Effect of lindane on the myelination process in the rat

After lindane administration at several doses, brain myelin fractions of litters of male and female Wistar rats show a significant diminution of CNP (2′,3′-cyclic nucleotide 3′-phosphodiestera activity. Furthermore, the immunohistochemical study of brains by means of a MBP (myelin basic protein) specific antibody reveals myelin deficits in some brain regions after lindane treatment. This loss of myelin protein is dose dependent. The deficit in myelin cannot be attributed to undernourishment of lindane-administered rats. This work shows the vulnerability of the developing central nervous system (CNS) to lindane and the correlation between a decrease in the CNPase activity and a deficit of MBP during the period of study of these animals.     

Effects of midazolam,DMCM and lindane on potentiated startle in the rat

Forty-eight male Wistar rats were exposed to contingent light-shock combinations and 48 rats received light and shock stimuli in a random order. One day after fear conditioning the animals were tested for startle potentation after injection of midazolam (0, 0.5, 1.0, 2.0 mg/kg, IP) or DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; 0, 0.1, 0.2, 0.4 mg/kg IP) or lindane (0, 7.5, 15.0, 30.0 mg/kg PO). Midazolam attenuated potentiated startle dose dependently and the inverse benzodiazepine agonist DMCM had the opposite effect. The effects of lindane on startle amplitudes were identical to those of DMCM, indicating that lindane has anxiogenic effects on behavior. It is suggested that the anxiogenic effects of lindane are mediated by an effect at the GABA-ionophore complex.     

On the effects of lindane on the plus-maze model of anxiety

The behavioral effects of an acute subconvulsant dose of the insecticide and ectoparasiticide γ-hexachlorocyclohexane, lindane, were compared in the plus-maze (+-maze) animal model of anxiety to those elicited by the anxiogenic GABA_A-antagonist pentylenetetrazole (PTZ) and the anxiolytic benzodiazepine diazepam. The effects of the coadministration of diazepam and lindane, and of diazepam and PTZ were also studied. The results from the analysis of the data with the multivariate statistical technique principal component analysis indicated that the effects of subconvulsant doses of lindane and PTZ on the behavior of rats in the +-maze are similar, and opposite to those elicited by diazepam, and that the administration of the convulsants would antagonize the effects of the benzodiazepine. The putative anxiogenic properties of the insecticide and the utility of the +-maze model in neurotoxicological research are discussed.     

The action of lindane in accelerating the spontaneous release of transmitter at the frog neuromuscular junction

Summary Lindane (5×10^–5M) causes a progressive and marked rise in MEPP frequency at the frog neuromuscular junction. Concentrations over a range of 5×10^–6M to 5×10^–4M were tested. The results suggest that it has two actions in promoting this effect. Its major effect is probably to cause an increase in Ca²⁺-permeability and a rise in Ca²⁺ entry. Its second, smaller effect, which persists in the absence of extracellular Ca²⁺, is probably also because of a rise in [Ca²⁺]_i. The ways in which these effects might be produced and the significance of these findings for explaining the known pharmacological actions of lindane are discussed.     

Effect of nitric oxide on apoptotic activity in the rat gastrointestinal tract.

The effect of nitric oxide (NO) on apoptosis in the gastrointestinal mucosa was investigated. Experiments involved long-term exposure of rat gastric mucosal cells in vitro to exogenous NO delivered from the NO, donor S-nitroso-N-acetyl-penicillamine, and the effect of intravenous administration of lipopolysaccharide in vivo, in the presence and absence of the selective inhibitor of inducible NO synthase N-(3-(aminomethyl)benzyl) acetamidine (1400 W). S-nitroso-N-acetyl-penicillamine produced a dose-related inhibition of caspase 3-like activity and DNA fragmentation in isolated gastric mucosal cells. Caspase 3-like activity and DNA fragmentation in gastric, ileal and colonic mucosa were increased both 5 and 24 h after injection of lipopolysaccharide (3 mg/kg, i.v.) to rats in vivo. Administration of 1400 W (5 mg/kg, i.v.) immediately after lipopolysaccharide enhanced caspase 3-like activity and DNA fragmentation above that found with lipopolysaccharide alone. In conclusion, data obtained both in vitro and in vivo suggest that NO exerts an anti-apoptotic effect on rat gastrointestinal mucosal cells.     

