C-fos expression in the rat nucleus basalis upon excitotoxic lesion with quisqualic acid: a study in adult and aged animals

Summary. A unilateral quisqualic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 24-month-old rats, and the animals were sacrificed at different times post-surgery. The morphology and the number of the cholinergic neurons of the nucleus basalis were analyzed by means of immunohistochemistry for cholineacetyltransferase, in order to evaluate the size and severity of the lesion. Immunohistochemistry for the immediate early gene c-fos was also performed in order to clarify its role in the process of neurodegeneration following the excitotoxin injection. The DNA laddering and TUNEL techniques were used to define the type of cell death involved. At short times (4 hr) the lesion induced alterations in the morphology of cholinergic neurons of the nucleus basalis. Subsequently, a significant decrease in the number of neurons was found in comparison to the contralateral unlesioned side. In the older animals the loss of cholineacetyltransferase immunoreactivity had an earlier onset (4 hr) than in the young (24 hr). C-fos expression was induced by the lesion and not by saline injection in the nucleus basalis and in neighbouring areas of the brain as early as 4 hr after surgery. The c-fos protein was no longer present by 24 hr. Furthermore, the c-fos gene product was consistently absent from the nuclei of cholinergic cells. The aged animals exhibited a slower and smaller increase in c-fos as measured by counting the labelled nuclei in the injected area. Analysis of DNA fragmentation did not provide any evidence for apoptosis as the type of cell death involved in the cholinergic degeneration. These results indicate that the c-fos protein might have a protective role in the response to excitotoxic lesions. Furthermore, we have shown that the aged brain displays a reduced ability to produce a c-fos-mediated plastic response to the lesion. Received December 17, 1997; accepted February 17, 1998     

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 1: 6-Methyl Derivatives

A range of 17 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. While many of the compounds show activity comparable to FAA in vitro, this essentially disappears in vivo, possibly due to degradation before the compounds can reach the tumour site.     

Changes of circadian blood pressure patterns and cardiovascular parameters indicate lateralization of sympathetic activation following hemispheric brain infarction

The effects of left- and right-sided hemispheric brain infarction on variability in circadian blood pressure and cardiovascular measures were investigated in 35 patients to test for asymmetry of the sympathetic consequences of stroke. No significant differences regarding age, size of infarction or extent and frequency of damage to the insular cortex could be detected between the two groups. Patients with right-sided infarction showed a significantly reduced circadian blood pressure variability [diastolic: -1% (95% CI -4 to 1) vs -6% (-9 to -2);P < 0.05] and a higher frequency of nocturnal blood pressure increase (47% vs 35%;P < 0.05) as compared with patients with left-sided infarction. Right-sided infarction was also associated with higher serum noradrenaline concentrations [546 pg/ml (95% CI 415–677) vs 405 pg/ml (266–544);P < 0.05], and ECG more frequently showed QT prolongation (53% vs 35%;P < 0.05) and cardiac arrhythmias (67% vs 20%;P < 0.005). However, irrespective of the hemisphere damaged, patients with insular infarction showed the most pronounced changes of these parameters. In addition, two patients with right-sided strokes (13%) involving the insula, but none with a left-sided infarction, developed myocardial infarction. These findings suggest lateralization of sympathetic activation with right-sided dominance for sympathetic effects following hemispheric stroke.Supported by the Friedrich-Schiedel-Stiftung     

The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: A 31P, 23Na and 87Rb NMR spectroscopic study

An increase in intracellular Na⁺ during ischaemia has been associated with myocardial injury. In this study, we determined whether inhibition of Na⁺/K⁺ ATPase activity contributes to this increase and whether Na⁺/K⁺ ATPase activity can be maintained by provision of glucose to perfused rat hearts during low flow, 0.5 ml/min, ischemia. We used ³¹P NMR spectroscopy to determine changes in myocardial energetics and intracellular and extracellular volumes. ²³Na NMR spectroscopy, with DyTTHA^3- present as a shift reagent, was used to measure changes in intracellular Na⁺ and ⁸⁷Rb NMR spectroscopy was used to estimate Na⁺/K⁺ ATPase activity from Rb⁺ influx rates, Rb⁺ being an NMR-sensitive congener of K⁺. In hearts provided with 11 mM glucose throughout ischemia, glycolysis continued and ATP was twofold higher than in hearts without glucose. In the glucose-hearts, Rb⁺ influx rate was threefold higher, intracellular Na⁺ was fivefold lower at the end of ischemia and functional recovery during reperfusion was twofold higher. We propose that continuation of glycolysis throughout low flow ischemia allowed maintenance of sufficient Na⁺/K⁺ ATPase activity to prevent the increase in intracellular Na⁺ that would otherwise have led to myocardial injury.     

