泌，VE作用后HSC产生丙二醛（MDA）下降，与分泌PCⅢ的抑制呈正相关。结论 VE可抑制大鼠HSC增殖和减少ECM的分泌。     

Effect of Ethanol Administration and Withdrawal on Serotonin Receptor Subtypes and Receptor-Mediated Phosphoinositide Hydrolysis in Rat Brain

The effect of short-term (15 days) and long-term (60 days) ethanol treatment and withdrawal on agonist-stimulated phosphoinositide (Pl) hydrolysis, serotonin receptor subtypes (5HT1A and 5HT2), and alpha 1-adrenergic receptors were studied in rat cerebral cortex. Short-term ethanol treatment had no significant effect on serotonin (5HT), norepinephrine (NE), and calcium ionophore (A23187)-stimulated [3H]-inositol-1-phosphate ([3H]-IP1) formation and 5-HT2 receptors as measured by 125I-lysergic acid diethylamide (125I-LSD) binding, in rat cerebral cortex. However, 15 days of ethanol treatment, followed by 24 hr of withdrawal resulted in a decrease in Bmax of 125I-LSD binding without significant change in KD, as well as a decrease in 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. 5HT1A and alpha 1-adrenergic receptors were determined by using [3H]-8-hydroxy-2-(di-N-propylamino)tetralin and [3H]-prazosin as radioligand, respectively. We also observed that long-term ethanol treatment had no significant effect on Bmax and KD of 5HT2, 5HT1A, and alpha 1-adrenergic receptors, as well as NE and A23187-stimulated [3H]-IP1 formation, but significantly decreased the 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. It is possible that a decrease in 5HT-induced PI turnover after long-term ethanol exposure may be due to a decrease in coupling of 5HT2 receptors to G protein or PLC enzyme, whereas the decrease in 5HT-induced PI turnover after withdrawal may be due to a decrease in functional 5HT2 receptor number.     

Promoting activity of di(2-ethylhexyl)phthalate in rat liver foci bioassay

Summary The plasticizer DEHP but not DEHS exerted a weak promoting effect in a 12-week rat liver foci bioassay, using weanling female Sprague-Dawley rats. The effect was similar after doses of 200 and 500 mg/kg body weight, given 3 times weekly by gavage for 11 consecutive weeks after initiation with a single oral dose of 8 mg DEN/kg body weight. Lower doses were ineffective. The incidence of foci with deficiency in ATPase was enhanced about twice compared to rats treated with DEN only. The incidence of foci with expression of GGTase was not affected by DEHP treatment. The results match the findings with lifetime exposure studies, when liver tumors were found in rats and mice. The actual risk for man from environmental DEHP contamination seems to be low; the intake from highly contaminated food is calculated to be about 400-fold lower than the lowest effective dose in this study.Abbreviations DEHP di(2-ethylhexyl)phthalate - DEHS di(2-ethylhexyl)sebacate - ATPase adenosine-5-triphosphatase (EC 3.6.1.3) - GGTase gamma-glutamyltranspeptidase (EC 2.3.2.2) - DEN diethylnitrosamine Supported by grants from Umweltbundesamt Berlin (UBA 10604017)     

Allelic variation in the GABA A receptor gamma2 subunit is associated with genetic susceptibility to ethanol-induced motor incoordination and hypothermia, conditioned taste aversion, and withdrawal in BXD/Ty recombinant inbred mice