Effect of rokitamycin on upper gastrointestinal contractile activity. Analysis of side-effects on gastrointestinal tract

In order to determine whether rokitamycin (RKM), one of the macrolide antibiotics, has any side effects on the gastrointestinal tract, the effect of intraduodenal administration of RKM (1.0, 3.0 and 9.0 mg/kg) on gastrointestinal contractile activity was studied by means of force transducers implanted chronically on the gastric body, gastric antrum, duodenum and upper jejunum in conscious dogs. Erythromycin (EM 0.3, 1.0 and 3.0 mg/kg) and kitasamycin (LM 1.0, 3.0 and 9.0 mg/kg), both macrolide antibiotics, were used as control drugs. RKM, when given at 3.0 mg/kg and 9.0 mg/kg doses, induced segmentation contractions only in the duodenum where it was administered. The duration of the RKM-induced contractions was 7.5 +/- 2.5 minutes for 3.0 mg/kg and 15.8 +/- 3.0 minutes for 9.0 mg/kg, and the contractile force of the contractions was 43 to 82% of the maximum contractile force of the interdigestive contractions in the duodenum. EM, at 0.3 mg/kg, evoked a series of strong contractions quite different from those induced by RKM but similar to the natural interdigestive contractions, and with large doses, dose-dependent long-lasting interdigestive contractions were induced. On the other hand, LM did not stimulate notable gastrointestinal contractile activity even at a 9.0 mg/kg dose. In order to eliminate the possibilities of the contraction being caused by the effect of RKM on the duodenum through the general circulation upon absorption, 3.0 mg/kg RKM was given intravenously. It was found that intravenous injection of RKM did not evoke any contractions attributable to the direct action of RKM in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Overexpression of cerebral and hepatic cytochrome P450s alters behavioral activity of rat offspring following prenatal exposure to lindane

Oral administration of different doses (0.0625, 0.125 or 0.25 mg/kg corresponding to 1/1400th, 1/700th or 1/350th of LD(50)) of lindane to the pregnant Wistar rats from gestation days 5 to 21 were found to produce a dose-dependent increase in the activity of cytochrome P450 (CYP)-dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in brain and liver of offspring postnatally at 3 weeks. The increase in the activity of CYP monooxygenases was found to be associated with the increase in the mRNA and protein expression of xenobiotic metabolizing CYP1A, 2B and 2E1 isoenzymes in the brain and liver of offspring. Dose-dependent alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 3 weeks have suggested that increase in CYP activity may possibly lead to the formation of metabolites to the levels that may be sufficient to alter the behavioral activity of the offspring. Interestingly, the inductive effect on cerebral and hepatic CYPs was found to persist postnatally up to 6 weeks in the offspring at the relatively higher doses (0.125 and 0.25 mg/kg) of lindane and up to 9 weeks at the highest dose (0.25 mg/kg), though the magnitude of induction was less than that observed at 3 weeks. Alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 6 and 9 weeks, though significant only in the offspring at 3 and 6-week of age, have further indicated that due to the reduced activity of the CYPs during the ontogeny, lindane and its metabolites may not be effectively cleared from the brain. The data suggest that low dose prenatal exposure to the pesticide has the potential to produce overexpression of xenobiotic metabolizing CYPs in brain and liver of the offspring which may account for the behavioral changes observed in the offspring.     

