Effect of propofol in altering pentylenetetrazol induced seizure threshold in rats

The present study was undertaken to evaluate the role of propofol in altering pentylenetetrazol induced seizure threshold in rats. Total 42 Wistar rats were used to evaluate different parameters (onset of action, duration of seizure, seizure severity score and number of seizure) following propofol injection. The present results showed that there was significant reduction in the time required for onset of seizure in propofol treated groups following PTZ treatment. If treated with propofol alone (2 and 5 mg/kg), there was no significant difference as compared to controls. In seizure severity score assessment, there was no significant difference with various doses of propofol alone treated groups, but the difference was observed in propofol (2 and 5 mg/kg) treated groups following PTZ treatment. Duration of seizure also significantly increased in propofol (5 mg/kg) treated group, but at 2 mg/kg of propofol treatment, no significant difference was observed. The present results showed that propofol ameliorate seizure threshold and caused prolongation of duration of seizure. However, further study and trials are needed to confirm the present results.     

Adenosine-angiotensin II interactions in pentylenetetrazol seizure threshold in mice.

The effects of adenosinergic and angiotensin IIergic agents and of their combinations on the seizure threshold in mice were determined by measuring the dose of timed-intravenous (tail vein) infused pentylenetetrazol (PTZ) required to elicit clonic seizures. All drugs were administered intracerebroventricularly (i.c.v.). Angiotensin II (ANG II), its peptide analogue sarmesin, the selective adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and 2-chloroadenosine (2-ClAdo) significantly increased the PTZ seizure threshold. The selective AT1 receptor antagonist losartan blocked the anticonvulsant effect of ANG II, sarmesin and CPA. The selective AT2 receptor antagonist PD 123319 failed to block the effect of ANG II and sarmesin on the PTZ seizure threshold but reversed the threshold-increasing effect of CPA. The selective adenosine A1 receptor antagonist 8-(p-sulfophenyl)-theophylline (8-p-SPT) alleviated the threshold-increasing effect of CPA and ANG II. Concurrent injection of 2-ClAdo and ANG II as well as of 2-ClAdo and sarmesin, at doses which had no significant effect on the PTZ seizure threshold when given alone, acted synergistically, producing greater effect on the threshold. Taken together, the findings support the possibility of specific ANG II-adenosine A1 receptor interactions in the regulation of the PTZ seizure threshold.     

The pharmacokinetics of intravenously administered diazepam in the rat influenced by composition of the lymph

Diazepam, a drug with hydrophobic properties, was used as a model drug for the study of its distribution after i.v. administration into the central lymph of the rat. The intestinal lymph, which prevails in the central lymph, was modified for the presence of total lipids chylomicrons by fasting and a normal or an artificial diet (olive oil). Lymphatic levels of diazepam in all three experimental conditions exceeded the corresponding blood levels, being lowest in the fasted group, higher in the normally fed animals and highest in the oil-fed group. Experimental blood and lymphatic data were subjected to pharmacokinetic analysis. The changes in the parameters were found to depend quantitatively upon the presence of chylomicrons in the lymph. Lymphatic availability of diazepam in the central lymph is stimulated by an increased content of the chylomicrons fraction of the lymph.     

The effects of intravenously administered bombesin on pentagastrin-stimulated acid secretion in cats

The effects of bombesin (BBS) infusion or BBS injection on the plateau gastric secretion stimulated by pentagastrin (Pg) were compared in cats fitted with gastric fistula (GF) and Heidenhain pouch (HP). Injection of 81 pmol/kg of BBS inhibited Pg-stimulated acid secretion in both GF and HP by 47 +/- 5% and 37 +/- 5% (P less than 0.01), respectively. Infusion of 324 pmol/kg.h of BBS did not significantly modify acid secretion, but as soon as the infusion stopped, an inhibition appeared which lasted 1 h (37 +/- 5% in GF and 53 +/- 4% in HP P less than 0.01). The inhibition was reversed in GF by infusion of BBS 324 pmol/kg.h. In HP, reversion of inhibition required the addition in the Pg infusion of subthreshold dose of carbachol. We suggest that under non-steady state conditions (i.e. injection or after the end of the infusion) a concentration gradient of BBS is created which favors the response of D-cells over that of G-cells, whereas under steady-state conditions (i.e. during infusion) the effects of BBS on G- and D-cells are balanced. This finding argues for a physiological role of BBS in the regulation of gastric acid secretion.     