BACKGROUND: Behavioral genomics has made dramatic progress toward mapping quantitative trait loci (QTLs) that contain genes responsible for phenotypic differences in a variety of behavioral responses to alcohol (ethanol). We previously identified a QTL on mouse Chromosome 11 that affects genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, this QTL (Alcw3) accounts for 12% of the genetic variability in withdrawal liability. Candidate genes within this QTL encode the gamma-aminobutyric acid type A (GABA A) receptor gamma2, alpha1, alpha6, and beta2 subunits. We recently identified a coding sequence polymorphism between the B6 and D2 strains for the GABA A receptor gamma2 subunit gene (Gabrg2). In this study, we expand our analysis to a panel of BXD strains derived from the B6 and D2 progenitor strains. These BXD strains provide 26 fixed recombinant genotypes that can be used to examine genetic correlations, for example, between a phenotype of interest and allelic variation in a candidate gene. METHODS: Gabrg2 was cloned and sequenced from the 26 BXD recombinant inbred strains. We analyzed genetic correlations between allelic variation in Gabrg2 and alcohol phenotypes previously measured in the BXD strain means. RESULTS: Allelic variation in Gabrg2 is correlated genetically with predisposition to acute alcohol withdrawal and may underlie the Alcw3 locus. In addition, Gabrg2 is associated with ethanol-conditioned taste aversion, ethanol-induced motor incoordination, and ethanol-induced hypothermia. A trend is observed for chronic ethanol withdrawal, ethanol-induced loss of righting reflex, and tolerance to ethanol-induced hypothermia and ataxia. CONCLUSIONS: Functionally relevant variation in Gabrg2, or a closely linked gene, is correlated genetically with some, but not all, behavioral responses to alcohol. The alcohol-related phenotypes associated with Gabrg2 generally may be characterized as debilitating or motivationally negative.     

Effect of the selective NMDA NR2B antagonist, ifenprodil, on acute tolerance to ethanol-induced motor impairment in adolescent and adult rats

Background: Adolescent rats have been observed to be less sensitive than adults to a number of acute ethanol effects, including ethanol‐induced motor impairment. These adolescent insensitivities may be related in part to the more rapid emergence of within session (acute) tolerance in adolescents than adults. Adolescent‐related alterations in neural systems that serve as ethanol target sites, including changes in NMDA receptor subunit expression, may influence the responsiveness of adolescents to acute ethanol effects. This study explored the role of NMDA NR2B receptors in the development of acute tolerance to ethanol‐induced motor impairment in male adolescent [postnatal day (P)28–30] and adult (P68–70) Sprague–Dawley rats. Methods: Motor‐impairing effects of ethanol on the stationary inclined plane and blood ethanol concentrations (BECs) were examined following challenge at each age with a functionally equivalent ethanol dose (adolescents: 2.25 g/kg; adults: 1.5 g/kg). Data were collected at two postinjection intervals (10 or 60 minutes) to compare rate of recovery from ethanol intoxication with BEC declines using the Radlow approach ( Radlow, 1994 ) and changes in motor impairment/BEC ratios over time for assessing acute tolerance. Results: Both vehicle‐treated adolescent and adult animals showed similar acute tolerance development to the motor‐impairing effects of ethanol at these functionally equivalent doses on the stationary inclined plane, as indexed by an increasing time‐dependent dissociation between BECs and ethanol‐induced motor impairment, with motor impairment declining faster than BECs, as well as by significant declines in motor impairment/BEC ratios over time. Acute tolerance development was reliably blocked by administration of the NR2B antagonist, ifenprodil, (5.0 mg/kg), in adult rats, whereas adolescents were affected by a higher dose (10.0 mg/kg). Conclusions: These data support the suggestion that alterations in NMDA receptor systems occurring during adolescence may contribute to reduced sensitivity to ethanol by enhancing the expression of acute tolerance development in adolescents relative to adults.     

比较氰钴胺和弥可保降低2型糖尿病小鼠同型半胱氨酸的作用

2型糖尿病Kkay小鼠,以蛋氨酸喂养制备高胱氨酸血症模型。弥可保治疗两周同型血半胱氨酸水平明显低于氰钴胺治疗(2.2±0.2 vs 3.2±0.6μmol/L,P<0.05)     

Intermittent intravenous followed by intermittent oral 1α(OH)D3 treatment of secondary hyperparathyroidism in uraemia