Testing double mutants of the enzyme nitroreductase for enhanced cell sensitisation to prodrugs: Effects of combining beneficial single mutations

Prodrug activation gene therapy for cancer involves expressing prodrug-activating enzymes in tumour cells, so they can be selectively killed by systemically administered prodrug. For example, Escherichia colinfsB nitroreductase (E.C. 1.6.99.7)(NTR), sensitises cells to the prodrug CB1954 (5-[aziridin-1-yl]-2,4-dinitrobenzamide), which it converts to a potent DNA-crosslinking agent. However, low catalytic efficiency with this non-natural substrate appears to limit the efficacy of this enzyme prodrug combination for eliminating the target cancer cells. To improve this, we aim to engineer NTR for improved prodrug activation. Previously, a number of single amino acid substitutions at six positions around the active site of the enzyme were found to increase activity, resulting in up to ∼5-fold enhanced cell sensitisation to CB1954. In this study we have made pairwise combinations among some of the best mutants at each of these 6 sites. A total of 53 double mutants were initially screened in E. coli, then the 7 most promising were inserted into an adenovirus vector and compared in SKOV3 human ovarian carcinoma cells for sensitisation to CB1954 and two alternative prodrugs. The most effective mutants, T41L/N71S and T41L/F70A, were 14-17-fold more potent than WT NTR at sensitising the cancer cells to CB1954. The best mutant for activation of the dinitrobenzamide mustard prodrug SN23862 was T41L/F70A (4.8-fold improvement); and S40A/F124M showed 1.7-fold improvement over WT with the nitrobenzylphosphoramide mustard prodrug LH7. In two tumour xenograft models using SKOV3 or human prostate carcinoma PC3, T41L/N71S NTR demonstrated greater CB1954-dependent anti-tumour activity than WT NTR.     

Similarities in lindane induced alteration in cytochrome P450s and associated signaling events in peripheral blood lymphocytes and brain

Studies were initiated to investigate the similarities in alterations in cytochrome P450s (CYPs) and associated signaling events in brain and peripheral blood lymphocytes (PBL) induced by lindane, an organochlorine pesticide. Adult male albino wistar rats were treated orally with different doses (2.5- or 5.0- or 10- or 15 mg/kg/body weight) of lindane daily for 4 days. In another experiment, the treatment of low dose (2.5 mg/kg) of lindane was continued for 15- and 21 days. A dose- and time-dependent increase was observed in the activity of CYP dependent enzymes in brain microsomes and PBL isolated from the treated rats. However, the magnitude of induction was several folds less in PBL. As observed in brain, RT-PCR and Western immunoblotting demonstrated that increase in CYP enzymes in PBL is due to the increase in the mRNA expression of specific CYP isoenzymes. Similarities were also observed in activation of ERK and JNK MAP kinases and c-jun in PBL or brain isolated from rats treated with lindane. Similarities in the induction of CYPs and activation of MAP kinases in PBL and brain suggest that CYP expression profiles in PBL could be used for monitoring the exposure and toxicity of environmental chemicals.     

山药及其麸炒品的多糖成分对脾虚小鼠胃肠功能的影响

目的:探讨山药麸炒前后多糖成分对脾虚模型小鼠胃肠功能的影响,为进一步探明山药补脾健胃作用的可能机制及为其炮制机理提供一定的依据.方法:通过灌胃给药,观察山药炮制前后粗多糖成分对脾虚模型小鼠胃排空率、肠推进率及脾脏指数、胸腺指数的影响.结果:与模型组相比,山药粗多糖能抑制脾虚小鼠胃排空及小肠推进,考察制品作用有优于生品的趋势,同时脾脏指数与胸腺指数均有一定增加,表明制品优于生品.结论:山药多糖成分对脾虚小鼠有一定的补脾健胃作用,初步推测调节免疫可能是其作用机制之一.     

Impaired aquaporins expression in the gastrointestinal tract of rat after mercury exposure