The pentylenetetrazol model of anxiety detects withdrawal from diazepam in rats

This experiment tested whether benzodiazepine withdrawal could be detected in an animal model of anxiety. Rats were trained in operant chambers using food reward to press one lever after pentylenetetrazol (PTZ), 20 mg/kg, injection and the other lever after saline injection. Previously, the PTZ cue has been shown to be simulated by anxiogenic drugs and blocked by anxiolytic drugs. After rats reliably performed this discrimination, they were injected with diazepam, 20 mg/kg, from 1 to 4 times a day for six days. For one group of subjects, on the third, fourth and sixth days, they were also injected with 40 mg/kg of RO 15-1788, a benzodiazepine receptor antagonist, and tested for lever selection: 50–80% of the subjects selected the PTZ lever; these results are in contrast to those obtained prior to chronic diazepam treatment in which RO 15-1788 did not generalize to PTZ. A second group of subjects was also injected for six days with diazepam and then allowed to withdraw spontaneously for eight days: PTZ lever selection over this period varied from 20 to 60% of rats. These data indicate that animals trained to discriminate a PTZ cue: 1) generalize the benzodiazepine withdrawal state to the PTZ cue, and 2) discriminate the withdrawal state for long periods of time, agreeing with clinical observations of long-lasting anxiety signs during benzodiazepine withdrawal.     

The distribution in mice of intravenously administered labelled Candida albicans.

The time dependence of the distribution of intravenously injected radiolabelled Candida albicans in the body of mice was studied. The Candida cells were labelled by cultivating them 7 days at 28 degrees C in a medium containing one of the following radionuclides: 46Sc, 95Nb, 59Fe, 144ce, 89Sr, 60Co, 65Zn, 54Mn, 45Ca, 51Cr and 91Y, which are listed in decreasing order in respect to amount bound. The labelled cells were killed by heating them 120 min at 60 degrees C, without loss of immunologic properties. Owing to the amount and strength of binding, 144Ce labelled Candida, together with 14C labelled cells was used in animal kinetic study. A rapid disappearance of the labelled cells from blood, interrupted by a small peak, was paralleled by a transient uptake in lungs and followed by a long lasting accumulation in the liver. The kidneys and spleen revealed only small uptakes of the labelled material.     

The stability and metabolism of intravenously administered neurotensin in the rat

The clearance and metabolism of synthetic and tritiated (³H) neurotensin (NT) were studied following its intravenous injection in a pharmacologic dose (500 pmol/kg) into anesthesized rats. Immunoreactive NT (iNT), measured in a radioimmunoassay (RIA) with use of a carboxyl-(C)-terminal directed antiserum, displayed an apparent half-life ($\text{t}\text{1}\text{2}$) of 0.55 min, while that measured by an amino-(N)-terminal directed antiserum had a $\text{t}\text{1}\text{2}$ of 5 min. The radiolabel from injected ³H-NT (³H on Tyr^3,11) had a $\text{t}\text{1}\text{2}$ of 6.5 min. High-pressure liquid chromatography of extracts of plasma obtained from the circulation 0.5–3 min after injection of NT and ³H-NT showed the presence of NT and the generation mainly of the fragments NT^1–8, NT^1–11, and NT^9–13, as well as free ³H-labeled tyrosine. The apparent half-lives of intravenously injected synthetic NT^1–8, NT^1–11 and NT^1–12 measured with the N-terminal RIA were 9, 5 and 5 min, respectively, while that for NT^9–13 was less than 0.5 min. These results indicate that exogenously injected NT is rapidly metabolized to form N-terminal fragments which are cleared more slowly than NT. These findings suggest that use of N-terminal antisera to detect the release of endogenous NT into the circulation is likely to yield measurements of the fragments NT^1–8 and NT^1–11 which thus far have been found to be biologically inactive.     

Effect of thiopental, propofol, and etomidate on vincristine toxicity in PC12 cells

Neurotoxicity is the dose-limiting side-effect of vincristine in cancer therapy. Using the nerve growth factor (NGF)-dependent neurite outgrowth and cell proliferation of the PC12 pheochromocytoma cell line as an in vitroassay, the protective effect of different intravenous anesthetics was assessed. Vincristine (1 nmol/L) significantly decreased the percentage of neurite-forming cells from 68%±9% to 27%±7% within a 3-day incubation period. The longer neurites (>2× cell body) in particular proved to be extremely sensitive to vincristine (from 17%±4% to 0% of total neurite-expressing cells). Flow cytometry results revealed an S-phase percentage of 15.85%±3.25% after NGF induction, with vincristine reducing this percentage to 0.68%±0.38%. Reversal of the inhibitory effect of vincristine was noted in the cells treated with thiopental or propofol but not etomidate. Bicuculline partially antagonized the protective effect of thiopental and propofol in both studies. We conclude that thiopental and propofol, but not etomidate, have a protective effect in vincristine-induced neurotoxicity. The protective effect produced by thiopental and propofol is probably secondary to activation of GABA_Areceptors. This revised version was published online in August 2006 with corrections to the Cover Date.     