Brandi L, Daugaard H, Egsmose C, Tvedegaard E, Kjærulff Nielsen P, Olgaard K (Medical Department P, Division of Nephrology, Rigshospitalet, University of Copenhagen, Denmark). Intermittent intravenous followed by intermittent oral 1α(OH)D₃ treatment of secondary hyperparathyroidism in uraemia. J Intern Med 1996; 239: 353–60. Objectives . To examine whether intermittent oral 1α(OH)D₃ treatment of patients on haemodialysis with secondary hyperparathyroidism (HPT) was able to maintain the marked suppression of PTH, which previously had been induced by an intermittent intravenous administration of 1α(OH)D₃. Simultaneously, the effect of the different routes of administration of 1α(OH)D₃ on the circulating levels of N-and C-terminal PTH fragments was measured. Design . An open study of patients on chronic haemodialysis. Setting . Renal division, Rigshospitalet, Copenhagen, Denmark. Subjects . A total of 26 patients started and five patients completed the total protocol. Interventions . The treatment protocol was divided into three parts: (i) 1α(OH)D₃ administered intravenously for >300 days; then (ii) 1α(OH)D₃ administered orally for 100 days, followed by (iii) 1α(OH)D₃ administered intravenously again for another 100 days. 1α(OH)D₃ was given three times a week at the end of each dialysis. Main outcome measures . Intact PTH, N- and C-terminal PTH. Results . Intact PTH levels were significantly (P<0.0001) suppressed by 90.4±3.3% after 56 days of intermittent intravenous 1α(OH)D₃ treatment. This degree of suppression remained stable during the following period of oral treatment and did not change further when intravenous treatment was reinstituted. The circulating levels of intact PTH and N- and C-terminal iPTH were not influenced by the administered route of 1α(OH)D₃. Conclusions . Intravenous 1α(OH)D₃ treatment of the secondary HPT in dialysis patients can safely be changed to oral treatment at the time when optimal suppression of PTH has been achieved.     

Characterization of the thromboxane synthase pathway product 12-oxoheptadeca-5(Z)-8(E)-10(E)-trienoic acid as a thromboxane A2 receptor antagonist with minimal intrinsic activity

Thromboxane synthase forms thromboxane (TX) A₂ and 12(S)-hydroxyheptadeca-5(Z)-8(E)-10(E)-trienoic acid (HHT) at equimolar amounts. Twelve-oxoheptadeca-5(Z)-8(E)-10(E)-trienoic acid (Oxo-HT) is the primary metabolite of HHT and has been described to be an inhibitor of platelet aggregation. Functional studies, Schild analysis and competitive binding studies were performed to clarify its mode of action. Oxo-HT was prepared biosynthetically as well as chemosynthetically, purified and characterized by gas chromatography and mass spectrometry. Platelet activation was assessed by determination of shape change, aggregation, fibrinogen binding and P-selectin expression using optical aggregometry and flow cytometry. Oxo-HT 0.1 n M to 50 μM did not induce platelet activation. Furthermore, it had no effect on platelet activation induced by thrombin, ADP or PAF. In contrast, Oxo-HT inhibited platelet aggregation, fibrinogen binding and P-selectin expression induced by U46619 in a competitive manner. Schild analysis for U46619-induced fibrinogen binding and P-selectin expression revealed pA₂ values of 6.1 and 6.6, respectively, which correspond to K_d values of approximately 0.8 μM and 0.3 μM , respectively. Oxo-HT also inhibited U46619 induced shape change (IC₅₀ ? 10 μM ). However, Oxo-HT over a concentration range of 0.1–1 μM enhanced the partial shape change induced by low concentrations of U46619. Thus Oxo-HT seems to possess a minimal agonistic potential, which alone is not sufficient to trigger a platelet activation but can enhance low levels of platelet activation. Oxo-HT blocked the binding of [³H]SQ 29548 in a concentration-dependent manner, whereas HHT did not displace [³H]SQ 29548. The K_d of Oxo-HT determined from competition binding studies was 7.7 μM , about 10–25-fold higher than the apparent K_d determined by Schild analysis. This discrepancy might be due to a desensitization of the TXA₂ receptor triggered by the minimal intrinsic activity of Oxo-HT. We conclude that Oxo-HT is a naturally occurring specific TXA₂ receptor antagonist with minimal intrinsic activity. Oxo-HT may contribute to the regulation of TXA₂-induced platelet activation in vivo.     