The main route of exposure to mercury in humans is through the diet. Consequently, the gastrointestinal mucosa is exposed to the mercurial forms, where they cause intestinal fluid accumulation, mucosal injuries and diarrhea. The relationship between inorganic mercury (HgCl₂) and methylmercury (CH₃HgCl) exposure and water movement in the gastrointestinal tract is still unexplored. The leading role of aquaporins (AQPs) in the rapid bidirectional movement of fluid in the gastrointestinal tract of mammals is well established. The present study evaluates the effect of HgCl₂ and CH₃HgCl exposure on AQP expression in different portions of the gastrointestinal tract of rats treated by gavage (5 mg kg^–1 of mercury species, single dose, 4 days). The results show that mercury species reduce mRNA and protein levels of AQPs in different parts of the gastrointestinal tract. In the stomach, treated rats show a significant reduction of expression of AQP3 (80–90% for mRNA and 50% for protein) and AQP4 (95–99% for mRNA and 20–40% for protein). In the small and large intestine, treated rats experience a significant reduction of AQP3 and AQP7 expression. Protein contents of both AQPs are reduced in similar proportions in jejunum (AQP3: 40–50%; AQP7: 45–50%) and colon (AQP3: 35–40%; AQP7: 45–60%), regardless of the treatment. Our results indicate that some AQPs are downregulated in the rat gastrointestinal tract by mercury exposure, suggesting a possible role of AQPs in the development of mercury gastrointestinal symptoms. Copyright © 2015 John Wiley & Sons, Ltd.     

Pharmacological characterization of 5-hydroxytryptamine-induced contraction in the chicken gastrointestinal tract

5-Hydroxytryptamine (5-HT) receptor subtypes involved in 5-HT-induced contraction of the chicken gastrointestinal tract were characterized pharmacologically using subtype-selective agonists and antagonists. The proventriculus (area of stomach adjacent to the oesophagus) and ileum are examined. 5-HT applied cumulatively caused sustained contraction of the proventriculus that was not decreased by tetrodotoxin, atropine or l-nitro-arginine methylester (l-NAME). alpha-Methyl-5-HT showed the same potency as that of 5-HT, indicating the involvement of the 5-HT(2) receptor. (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI), 5-methoxytryptamine and 1-(3-chlorophenyl)piperazine hydrochloride (mCPP) were potent, and 2-methyl-5-HT, 5-carboxamidotryptamine, BW723C86 and 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride (MK212) were moderate, but (+/-)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT), [endo-N-8-methyl-8-azabicyclo-(3,2,1)oct-3-yl]-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H-benzimidazol-1-carboxamide (BIMU-8) and cisapride were weak agonists. Correlation of pEC(50) values of these agonists with documented pEC(50) values for 5-HT(2C) receptor was higher than 5-HT(2A) and 5-HT(2B). Cinanserin, ketanserin, methiothepin, methysergide, mianserin, (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido)phenyl-5-oxopentyl)-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride (RS102221), N-(1-methyl-1H-indolyl-5-yl)-N'-(3-methyl-5-isothiazolyl)urea (SB204741), spiperone and N-desmethylclozapine concentration-dependently inhibited the contractile responses to 5-HT. Correlation of pK(b)/pA(2) of antagonists with documented pK(i) for 5-HT(2C) receptor was highest among 5-HT(2) receptor subtypes. In the methysergide- and ketanserin-treated proventriculus, 5-HT, 2-methyl-5-HT and cisapride did not enhance the electrical field stimulation (5 Hz)-induced cholinergic contractions. 5-HT applied non-cumulatively caused transient contraction of ileum, and the responses were partly decreased by atropine or tetrodotoxin. 5-Methoxytryptamine, alpha-methyl-5-HT, 5-carboxamidotryptamine, L692,247 and DOI were potent agonists. However, 2-methyl-5-HT, cisapride, BW723C86, 8-OH-DPAT and 5-nonyloxytryptamine, mCPP and MK212 were less effective. Ketanserin and methysergide decreased the 5-HT-induced ileal contraction, but neither GR113808 nor SB269970 inhibited the responses. In conclusion, 5-HT causes contraction of the proventriculus via 5-HT(2C)-like receptors present on smooth muscle. 5-HT also causes contraction of the ileum, but the underlying mechanisms are complex, involving neural and smooth muscle components, and both 5-HT(1)- and 5-HT(2)-like receptors. Neural 5-HT receptors similar to 5-HT(3)/5-HT(4) receptors were not found in the chicken proventriculus and ileum.     