Distribution and histologic effects of intravenously administered amorphous nanosilica particles in the testes of mice

Amorphous nanosilica particles (nSP) are being utilized in an increasing number of applications such as medicine, cosmetics, and foods. The reduction of the particle size to the nanoscale not only provides benefits to diverse scientific fields but also poses potential risks. Several reports have described the in vivo and in vitro toxicity of nSP, but few studies have examined their effects on the male reproductive system. The aim of this study was to evaluate the testicular distribution and histologic effects of systemically administered nSP. Mice were injected intravenously with nSP with diameters of 70 nm (nSP70) or conventional microsilica particles with diameters of 300 nm (nSP300) on two consecutive days. The intratesticular distribution of these particles 24h after the second injection was analyzed by transmission electron microscopy. nSP70 were detected within sertoli cells and spermatocytes, including in the nuclei of spermatocytes. No nSP300 were observed in the testis. Next, mice were injected intravenously with 0.4 or 0.8 mg nSP70 every other day for a total of four administrations. Testes were harvested 48 h and 1 week after the last injection and stained with hematoxylin-eosin for histologic analysis. Histologic findings in the testes of nSP70-treated mice did not differ from those of control mice. Taken together, our results suggest that nSP70 can penetrate the blood-testis barrier and the nuclear membranes of spermatocytes without producing apparent testicular injury.     

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system

Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.     

Synchronizing, sedative and anticonvulsive effects of centrally administered somatostatin in the conscious rabbit

The effects of intracerebroventricular injection of somatostatin-14 on the cortical and deep structure electrical activity, somatic behavior and rectal temperature, were studied in 45 unanesthetized rabbits. In addition the antiepileptic action of the peptide was tested in these models: pentamethylenetetrazole-induced cortical spikes and waves, epileptic focus by topical application of strychnine and voltage-threshold for amygdala after-discharge. The results indicate that somatostatin exerts synchronizing, sedative and weak antiepileptic effects when centrally administered to rabbits.     

Metabolism of intravenously administered 7 alpha-hydroxycholesterol-3 beta-stearate in the hamster.

In order to investigate the metabolic fate of serum esterified 7 alpha-hydroxycholesterol, [4-14C]7 alpha-hydroxycholesterol-3 beta-stearate was synthesized from labeled cholesterol and administered to bile fistula hamsters intravenously. Bile samples were collected at every 20 min for 7 h. Radioactivity was detected in bile 40 min after the beginning of the infusion of the labeled compound and 56.5 +/- 5.7% (48.7-66.0%) of the administered radioactivity was recovered in bile during 7 h. The liver contained appreciable radioactivity (19.5 +/- 7.6% of the administered dose) at the time of sacrifice. Only a trace amount of radioactivity was detected in urine and blood. Cumulative recovery of the radioactivity was 76.3 +/- 8.6% (63.3-90.4%). Major radioactive metabolites in the bile samples were identified to be taurine- and glycine-conjugated cholic acid and chenodeoxycholic acid by radioactive thin-layer chromatographic analysis of the bile samples before and after enzymatic hydrolysis and 3 alpha-hydroxysteroid dehydrogenase treatment. The conversion was nearly complete and we could not detect neutral metabolites, such as the mother compound, free 7 alpha-hydroxycholesterol and bile alcohols, as well as glucuronidated or sulfated bile acids. It is concluded that serum esterified 7 alpha-hydroxycholesterol could be effectively taken up by the liver, hydrolyzed by cholesterol esterase and metabolized via the normal biosynthetic pathway to taurine- or glycine-conjugated primary bile acids to be excreted into bile.     

Binders of intravenously administered 65-zinc in rat liver cytoplasm.

The fate of an i.v. injected trace dose of 65Zn2+ in the rat, was studied over a period of 10 days after injection. Tissue distributions were determined and a special study was made of 65Zn binders in liver cytoplasm. A total of 6 65Zn-binding fractions were observed in liver cytoplasm with apparent molecular weights of about 113,000, 66,400, 47,400, 29,000, 23,000 and 11,400. A time study showed that 4 hours after the injection the most prominent cytoplasmatic 65Zn binders are the 113,000, 66,400 and 23,000 molecular weight fractions. A tentative identification of the main Zn binders in the six 65Zn fractions is given, using the collected data regarding their apparent molecular weight, time dependent prominence and content of stable Zn.