Attenuation of alcohol-induced apoptosis of hepatocytes in rat livers by polyenylphosphatidylcholine (PPC)

BACKGROUND: Alcohol consumption increases apoptosis of hepatocytes. This effect appears to be mediated by the induction of hepatic cytochrome P-4502E1(CYP2E1) and its generation of free radicals, which results in an enhanced lipid peroxidation that initiates apoptosis. Because polyenylphosphatidylcholine (PPC), a soybean extract rich in polyunsaturated phosphatidylcholines, decreases the induction of ethanol-specific CYP2E1 and opposes oxidative stress, we hypothesized that PPC supplementation may attenuate hepatocyte apoptosis caused by ethanol ingestion. METHODS: Twenty-eight male Sprague Dawley rats were pair-fed Lieber-DeCarli liquid diets containing 36% of energy as alcohol or an isocaloric amount of carbohydrate for 28 days. Half of the rats were given PPC (3 g/liter), whereas the other half received the same amount of linoleate (as safflower oil) and of choline as the bitartrate. An additional dose of alcohol (3 g/kg) was given intragastrically 90 min before the livers were removed. We assessed apoptosis in formalin-fixed, paraffin-embedded liver sections by using the TUNEL (terminal transferase dUTP nick end labeling) assay. Apoptotic hepatocytes were identified by positive TUNEL staining in conjunction with condensation of nucleoplasm or margination of chromatin. In each rat, 20,000 to 60,000 hepatocytes were counted by light microscopy by using Image-Pro Plus computer software, and the incidence of apoptosis was expressed as the percentage of total hepatocytes. RESULTS: Alcohol feeding resulted in a 4.5-fold increase in apoptosis of hepatocytes compared to pair-fed control rats; PPC supplementation decreased the alcohol-induced apoptosis to less than half. No difference in the incidence of apoptosis between the control and PPC-supplemented rats was found in the absence of alcohol. Apoptosis was distributed randomly in the liver lobules of the rats fed the control diet, whereas the alcohol-induced apoptosis was significantly increased in the perivenular area. PPC supplementation strikingly reduced this effect. CONCLUSIONS: PPC attenuates alcohol-induced apoptosis of hepatocytes; this effect may provide a mechanism for PPC's protection against liver injury, possibly in association with its antioxidative action via the down-regulation of ethanol-mediated CYP2E1 induction.     

润肺口服液对慢性支气管炎大鼠支气管TNF-α、ICAM-1蛋白及IL-8表达的影响

目的研究中药复方润肺口服液对慢性支气管炎（CB，CB）支气管肿瘤坏死因子（TNF-α）、细胞间黏附分子-1（ICAM-1）及白介素-8（IL-8）表达的影响，探讨其治疗CB的疗效机制。方法雄性Wistar大鼠随机分为假手术组、慢性支气管炎组、慢性支气管炎氢化可的松治疗组及慢性支气管炎润肺口服液治疗组，每组8只。大鼠慢性支气管炎模型通过熏香烟加气管内注入低剂量脂多糖制成，利用免疫组织化学观察各组大鼠支气管TNF-α、ICAM-1蛋白及IL-8的表达情况。结果熏香烟加气管内低剂量脂多糖注射可复制出较理想的慢性支气管炎模型，假手术组支气管上皮内可见TNF-α、ICAM-1蛋白及IL-8弱阳性表达；慢性支气管炎组支气管TNF-α、ICAM-1蛋白及IL-8在支气管上皮细胞、支气管周围的淋巴滤泡炎性细胞和肺泡间质细胞中可见强阳性表达；半定量图像分析显示，慢性支气管炎组TNF-α、ICAM-1蛋白及IL-8的表达明显强于假手术组（P〈0．05），慢性支气管炎润肺口服液治疗组的表达则明显弱于支气管炎组（P〈0．05）。结论润肺口服液通过下调支气管上皮细胞中TNF-α、ICAM-1蛋白及IL-8的表达，从而减轻气道炎症反应是其治疗慢性支气管炎的机制之一。     

Impact of circulating testosterone on iodomelatonin binding sites in the male rat brain

The effects of castration and subsequent testosterone and estradiol treatment and of a single injection of ethylene-1,2-dimethanesulphonate (EDS) on the distribution of [2-¹²⁵I]iodomelatonin ([¹²⁵I]melatonin) binding sites in the male rat brain were investigated. Castration produced a marked testosterone-reversible decrease in [¹²⁵I]melatonin binding in the male rat brain, particularly in the hypothalamus and hippocampus. In contrast, [¹²⁵I]melatonin binding in the parietal cortex, medulla-pons and cerebellum was generally unaffected by castration. Estradiol did not reverse the effect of castration on [¹²⁵I]melatonin binding.