小肠憩室并发症的临床分析

目的提高小肠憩室并发症的诊治水平.方法对1 996-2 005年间诊治的小肠憩室并发症进行回顾性分析.结果十二指肠憩室出血7例,治愈5例,好转2例.空肠憩室致肠梗阻2例,治愈1例,吻合口漏转院1例.美克尔憩室7例中,肠梗阻4例,炎症、出血、穿孔各1例,治愈5例,2例死于中毒性休克.结论对原因不明的复发性腹痛病患者,应作钡餐检查,必要时腹腔镜检是一种较好的方法.     

Effect of cadmium on the extracellular Na+, K+, and Ca2+ in the gill and small intestine of Goldfish Carassius auratus

In this study, the toxic effect of cadmium on extracellular Na⁺, K⁺, and Ca²⁺ in the gill and small intestine of goldfish Carassius auratus was determined with the technique of ion chromatograph. Two-way ANOVA indicated that the two factors (Cd²⁺ treatment and time) and the interaction factor had significant effect on the level of Na⁺, K⁺, and Ca²⁺ in the small intestine and gill. 1.0 mg/L Cd²⁺ significantly increased Ca²⁺ level in the small intestine, but Ca²⁺ level in the gill was significantly decreased by 1.0 and 5.0 mg/L Cd²⁺ at 24, 48, and 72 h. Na⁺ and K⁺ level in the small intestine and gill was increased by 1.0 mg/L Cd²⁺ at three time points, but increased by 5.0 mg/L Cd²⁺ at a certain different time. In addition, Na⁺ level was significantly decreased by 5.0 mg/L Cd²⁺ at 24 or 48 h in the small intestine and gill. The results indicated that Cd²⁺ played an important role in regulating the level of Na⁺, K⁺, and Ca²⁺ in the small intestine and gill of goldfish C. auratus. A method was constructed to investigate the extracellular Na⁺, K⁺ and Ca²⁺ in the tissues of gold fish with ion chromatography.     

A novel aspect of lindane testicular toxicity: in vitro effects on peritubular myoid cells

The in vitro effects of the insecticide lindane have been investigated in rat testis peritubular myoid cells (PMCs). Upon PMC exposure to lindane, polarity increase and decrease of dipole dynamics were seen at the membrane level (EC50 20 μM), leading to a partial dissipation of the membrane intrinsic dipole potential. The initial membrane depolarization was increased by Cl⁻ efflux and limited by Ca²⁺-activated repolarizing currents. Concomitantly, lindane produced an increase in [Ca²⁺]_i (EC50 125 μM) resulting from both Ca²⁺ release from an inositol 1,4,5-trisphosphate-sensitive intracellular store and a voltage-dependent Ca²⁺ influx from the extracellular medium. Of particular interest from a toxicologic point of view, insecticide concentrations well below those effective in altering ion homeostasis potently inhibited both [Ca²⁺]_i increase and contraction induced by the natural agonists vasopressin and endothelin-1 (IC50s < 10 μM). These data demonstrate that PMCs are highly susceptible to lindane and suggest that the insecticide may exert testicular toxicity by interfering with hormone-regulated PMC function.     

Effect of repeated exposure to lindane and cadmium on lindane metabolism in rats

The effects of daily administration of cadmium and lindane for 35 days on the metabolism of lindane in rats were investigated. The results indicate that cadmium induces a significant inhibition of lindane metabolism, since the group dosed with lindane plus cadmium had a significantly higher concentration of lindane in plasma and tissues than the group dosed with lindane alone. The inhibition in the metabolic rate of lindane is associated with the cadmium-induced alterations in the disposition of essential trace elements, Zn, Cu and Fe, in the liver.     

Effect of multiple doses of clonazepam on the nitroreductase activity in hepatic microsomal preparation from rat

The hepatic microsomal nitroreductase activity and urinary excretion of the sum of the main metabolites of clonazepam (CNZ) were investigated in rats that had received 7 daily injections of 2 mg/kg of the compound. Despite the significant decrease in CNZ nitroreductase activity, there was only poor correlation between the enzyme activity and excretion of the assayed metabolites.