Treatment of chronic lymphocytic leukemia in early and stable phase of the disease: Long-term results of a randomized trial

Abstract: In 1982 the IGCI CLL cooperative group decided to investigate the usefulness of treating, at diagnosis B-cell chronic lymphocytic leukemia (CLL) in early and stable phase of the disease. From January 1982 to December 1986, 148 patients were randomized either to receive immediate treatment with chlorambucil (CLB) or to defer therapy to the time of progression. The early and stable phase of the disease was defined by a total tumor mass (TTM) score < 9, the absence of anemia or thrombocytopenia and a doubling time > 12 months. The main end-point of the study was survival. At the last evaluation in April 1993, after a median follow-up of 75 months, no significant difference was found in overall survival between early vs. deferred treatment patients from every cause of death as well as from death due to CLL-related causes only. The same results were obtained when the patients in more favorable stages, such as Binet stage A and TTM < 4.5, were considered. Interestingly, the incidence of epithelial cancer was similar in the two groups. Early treatment was associated with a significantly better response and a lower progression rate. From this long-term experience, it can be concluded that immediate chemotherapy with CLB is not beneficial for CLL patients in early and stable phase of the disease in terms of survival.     

Effects of cocaine on the EEG power spectrum of rats are significantly altered after its repeated administration: do they reflect sensitization phenomena?

It was previously shown that a moderate dose of cocaine (10 mg/kg i.p.) produces a pattern in the EEG power spectrum which indicates a preferential activation of dopamine D₁-like receptors, namely a decrease of power in most of the frequency bands. In contrast, a large dose of cocaine (30 mg/kg i.p.) produces a decrease of power in most of the frequency bands as well, but a selective increase in the alpha-1 band, characteristic for an additional activation of dopamine D₂-like receptors.In the present experiments, it was studied in rats, if in the course of sensitization, a shift from D₁-like to additional D₂-like receptor activation will occur or not. For this study, the animals were treated 10 times with cocaine (either 10 or 20 mg/kg) and, after a drug free interval of 4 days, tested with the same dose administered previously. Acute administration of 10 mg/kg of cocaine increased the Locomotor activity slightly and its effect tended to be enhanced after repeated administration. Twenty mg/kg cocaine increased the locomotor activity more than the 10 mg/kg dose and its effect was significantly enhanced after repeated treatment. In addition, it was shown that the dose of 10 mg/kg of cocaine which activates D₁- but not D₂-like receptors is sufficient to elicit conditioned place preference.Ten mg/kg of cocaine produced a decrease of power in most of the frequency bands and this effect was slightly more pronounced after repeated treatment. Twenty mg/kg of cocaine acutely also produced a decrease in power in most of the frequency bands, but did not decrease the power in the alpha-1 band, being just at the threshold of activating D₂-like receptors as well. Repeated administration led to a significant increase in power in the alpha-1 band and a less pronounced one in the alpha-2 band. This observation demonstrates that sensitization to cocaine can be manifest in the EEG and that after a certain dosage, a shift from an activation of D₁-like dopamine receptors to an additional activation of D₂-like receptors becomes obvious.     

Pharmacological properties of a lyophilizate from Galeopsis ladanum on the central nervous system of rodents

The influence of a fraction obtained from Galeopsis ladanum L. on the central nervous system of rodents was examined. The results of these investigations show that the fraction impeded CNS activity. It is practically nontoxic and at a dose of 2000 mg/kg i.p. it does not have a soporific influence on mice. It reduces considerably the spontaneous locomotor activity of mice as well as the locomotor activity of mice stimulated by caffeine, but did not influence the locomotor activity induced by amphetamine. The extract did not exhibit a synergetic effect with barbiturates. The results suggest that the pharmacological activity of the extract resembled the activity of drugs which generally depress the CNS, being on the border between ataractic and sedative drugs.     