A single injection of EDS which causes the destruction of Leydig cells led to a marked decrease in [¹²⁵I]melatonin binding in the brain of the rats between 3 and 7 days after treatment. This decrease correlated with the decline in serum concentrations of testosterone. Specific [¹²⁵I]melatonin binding and serum concentrations of testosterone subsequently increased to control levels within 37 days after treatment in accord with the repopulation of the Leydig cells. The results clearly show that testosterone regulates the density of melatonin receptors in the hypothalamus and hippocampus of the male rat.     

Tissue-type plasminogen activator prevents formation of intra-abdominal abscesses after surgical treatment of secondary peritonitis in a rat model

Background Optimal therapy of secondary peritonitis frequently results in the formation of residual abscesses, which bear a substantial mortality and morbidity. This study aims to prove that fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) can reduce abscess formation after surgical treatment of secondary peritonitis in a rat model, without causing unwanted side effects. Materials and methods Male Wistar rats received an intra-abdominal injection with a suspension of sterile feces, 10⁵ cfu Escherichia coli and 10⁴ cfu Bacteroides fragilis. Surgical debridement was performed 1 h after inoculation. Animals were randomized into four groups (n = 14 each). Three groups received human rtPA at 1 h (rtPA1); 1 h and 6 h (rtPA2); and 1, 6, and 24 h (rtPA3), respectively. Each dose contained 1.25 mg rtPA. Controls received saline only. Animals were killed after 5 days. Results rtPA treatment reduced abscess formation in surviving animals, depending on number of doses given. Animals in group rtPA3 had no abscesses in contrast to 88% of the controls (mean 3.6 ± 2.7 abscesses per rat; p < 0.05). In the rtPA1 and rtPA2 group, frequency of abscess formation was 58 and 33%, respectively. Mortality, course of body weight, and bacteremia were not affected by rtPA and neither were peritoneal cell counts and levels of TNF-α, IL-1β, IL-6 and IL-10. No bleeding complications were observed. Conclusion rtPA reduces intra-abdominal abscess formation after surgical treatment of generalized peritonitis without increasing mortality or affecting the local inflammatory response.     

Ribavirin in the treatment of chronic hepatitis C

Background and Aim:  Current practice guidelines recommend that individuals chronically infected with the hepatitis C virus (HCV) be treated with pegylated interferon plus ribavirin. Ribavirin, however, is associated with serious adverse events (AE), especially anemia. We review its mechanism of action, its importance in treating chronic hepatitis C (CHC) patients, the AE associated with its use, and techniques used to lessen these AE.
Methods:  Medline searches were performed using the keywords ribavirin and hepatitis, together with the keywords mechanism, anemia, liver transplant, renal function, pharmacokinetics, and dose reduction. Searches of abstracts of recent Digestive Diseases Week, American Association for the Study of Liver Diseases, and European Association for the Study of Liver Diseases meetings were also performed.
Results:  Ribavirin may be effective in treating CHC by affecting the virus or the host; for example by inducing viral mutations, blocking cellular enzymes, or affecting the host immune response. Although the pegylated interferons are the primary drugs used to treat CHC, a combination with ribavirin is more effective than pegylated interferon alone. Ribavirin-associated AE may be lessened by ribavirin dose reductions and by maintenance of the hematocrit.
Conclusions:  Treatments of ribavirin toxicities, especially anemia, can allow patients to continue full-dose combination therapy with peginterferon and ribavirin, enhancing their probability of attaining a sustained virologic response (SVR). Treatment of CHC should be tailored to individual patients, especially those with renal dysfunction, and should include agents that treat the side-effects of CHC treatment. Monitoring of plasma ribavirin concentrations during treatment may help in the future.