Chlorocarbamate-mustard-linked 1,1,2-triphenylbut-1-enes with a selective antitumor activity on mammary tumors containing estrogen receptors

Summary A 1,1,2-triphenylbut-1-ene with a 4-OH group at one C-1 phenyl ring and a chlorocarbamate mustard moiety at the second C-1 ring (compound 3) was synthesized in order to obtain a cytotoxic estrogen with a specific antitumor effect on estrogen-receptor-containing tumors. This compound was tested in comparison to the carrier (compound 1) and a compound (2) having a carbamate mustard group on both C-1 phenyl rings. The estrogen receptor affinity of compound 3 was only about one-quarter lower than that of compound 1, but much higher than that of compound 2. Compounds 2 and 3 showed only partially irreversible binding to the receptor owing to their relatively low alkylating properties. The growth inhibition of the receptor-positive MCF-7 breast cancer cell line by compound 3, but not by compound 1 or 2, was more pronounced than the inhibition of the receptor-negative line MDA. In vivo the hormone-dependent, transplantable mammary tumor MXT M3.2 of the mouse was much better inhibited by compound 3 than its hormone-resistent line MXT OVEX. Compounds 1–3 had no antiestrogenic properties in the mouse, but estrogenic activity was in the order 1>3>2. From these results and because the antitumor activity of compound 3 was superior to that of compounds 1 and 2 in the hormone-dependent tumor models, a selective, receptor-mediated cytotoxic effect of compound 3 on estrogen-receptor-positive tumors in obvious.Supported by the Deutsche Forschungsgemeinschaft, SFB 234 and the Matthias Lackas StiftungDedicated to Prof. Dr. M. F. El Etreby on the occasion of his 50th birthday     

Effects of acetylsalicylic acid on electromechanical activity ofin vivo rabbit ileum

Aspirin has antisecretory and ulcerogenic properties in the gastrointestinal tract. The aim of this study was to determine the effects of acetylsalicylic acid (ASA) on the electrical and mechanical activity of the ileum in anesthetized New Zealand White rabbits. Ileal electromechanical activity was recorded from serosal electrodes and a miniature intraluminal balloon. Thirty minutes after injection of ASA (30, 60 and 100 mg/kg intravenous) significant and dose-dependent increases in the percentage of slow waves with action potentials were observed when compared with saline-injected animals. The onset of action potentials correlated with phasic increases in intraluminal pressure, indicating the onset of circular muscle contractions. Injection of 15 mg/kg ASA, sodium salicylate (100 mg/kg intravenous) or saline had no effect on baseline action potential activity. Prostaglandin E ₂ (PGE ₂)(5 and 10 g/kg intravenous) significantly increased slow-wave frequency and decreased ASA-induced action potential activity. This study demonstrates that (1) ASA, but not sodium salicylate, stimulates phasic ileal action potential and contractile activity and (2) in ASA-treated animals, PGE ₂ produces differential effects on in vivoslow-wave frequency and action potential activity.     

Monoamine oxidase-B inhibition: a comparison of in vivo and ex vivo measures of reversible effects

Summary A behavioural test involving potentiation of the effects of an acute injection of -phenylethylamine (10 mg kg^–1 i.p.) was used to assess the time-course of type-B MAO inhibition after administration of (–)deprenyl (5 mg kg^–1 i.p.) and of MD 240928 (20 mg kg^–1 i.p.) respectively. Potentiation of the effects of -phenylethylamine was observed 1 h after injection of (–)deprenyl or MD 240928. This effect was still evident 120 h after administration of (–)deprenyl but not 24 h after administration of MD 240928. Comparisons of ex vivo estimates of MAO activity yielded a corresponding time-course for the recovery of this enzyme. The extent of MAO inhibition required for potentiation of the effects of -phenylethylamine was inferred from a comparison of the behavioural test results and the ex vivo MAO activity observed after (–)deprenyl administration. These comparisons indicate a significant underestimation of MD 240928-induced MAO inhibition using ex vivo measures. This underestimation is interpreted as evidence fordilution effects in the ex vivo assay of MAO inhibition. The potentiation of effects of -phenylethylamine under the present conditions is proposed as a useful and simple test for effects of reversible type-B MAO inhibitors.